2018-khera.pdf: “Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations”, Amit V. Khera, Mark Chaffin, Krishna G. Aragam, Mary E. Haas, Carolina Roselli, Seung Hoan Choi, Pradeep Natarajan, Eric S. Lander, Steven A. Lubitz, Patrick T. Ellinor, Sekar Kathiresan
Suicide is the 10th leading cause of death in the US. While environment has undeniable impact, evidence suggests genetic factors play a significant role in completed suicide. We linked a resource of >4,500 DNA samples from completed suicides obtained from the Utah Medical Examiner to genealogical records and medical records data available on over 8 million individuals. This linking has resulted in the identification of high-risk extended families (7-9 generations) with significant familial risk of completed suicide. Familial aggregation across distant relatives minimizes effects of shared environment, provides more genetically homogeneous risk groups, and magnifies genetic risks through familial repetition. We analyzed Illumina PsychArray genotypes from suicide cases in 43 high-risk families, identifying 30 distinct shared genomic segments with genome-wide evidence (p = 2.02E-07 to 1.30E-18) of segregation with completed suicide. The 207 genes implicated by the shared regions provide a focused set of genes for further study; 18 have been previously associated with suicide risk. While PsychArray variants do not represent exhaustive variation within the 207 genes, we investigated these for specific segregation within the high-risk families, and for association of variants with predicted functional impact in ~1300 additional Utah suicides unrelated to the discovery families. None of the limited PsychArray variants explained the high-risk family segregation; sequencing of these regions will be needed to discover segregating risk variants, which may be rarer or regulatory. However, additional association tests yielded four significant PsychArray variants (SP110, rs181058279; AGBL2, rs76215382; SUCLA2, rs121908538; APH1B, rs745918508), raising the likelihood that these genes confer risk of completed suicide.
2006-cobb.pdf: “nrg1948.indd”, Shadwell, Judith
1894-housman.pdf: “Robert Bakewell”, William Housman
1805-lawrence.pdf: “Robert Bakewell”, John Lawrence
Genomic disorders resulting from large rearrangements of the genome remain an important unsolved issue in gene therapy. Chromosome transplantation, defined as the perfect replacement of an endogenous chromosome with a homologous one, has the potential of curing this kind of disorders. Here we report the first successful case of chromosome transplantation by replacement of an endogenous X chromosome carrying a mutation in the Hprt genewith a normal one in mouse embryonic stem cells (ESCs), correcting the genetic defect. The defect was also corrected by replacing the Y chromosome with an X chromosome. Chromosome transplanted clones maintained in vitro and in vivo features of stemness and contributed to chimera formation. Genome integrity was confirmed by cytogenetic and molecular genome analysis. The approach here proposed, with some modifications, might be used to cure various disorders due to other X chromosome aberrations in induced pluripotent stem (iPS) cells derived from affected patients.
“Crunch: Building a better apple”, (2011-11-14):
Profile of the development & launch of the SweeTango apple, a successor to Honeycrisp (via a hybridization with Zestar), developed by the University of Minnesota apple breeding program, which has been running since 1878 and created 27 notable apples (earning its role as the state fruit).
Breeding programs like that are part of why Americans have historically shifted from consuming hard cider (made with inedible wild-types) to ‘eating apples’, but progress was set back by a drastic decrease in variety to the McIntosh/Golden Delicious/Red Delicious triumvirate—Red Delicious degrading rapidly in quality. The apple revolution began in the 1970s when Granny Smith proved US consumers would buy a better apple, and was followed by the Fuji, Braeburn, and Gala.
How does one breed a new apple? Apples do not breed true and every offspring is wildly different. Apple breeders use brute force and brutally stringent screening: an acre of thousands of saplings will be grown, and in all, the breeders will walk the row, grab 1 apple, chew it briefly, spit it out, and mark the tree if good. Any sapling which is marked several years in a row (a few score out of thousands) survives; clones of it will be transplanted elsewhere for further testing, and evaluated similarly for another decade. If and only a new apple tree & clones pass all these tests, will it even be considered for commercialization.
“I’d like to give a tree a couple chances, but I just don’t have the mouth time for that”, Bedford explained. “So it’s one strike and you’re out. With all these new trees coming on each year, you won’t have space unless you thin out the duds.” He sprayed another tree trunk with the mark of death. “But it is kind of nerve-racking, because you want to give the tree a chance to do its best. No one wants to be known as the guy who killed the next Honeycrisp.”
The winner of such a process must be both brilliant and lucky, and Honeycrisp was both. But UMinn breeders watched with dismay as they felt the released Honeycrisp saplings were mistreated or poorly-raised by careless commercial growers, and decided the next apple, SweeTango, would be a “club apple”: it would be fully patented & controlled, and sold only to select apple growers who would be required to follow stringent rules.
The “club apple” business model has proven to be its own revolution by internalizing the costs & benefits, incentivizing the creation of a dizzying variety of new apples reaching the American grocery market every year.
“Large-Scale Study of Curiosity-Driven Learning”, (2018-08-13):
Reinforcement learning algorithms rely on carefully engineering environment rewards that are extrinsic to the agent. However, annotating each environment with hand-designed, dense rewards is not scalable, motivating the need for developing reward functions that are intrinsic to the agent. Curiosity is a type of intrinsic reward function which uses prediction error as reward signal. In this paper: (a) We perform the first large-scale study of purely curiosity-driven learning, i.e. without any extrinsic rewards, across 54 standard benchmark environments, including the Atari game suite. Our results show surprisingly good performance, and a high degree of alignment between the intrinsic curiosity objective and the hand-designed extrinsic rewards of many game environments. (b) We investigate the effect of using different feature spaces for computing prediction error and show that random features are sufficient for many popular RL game benchmarks, but learned features appear to generalize better (e.g. to novel game levels in Super Mario Bros.). (c) We demonstrate limitations of the prediction-based rewards in stochastic setups. Game-play videos and code are at https://pathak22.github.io/large-scale-curiosity/
Unsupervised image-to-image translation techniques are able to map local texture between two domains, but they are typically unsuccessful when the domains require larger shape change. Inspired by semantic segmentation, we introduce a discriminator with dilated convolutions that is able to use information from across the entire image to train a more context-aware generator. This is coupled with a multi-scale perceptual loss that is better able to represent error in the underlying shape of objects. We demonstrate that this design is more capable of representing shape deformation in a challenging toy dataset, plus in complex mappings with significant dataset variation between humans, dolls, and anime faces, and between cats and dogs.
2018-gensowski.pdf: “Personality, IQ, and lifetime earnings”, (2018-04; ):
[Published version of Gensowski et al 2011]
- This paper estimates the effects of personality traits and IQ on lifetime earnings, both as a sum and individually by age.
- The payoffs to personality traits display a concave life-cycle pattern, with the largest effects between the ages of 40 and 60.
- The largest effects on earnings are found for Conscientiousness, Extraversion, and Agreeableness (negative).
- An interaction of traits with education reveals that personality matters most for highly educated men.
- The overall effect of Conscientiousness operates partly through education, which also has substantial returns.
This paper estimates the effects of personality traits and IQ on lifetime earnings of the men and women of the Terman study, a high-IQ U.S. sample. Age-by-age earnings profiles allow a study of when personality traits affect earnings most, and for whom the effects are strongest. I document a concave life-cycle pattern in the payoffs to personality traits, with the largest effects between the ages of 40 and 60. An interaction of traits with education reveals that personality matters most for highly educated men. The largest effects are found for , Extraversion, and (negative), where Conscientiousness operates partly through education, which also has substantial returns.
[Keywords: Personality traits, Socio-emotional skills, Cognitive skills, Returns to education, Lifetime earnings, Big Five, Human capital, Factor analysis]
A positive relationship between brain volume and intelligence has been suspected since the 19th century, and empirical studies seem to support this hypothesis. However, this claim is controversial because of concerns about publication bias and the lack of systematic control for critical confounding factors (eg., height, population structure). We conducted a preregistered study of the relationship between brain volume and cognitive performance using a new sample of adults from the United Kingdom that is about 70% larger than the combined samples of all previous investigations on this subject (N = 13,608). Our analyses systematically controlled for sex, age, height, socioeconomic status, and population structure, and our analyses were free of publication bias. We found a robust association between total brain volume and fluid intelligence (r = 0.19), which is consistent with previous findings in the literature after controlling for measurement quality of intelligence in our data. We also found a positive relationship between total brain volume and educational attainment (r = 0.12). These relationships were mainly driven by gray matter (rather than white matter or fluid volume), and effect sizes were similar for both sexes and across age groups.
[Keywords: intelligence, educational attainment, brain volume, UK Biobank, open data, open materials, ]analysis,
Lucid dreaming is a remarkable state of consciousness in which one is aware of the fact that one is dreaming while continuing to dream. Based on the strong relationship between physiological activation during rapid eye-movement sleep and lucid dreaming, our pilot research investigated whether enhancing cortical activation via acetylcholinesterase inhibition (AChEI) would increase the frequency of lucid dreams and found AChEI to be a promising method for lucid dream induction. In the current study we sought to quantify the size and reliability of the effect of AChEI on lucid dreaming, dream recall and dream content as well as to test the effectiveness of an integrated lucid dream induction protocol which combined cholinergic stimulation with other methods for lucid dream induction. Participants (n = 121) with high dream recall and an interest in were randomly assigned counterbalanced orders of 3 doses of galantamine (0, 4 and 8 mg). On 3 consecutive nights, they awoke approximately 4.5 hours after lights out, recalled a dream, ingested the capsules and stayed out of bed for at least 30 minutes. Participants then returned to bed and practiced the Mnemonic Induction of Lucid Dreams technique while returning to sleep. The percentage of participants who reported a lucid dream was statistically-significantly increased for both 4 mg (27%, odds ratio = 2.29) and 8 mg doses (42%, odds ratio = 4.46) compared to the active placebo procedure (14%). Galantamine also statistically-significantly increased dream recall, sensory vividness and complexity (p < 0.05). Dream recall, cognitive clarity, control, positive emotion, vividness and self-reflection were increased during lucid compared to non-lucid dreams (p < 0.0001). These results show that galantamine increases the frequency of lucid dreams in a dose-related manner. Furthermore, the integrated method of taking galantamine in the last third of the night with at least 30 minutes of sleep interruption and with an appropriately focused mental set is one of the most effective methods for inducing lucid dreams available today.
