Artificial intelligence for drug response prediction in disease models

Non peer reviewe

J Addict Med

Objectives:Addiction and overdose related to prescription drugs continues to be a leading cause of morbidity and mortality in the US. We aimed to characterize the prescribing of opioids and benzodiazepines to patients who had previously presented with an opioid or benzodiazepine overdose.Methods:This was a retrospective chart review of patients who were prescribed an opioid or benzodiazepine in a one-month time-period in 2015 (May) and had a previous presentation for opioid or benzodiazepine overdose at a large healthcare system.Results:We identified 60,129 prescribing encounters for opioids and/or benzodiazepines, 543 of which involved a patient with a previous opioid or benzodiazepine overdose. There were 404 unique patients in this cohort, with 97 having more than one visit including a prescription opioid and/or benzodiazepine. A majority of prescriptions (54.1%) were to patients with an overdose within the two years of the documented prescribing encounter. Prescribing in the outpatient clinical setting represented half (49.9%) of encounters, while emergency department prescribing was responsible for nearly a third (31.5%).Conclusions:In conclusion, prescribing of opioids and benzodiazepines occurs across multiple locations in a large health care system to patients with a previous overdose. Risk factors such as previous overdose should be highlighted through clinical decision support tools in the medical record to help prescribers identify patients at higher risk and to mobilize resources for this patient population. Prescribers need further education on factors that place their patients at risk for opioid use disorder and on alternative therapies to opioids and benzodiazepines.U01 CE002520/CE/NCIPC CDC HHS/United States2020-09-04T00:00:00Z30844876PMC67220406629vault:3383

House mouse colonization patterns on the sub-Antarctic Kerguelen Archipelago suggest singular primary invasions and resilience against re-invasion

Starting from Western Europe, the house mouse (Mus musculus domesticus) has spread across the globe in historic times. However, most oceanic islands were colonized by mice only within the past 300 years. This makes them an excellent model for studying the evolutionary processes during early stages of new colonization. We have focused here on the Kerguelen Archipelago, located within the sub-Antarctic area and compare the patterns with samples from other Southern Ocean islands

Computing and applying atomic regulons to understand gene expression and regulation

The Supplementary Material for this article can be found online at: http://journal.frontiersin.org/article/10.3389/fmicb.2016.01819/full#supplementary-materialUnderstanding gene function and regulation is essential for the interpretation prediction and ultimate design of cell responses to changes in the environment. An important step toward meeting the challenge of understanding gene function and regulation is the identification of sets of genes that are always co-expressed. These gene sets Atomic Regulons ARs represent fundamental units of function within a cell and could be used to associate genes of unknown function with cellular processes and to enable rational genetic engineering of cellular systems. Here we describe an approach for inferring ARs that leverages large-scale expression data sets gene context and functional relationships among genes. We computed ARs for Escherichia coli based on 907 gene expression experiments and compared our results with gene clusters produced by two prevalent data-driven methods: hierarchical clustering and k-means clustering. We compared ARs and purely data-driven gene clusters to the curated set of regulatory interactions for E. coli found in RegulonDB showing that ARs are more consistent with gold standard regulons than are data-driven gene clusters. We further examined the consistency of ARs and data-driven gene clusters in the context of gene interactions predicted by Context Likelihood of Relatedness CLR analysis finding that the ARs show better agreement with CLR predicted interactions. We determined the impact of increasing amounts of expression data on AR construction and find that while more data improve ARs it is not necessary to use the full set of gene expression experiments available for E. coli to produce high quality ARs. In order to explore the conservation of co-regulated gene sets across different organisms we computed ARs for Shewanella oneidensis Pseudomonas aeruginosa Thermus thermophilus and Staphylococcus aureus each of which represents increasing degrees of phylogenetic distance from E. coli. Comparison of the organism-specific ARs showed that the consistency of AR gene membership correlates with phylogenetic distance but there is clear variability in the regulatory networks of closely related organisms. As large scale expression data sets become increasingly common for model and non-model organisms comparative analyses of atomic regulons will provide valuable insights into fundamental regulatory modules used across the bacterial domain.JF acknowledges funding from [SFRH/BD/70824/2010] of the FCT (Portuguese Foundation for Science and Technology) PhD program. CH and PW were supported by the National Science Foundation under grant number EFRI-MIKS-1137089. RT was supported by the Genomic Science Program (GSP), Office of Biological and Environmental Research (OBER), U.S. Department of Energy(DOE),and his work is a contribution of the Pacific North west National Laboratory (PNNL) Foundational Scientific Focus Area. This work was partially supported by an award from the National Science Foundation to MD, AB, NT, and RO (NSFABI-0850546). This work was also supported by the United States National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Service [Contract No. HHSN272201400027C]

