EXPLORATION OF DOMAIN-SPECIFIC KNOWLEDGE GRAPHS FOR TESTABLE HYPOTHESIS GENERATION

In the span of a decade, we have brought about a fundamental shift in the way we structure, organize, store, and conceptualize biomedical datasets. Data which had previously been siloed has been gathered, organized, and aggregated into central repositories, interlinked with each other by categorizing these vast sums of knowledge into well defined ontologies. These interlinked databases, better known as knowledge graphs, have come to redefine our ability to explore the current state of our knowledge, answer complex questions about how objects relate to each other, and invent novel connections in vastly different research disciplines. With these knowledge graphs, new ideas can be quickly formulated, instead of relying upon the insight of a single scientist or small team of experts, these ideas can be made leveraging the vast historical catalog of research progress that has been captured in biomedical databases. Knowledge graphs can be used to propose hypotheses which narrow the nearly infinite array of possible explorations which can link any pair of ideas to only those which have some historical and practical considerations. In this way, we hope to utilize these knowledge graphs to produce hypotheses, promote those which are viable, and provide them to biomedical experts. In this work, we aim to develop methodologies to produce meaningful hypotheses using these graphs as inputs. We approach this problem by (i) utilizing intrinsic mathematical properties of the intermediate nodes along a pathways, (ii) translating existing biomedical ideas into graphical structures, and (iii) incorporating niche domain-specific biomedical datasets to explore domain problems. We have shown the ability of these methods to produce practical and useful hypotheses and pathways which can be utilized by experts for immediate exploration.Doctor of Philosoph

Investigation of the Parasympathetic Effects of Lavender Essential Oil in Humans

The purpose of this study will be to investigate the claim that administration of lavender (Lavandula angustifolia) essential oil (topically, orally, and/or respiratorily) produces a relaxative effect in human subjects. This investigation will theoretically be conducted in two stages. Stage one will focus primarily on determining the presence of therapeutic effects and the relative effectiveness of lavender in several application modalities. Stage two will proceed based on findings from stage one. If significant parasympathetic effects are observed in relation to one or more of the lavender oil modalities described above, a more focused investigation will be conducted in stage two to ascertain the specific active chemical component(s) in the oil that stimulate(s) the therapeutic effect

Collaboration networks of the implementation science centers for cancer control: A social network analysis

BACKGROUND: Multi-center research initiatives offer opportunities to develop and strengthen connections among researchers. These initiatives often have goals of increased scientific collaboration which can be examined using social network analysis. METHODS: The National Cancer Institute (NCI)-funded Implementation Science Centers in Cancer Control (ISC RESULTS: Of the 192 invitees, 182 network members completed the survey (95%). The most prevalent roles were faculty (60%) and research staff (24%). Almost one-quarter (23%) of members reported advanced expertise in IS, 42% intermediate, and 35% beginner. Most members were female (69%) and white (79%). One-third (33%) of collaboration ties were among members from different centers. Across all collaboration activities, the network had a density of 14%, suggesting moderate cohesion. Degree centralization (0.33) and betweenness centralization (0.07) measures suggest a fairly dispersed network (no single or few central member(s) holding all connections). The most prevalent and densely connected collaboration was in planning/conducting research (1470 ties; 8% density). Practice/policy dissemination had the fewest collaboration, lowest density (284 ties\u27 3% density), and the largest number of non-connected members (n=43). Access to the ISC CONCLUSIONS: Results establish a baseline for assessing the growth of cross-center collaborations, highlighting specific areas in need of particular growth in network collaborations such as increasing engagement of racial and ethnic minorities and trainees or those with less expertise in IS

Non-Sequential Double Ionization of Ne in Intense Laser Pulses: A Coincidence Experiment

The dynamics of Neon double ionization by 25 fs, 1.0 PW/cm2 laser pulses at 795 nm has been studied in a many particle coincidence experiment. The momentum vectors of all ejected atomic fragments (electrons and ions) have been measured using combined electron and recoil-ion momentum spectroscopy. Electron emission spectra for double and single ionization will be discussed. In both processes the mean electron energies differ considerably and high energetic electrons with energies of more than 120 eV have been observed for double ionization. The experimental results are in qualitative agreement with the rescattering model

Separation of Recollision Mechanisms in Nonsequential Strong Field Double Ionization of Ar: The Role of Excitation Tunneling

Vector momentum distributions of two electrons created in double ionization of Ar by 25 fs, 0.25PW/cm2 laser pulses at 795 nm have been measured using a “reaction microscope.” At this intensity, where nonsequential ionization dominates, distinct correlation patterns are observed in the two-electron momentum distributions. A kinematical analysis of these spectra within the classical “recollision model” revealed an (e,2e)-like process and excitation with subsequent tunneling of the second electron as two different ionization mechanisms. This allows a qualitative separation of the two mechanisms demonstrating that excitation-tunneling is the dominant contribution to the total double ionization yield

90Y-clivatuzumab tetraxetan with or without low-dose gemcitabine: A phase Ib study in patients with metastatic pancreatic cancer after two or more prior therapies

AbstractBackgroundFor patients with metastatic pancreatic adenocarcinoma, there are no approved or established treatments beyond the 2nd line. A Phase Ib study of fractionated radioimmunotherapy was undertaken in this setting, administering 90Y-clivatuzumab tetraxetan (yttrium-90-radiolabelled humanised antibody targeting pancreatic adenocarcinoma mucin) with or without low radiosensitising doses of gemcitabine.MethodsFifty-eight patients with three (2–7) median prior treatments were treated on Arm A (N=29, 90Y-clivatuzumab tetraxetan, weekly 6.5mCi/m2doses×3, plus gemcitabine, weekly 200mg/m2 doses×4 starting 1week earlier) or Arm B (N=29, 90Y-clivatuzumab tetraxetan alone, weekly 6.5mCi/m2doses×3), repeating cycles after 4-week delays. Safety was the primary endpoint; efficacy was also evaluated.ResultsCytopaenias (predominantly transient thrombocytopenia) were the only significant toxicities. Fifty-three patients (27 Arm A, 26 Arm B, 91% overall) completed ⩾1 full treatment cycles, with 23 (12 Arm A, 11 Arm B; 40%) receiving multiple cycles, including seven (6 Arm A, 1 Arm B; 12%) given 3–9 cycles. Two patients in Arm A had partial responses by RECIST criteria. Kaplan–Meier overall survival (OS) appeared improved in Arm A versus B (hazard ratio [HR] 0.55, 95% CI: 0.29–0.86; P=0.017, log-rank) and the median OS for Arm A versus Arm B increased to 7.9 versus 3.4months with multiple cycles (HR 0.32, P=0.004), including three patients in Arm A surviving >1year.ConclusionsClinical studies of 90Y-clivatuzumab tetraxetan combined with low-dose gemcitabine appear feasible in metastatic pancreatic cancer patients beyond 2nd line and a Phase III trial of this combination is now underway in this setting

Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing

Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data: the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (~1.5–5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing.National Institutes of Health (U.S.) (Intramural Research Program)National Human Genome Research Institute (U.S.)Charles University (program UNCE 204011)Charles University (program PRVOUK-P24/LF1/3)Czech Republic. Ministry of Education, Youth, and Sports (grant NT13116-4/2012)Czech Republic. Ministry of Health (grant NT13116-4/2012)Czech Republic. Ministry of Health (grant LH12015)National Institutes of Health (U.S.) (Harvard Digestive Diseases Center, grant DK34854

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 x 10(-8)) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.Peer reviewe

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements