Reducing the Variance of Gaussian Process Hyperparameter Optimization with Preconditioning

Gaussian processes remain popular as a flexible and expressive model class, but the computational cost of kernel hyperparameter optimization stands as a major limiting factor to their scaling and broader adoption. Recent work has made great strides combining stochastic estimation with iterative numerical techniques, essentially boiling down GP inference to the cost of (many) matrix-vector multiplies. Preconditioning -- a highly effective step for any iterative method involving matrix-vector multiplication -- can be used to accelerate convergence and thus reduce bias in hyperparameter optimization. Here, we prove that preconditioning has an additional benefit that has been previously unexplored. It not only reduces the bias of the $\log$-marginal likelihood estimator and its derivatives, but it also simultaneously can reduce variance at essentially negligible cost. We leverage this result to derive sample-efficient algorithms for GP hyperparameter optimization requiring as few as $\mathcal{O}(\log(\varepsilon^{-1}))$ instead of $\mathcal{O}(\varepsilon^{-2})$ samples to achieve error $\varepsilon$. Our theoretical results enable provably efficient and scalable optimization of kernel hyperparameters, which we validate empirically on a set of large-scale benchmark problems. There, variance reduction via preconditioning results in an order of magnitude speedup in hyperparameter optimization of exact GPs

Identification of candidate genes affecting Delta9-tetrahydrocannabinol biosynthesis in Cannabis sativa.

RNA isolated from the glands of a Delta(9)-tetrahydrocannabinolic acid (THCA)-producing strain of Cannabis sativa was used to generate a cDNA library containing over 100 000 expressed sequence tags (ESTs). Sequencing of over 2000 clones from the library resulted in the identification of over 1000 unigenes. Candidate genes for almost every step in the biochemical pathways leading from primary metabolites to THCA were identified. Quantitative PCR analysis suggested that many of the pathway genes are preferentially expressed in the glands. Hexanoyl-CoA, one of the metabolites required for THCA synthesis, could be made via either de novo fatty acids synthesis or via the breakdown of existing lipids. qPCR analysis supported the de novo pathway. Many of the ESTs encode transcription factors and two putative MYB genes were identified that were preferentially expressed in glands. Given the similarity of the Cannabis MYB genes to those in other species with known functions, these Cannabis MYBs may play roles in regulating gland development and THCA synthesis. Three candidates for the polyketide synthase (PKS) gene responsible for the first committed step in the pathway to THCA were characterized in more detail. One of these was identical to a previously reported chalcone synthase (CHS) and was found to have CHS activity. All three could use malonyl-CoA and hexanoyl-CoA as substrates, including the CHS, but reaction conditions were not identified that allowed for the production of olivetolic acid (the proposed product of the PKS activity needed for THCA synthesis). One of the PKS candidates was highly and specifically expressed in glands (relative to whole leaves) and, on the basis of these expression data, it is proposed to be the most likely PKS responsible for olivetolic acid synthesis in Cannabis glands

Validating a predictive model of cannabinoid inheritance with feral, clinical, and industrial Cannabis sativa

© 2020 The Authors. American Journal of Botany published by Wiley Periodicals LLC on behalf of Botanical Society of America Premise: How genetic variation within a species affects phytochemical composition is a fundamental question in botany. The ratio of two specialized metabolites in Cannabis sativa, tetrahydrocannabinol (THC) and cannabidiol (CBD), can be grouped into three main classes (THC-type, CBD-type, and intermediate type). We tested a genetic model associating these three groups with functional and nonfunctional alleles of the cannabidiolic acid synthase gene (CBDAS). Methods: We characterized cannabinoid content and assayed CBDAS genotypes of \u3e300 feral C. sativa plants in Minnesota, United States. We performed a test cross to assess CBDAS inheritance. Twenty clinical cultivars obtained blindly from the National Institute on Drug Abuse and 12 Canadian-certified grain cultivars were also examined. Results: Frequencies of CBD-type, intermediate-type, and THC-type feral plants were 0.88, 0.11, and 0.01, respectively. Although total cannabinoid content varied substantially, the three groupings were perfectly correlated with CBDAS genotypes. Genotype frequencies observed in the test cross were consistent with codominant Mendelian inheritance of the THC:CBD ratio. Despite significant mean differences in total cannabinoid content, CBDAS genotypes blindly predicted the THC:CBD ratio among clinical cultivars, and the same was true for industrial grain cultivars when plants exhibited \u3e0.5% total cannabinoid content. Conclusions: Our results extend the generality of the inheritance model for THC:CBD to diverse C. sativa accessions and demonstrate that CBDAS genotyping can predict the ratio in a variety of practical applications. Cannabinoid profiles and associated CBDAS segregation patterns suggest that feral C. sativa populations are potentially valuable experimental systems and sources of germplasm

Identification of candidate genes affecting Δ9-tetrahydrocannabinol biosynthesis in Cannabis sativa

RNA isolated from the glands of a Δ9-tetrahydrocannabinolic acid (THCA)-producing strain of Cannabis sativa was used to generate a cDNA library containing over 100 000 expressed sequence tags (ESTs). Sequencing of over 2000 clones from the library resulted in the identification of over 1000 unigenes. Candidate genes for almost every step in the biochemical pathways leading from primary metabolites to THCA were identified. Quantitative PCR analysis suggested that many of the pathway genes are preferentially expressed in the glands. Hexanoyl-CoA, one of the metabolites required for THCA synthesis, could be made via either de novo fatty acids synthesis or via the breakdown of existing lipids. qPCR analysis supported the de novo pathway. Many of the ESTs encode transcription factors and two putative MYB genes were identified that were preferentially expressed in glands. Given the similarity of the Cannabis MYB genes to those in other species with known functions, these Cannabis MYBs may play roles in regulating gland development and THCA synthesis. Three candidates for the polyketide synthase (PKS) gene responsible for the first committed step in the pathway to THCA were characterized in more detail. One of these was identical to a previously reported chalcone synthase (CHS) and was found to have CHS activity. All three could use malonyl-CoA and hexanoyl-CoA as substrates, including the CHS, but reaction conditions were not identified that allowed for the production of olivetolic acid (the proposed product of the PKS activity needed for THCA synthesis). One of the PKS candidates was highly and specifically expressed in glands (relative to whole leaves) and, on the basis of these expression data, it is proposed to be the most likely PKS responsible for olivetolic acid synthesis in Cannabis glands

The chemistry and kinematics of two molecular clouds near Sagittarius A

We have analysed the chemical and kinematic properties of the 20 and 50 km s−1 molecular clouds in the Central Molecular Zone of the Milky Way Galaxy, as well as those of the molecular ridge bridging these two clouds. Our work has utilized 37 molecular transitions in the 0.65, 3 and 7-mm wavebands, from the Mopra and NANTEN2 telescopes. The 0.65-mm NANTEN2 data highlights a dense condensation of emission within the western part of the 20 km s−1 cloud, visible in only four other transitions, which are 3-mm H13CN (1–0), H13CO+ (1–0), HNC (1–0) and N2H+ (1–0), suggesting that the condensation is moderately optically thick and cold. We find that while the relative chemical abundances between both clouds are alike in many transitions, suggesting little variation in the chemistry between both clouds; the 20 km s−1, cold cloud is brighter than the 50 km s−1 cloud in shock and high density tracers. The spatial distribution of enhanced emission is widespread in the 20 km s−1 cloud, as shown via line ratio maps. The position velocity diagrams across both clouds indicate that the gas is well mixed. We show that the molecular ridge is most likely part of the 20 km s−1 cloud and that both of them may possibly extend to include the 50 km s−1 cloud, as part of one larger cloud. Furthermore, we expect that the 20 km s−1 cloud is being tidally sheared as a result of the gravitational potential from Sgr A*

The linear polarisation of southern bright stars measured at the parts-per-million level