Tomato: a crop species amenable to improvement by cellular and molecular methods

Tomato is a crop plant with a relatively small DNA content per haploid genome and a well developed genetics. Plant regeneration from explants and protoplasts is feasable which led to the development of efficient transformation procedures. In view of the current data, the isolation of useful mutants at the cellular level probably will be of limited value in the genetic improvement of tomato. Protoplast fusion may lead to novel combinations of organelle and nuclear DNA (cybrids), whereas this technique also provides a means of introducing genetic information from alien species into tomato. Important developments have come from molecular approaches. Following the construction of an RFLP map, these RFLP markers can be used in tomato to tag quantitative traits bred in from related species. Both RFLP's and transposons are in the process of being used to clone desired genes for which no gene products are known. Cloned genes can be introduced and potentially improve specific properties of tomato especially those controlled by single genes. Recent results suggest that, in principle, phenotypic mutants can be created for cloned and characterized genes and will prove their value in further improving the cultivated tomato.

Linkages between the cold summer mesopause and thermospheric zonal mean circulation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95392/1/grl28827.pd

Leveraging population admixture to characterize the heritability of complex traits.

Despite recent progress on estimating the heritability explained by genotyped SNPs (h(2)g), a large gap between h(2)g and estimates of total narrow-sense heritability (h(2)) remains. Explanations for this gap include rare variants or upward bias in family-based estimates of h(2) due to shared environment or epistasis. We estimate h(2) from unrelated individuals in admixed populations by first estimating the heritability explained by local ancestry (h(2)γ). We show that h(2)γ = 2FSTCθ(1 - θ)h(2), where FSTC measures frequency differences between populations at causal loci and θ is the genome-wide ancestry proportion. Our approach is not susceptible to biases caused by epistasis or shared environment. We applied this approach to the analysis of 13 phenotypes in 21,497 African-American individuals from 3 cohorts. For height and body mass index (BMI), we obtained h(2) estimates of 0.55 ± 0.09 and 0.23 ± 0.06, respectively, which are larger than estimates of h(2)g in these and other data but smaller than family-based estimates of h(2)

Two Novel Susceptibility Loci for Prostate Cancer in Men of African Ancestry

Prostate cancer incidence is 1.6-fold higher in African Americans than in other populations. The risk factors that drive this disparity are unknown and potentially consist of social, environmental, and genetic influences. To investigate the genetic basis of prostate cancer in men of African ancestry, we performed a genome-wide association meta-analysis using two-sided statistical tests in 10 202 case subjects and 10 810 control subjects. We identified novel signals on chromosomes 13q34 and 22q12, with the risk-associated alleles found only in men of African ancestry (13q34: rs75823044, risk allele frequency = 2.2%, odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.37 to 1.76, P = 6.10 × 10−12; 22q12.1: rs78554043, risk allele frequency = 1.5%, OR = 1.62, 95% CI = 1.39 to 1.89, P = 7.50 × 10−10). At 13q34, the signal is located 5’ of the gene IRS2 and 3’ of a long noncoding RNA, while at 22q12 the candidate functional allele is a missense variant in the CHEK2 gene. These findings provide further support for the role of ancestry-specific germline variation in contributing to population differences in prostate cancer risk