Psilocybin is a psychoactive compound with clinical applications produced by dozens of mushroom species1. There has been a longstanding interest in psilocybin research with regard to treatment for addiction2, depression3, and end-of-life suffering4. However, until recently very little was known about psilocybin biosynthesis and its ecological role. Here we confirm and refine recent findings5 about the genes underpinning psilocybin biosynthesis, discover that there is more than one psilocybin biosynthesis cluster in mushrooms, and we provide the first data directly addressing psilocybin’s ecological role. By analysing independent genome assemblies for the hallucinogenic mushrooms Psilocybe cyanescens and Pluteus salicinus we recapture the recently discovered biosynthesis cluster5,6 and show that a transcription factor previously implicated in its regulation is actually not part of the cluster. Further, we show that the mushroom Inocybe corydalina produces psilocybin but does not contain the established biosynthetic cluster, and we present an alternative cluster. Finally, a meta-transcriptome analysis of wild-collected mushrooms provides evidence for intra-mushroom insect gene expression of flies whose larvae grow inside Psilocybe cyanescens. These larvae were successfully reared into adults. Our results show that psilocybin does not confer complete protection against insect mycophagy, and the hypothesis that it is produced as an adaptive defense compound may need to be reconsidered.
Entomopathogenic fungi routinely kill their hosts before releasing infectious conidia, but select species keep their hosts alive while sporulating to enhance spore dispersal. Recent expression and metabolomics studies involving “host-killing” entomopathogens have helped unravel infection processes and host responses, yet the mechanisms underlying “active host transmission” in insects with Entomophthoralean fungal infections are completely unexplored. Here we report the discovery, through global and targeted metabolomics supported by metagenomics and proteomics, of the plant amphetamine, cathinone, in Massospora cicadina-infected periodical cicadas, and the mushroom tryptamine, prior to death., in M. platypediae- and M. levispora-infected annual cicadas. The neurogenic activities of these alkaloids provide a hypothetical framework for a chemically induced extended phenotype of Massospora that alters cicada behavior by increasing endurance and suppressing feeding
Recently popular sub-perceptual doses of psychedelic substances such as truffles, referred to as microdosing, allegedly have multiple beneficial effects including creativity and problem solving performance, potentially through targeting serotonergic 5-HT2A receptors and promoting cognitive flexibility, crucial to creative thinking. Nevertheless, enhancing effects of microdosing remain anecdotal, and in the absence of quantitative research on microdosing psychedelics it is impossible to draw definitive conclusions on that matter. Here, our main aim was to quantitatively explore the cognitive-enhancing potential of microdosing psychedelics in healthy adults.
Methods: During a microdosing event organized by the Dutch Psychedelic Society, we examined the effects of psychedelic truffles (which were later analyzed to quantify active psychedelic alkaloids) on two creativity-related problem-solving tasks: the Picture Concept Task assessing convergent thinking, and the Alternative Uses Task assessing divergent thinking. A short version of the Ravens Progressive Matrices task assessed potential changes in fluid intelligence. We tested once before taking a microdose and once while the effects were manifested.
Results: We found that both convergent and divergent thinking performance was improved after a non-blinded microdose, whereas fluid intelligence was unaffected.
Conclusion: While this study provides quantitative support for the cognitive enhancing properties of microdosing psychedelics, future research has to confirm these preliminary findings in more rigorous placebo-controlled study designs. Based on these preliminary results we speculate that psychedelics might affect cognitive metacontrol policies by optimizing the balance between cognitive persistence and flexibility. We hope this study will motivate future microdosing studies with more controlled designs to test this hypothesis.
“Chaff Bugs: Deterring Attackers by Making Software Buggier”, (2018-08-02):
Sophisticated attackers find bugs in software, evaluate their exploitability, and then create and launch exploits for bugs found to be exploitable. Most efforts to secure software attempt either to eliminate bugs or to add mitigations that make exploitation more difficult. In this paper, we introduce a new defensive technique called chaff bugs, which instead target the bug discovery and exploit creation stages of this process. Rather than eliminating bugs, we instead add large numbers of bugs that are provably (but not obviously) non-exploitable. Attackers who attempt to find and exploit bugs in software will, with high probability, find an intentionally placed non-exploitable bug and waste precious resources in trying to build a working exploit. We develop two strategies for ensuring non-exploitability and use them to automatically add thousands of non-exploitable bugs to real-world software such as nginx and libFLAC; we show that the functionality of the software is not harmed and demonstrate that our bugs look exploitable to current triage tools. We believe that chaff bugs can serve as an effective deterrent against both human attackers and automated Cyber Reasoning Systems (CRSes).
1688-delavega-confusionofconfusions.pdf: “Confusion de Confusiones (Confusion of Confusions)”, Joseph de la Vega, Hermann Kellenbenz