We report observations of the linear polarisation of a sample of 50 nearby southern bright stars measured to a median sensitivity of ~4.4 x 10^{-6}. We find larger polarisations and more highly polarised stars than in the previous PlanetPol survey of northern bright stars. This is attributed to a dustier interstellar medium in the mid-plane of the Galaxy, together with a population containing more B-type stars leading to more intrinsically polarised stars, as well as using a wavelength more sensitive to intrinsic polarisation in late-type giants. Significant polarisation had been identified for only six stars in the survey group previously, whereas we are now able to deduce intrinsic polarigenic mechanisms for more than twenty. The four most highly polarised stars in the sample are the four classical Be stars (alpha Eri, alpha Col, eta Cen and alpha Ara). For the three of these objects resolved by interferometry, the position angles are consistent with the orientation of the circumstellar disc determined. We find significant intrinsic polarisation in most B stars in the sample; amongst these are a number of close binaries and an unusual binary debris disk system. However these circumstances do not account for the high polarisations of all the B stars in the sample and other polarigenic mechanisms are explored. Intrinsic polarisation is also apparent in several late type giants which can be attributed to either close, hot circumstellar dust or bright spots in the photosphere of these stars. Aside from a handful of notable debris disk systems, the majority of A to K type stars show polarisation levels consistent with interstellar polarisation.Peer reviewe

A WD40 Repeat Protein from Medicago truncatula

WD40 repeat proteins regulate biosynthesis of anthocyanins, proanthocyanidins (PAs), and mucilage in the seed and the development of trichomes and root hairs. We have cloned and characterized a WD40 repeat protein gene from Medicago truncatula (MtWD40-1) via a retrotransposon-tagging approach. Deficiency of MtWD40-1 expression blocks accumulation of mucilage and a range of phenolic compounds, including PAs, epicatechin, other flavonoids, and benzoic acids, in the seed, reduces epicatechin levels without corresponding effects on other flavonoids in flowers, reduces isoflavone levels in roots, but does not impair trichome or root hair development. MtWD40-1 is expressed constitutively, with highest expression in the seed coat, where its transcript profile temporally parallels those of PA biosynthetic genes. Transcript profile analysis revealed that many genes of flavonoid biosynthesis were down-regulated in a tissue-specific manner in M. truncatula lines harboring retrotransposon insertions in the MtWD40-1 gene. MtWD40-1 complemented the anthocyanin, PA, and trichome phenotypes of the Arabidopsis (Arabidopsis thaliana) transparent testa glabrous1 mutant. We discuss the function of MtWD40-1 in natural product formation in M. truncatula and the potential use of the gene for engineering PAs in the forage legume alfalfa (Medicago sativa)

How external and internal resources influence user action: the case of infusion devices

Human error can have potentially devastating consequences in contexts such as healthcare, but there is a rarely a simple dichotomy between errors and correct behaviour. Furthermore, there has been little consideration of how the activities of users (erroneous and otherwise) relate to the conceptual fit between user and device, despite the fact that healthcare technologies are becoming increasingly prevalent and complex. In this article, we present a study in which nurses’ conceptions of infusion device practice were elicited to identify misfits. By focusing on key concepts that users work with when setting up infusions and the extent to which the system supports them, our analysis highlights how actions are influenced by the different resources available to users including: the device itself; supporting artefacts; the conceptual understanding of the user; and the community of practice the user is part of. The findings reveal the ways in which users are resourceful in their day-to-day activities and also suggest potential vulnerabilities within the wider system that could threaten patient safety. Our approach is able to make previously under-explored aspects of practice visible, thus enabling insight into how users act and why

Health and Oral Health Care Needs and Health Care-Seeking Behavior Among Homeless Injection Drug Users in San Francisco

Few existing studies have examined health and oral health needs and treatment-seeking behavior among the homeless and injection drug users (IDUs). This paper describes the prevalence and correlates of health and oral health care needs and treatment-seeking behaviors in homeless IDUs recruited in San Francisco, California, from 2003 to 2005 (N = 340). We examined sociodemographic characteristics, drug use patterns, HIV status via oral fluid testing, physical health using the Short Form 12 Physical Component Score, self-reported needs for physical and oral health care, and the self-reported frequency of seeking medical and oral health care. The sample had a lower health status as compared to the general population and reported a frequent need for physical and oral health care. In bivariate analysis, being in methadone treatment was associated with care-seeking behavior. In addition, being enrolled in Medi-Cal, California’s state Medicaid program, was associated with greater odds of seeking physical and oral health care. Methamphetamine use was not associated with higher odds of needing oral health care as compared to people who reported using other illicit drugs. Homeless IDUs in San Francisco have a large burden of unmet health and oral health needs. Recent cuts in Medi-Cal’s adult dental coverage may result in a greater burden of oral health care which will need to be provided by emergency departments and neighborhood dental clinics