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ABSTRACT IMPACT: Screening the effect of thousands of non-coding genetic variants will help identify variants important in the etiology of diseases OBJECTIVES/GOALS: Massively parallel reporter assays (MPRAs) can experimentally evaluate the impact of genetic variants on gene expression. In this study, our objective was to systematically evaluate the functional activity of 3’-UTR SNPs associated with neurological disorders and use those results to help understand their contributions to disease etiology. METHODS/STUDY POPULATION: To choose variants to evaluate with the MPRA, we first gathered SNPs from the GWAS Catalog that were associated with any neurological disorder trait with p-value < 10-5. For each SNP, we identified the region that was in linkage disequilibrium (r2 > 0.8) and retrieved all the common 3’-UTR SNPs (allele-frequency > 0.05) within that region. We used an MPRA to measure the impact of these 3’-UTR variants in SH-SY5Y neuroblastoma cells and a microglial cell line. These results were then used to train a deep-learning model to predict the impact of variants and identify features that contribute to the predictions. RESULTS/ANTICIPATED RESULTS: Of the 13,515 3’-UTR SNPs tested, 400 and 657 significantly impacted gene expression in SH-SY5Y and microglia, respectively. Of the 84 SNPs significantly impacted in both cells, the direction of impact was the same in 81. The direction of eQTL in GTEx tissues agreed with the assay SNP effect in SH-SY5Y cells but not microglial cells. The deep-learning model predicted sequence activity level correlated with the experimental activity level (Spearman’s corr = 0.45). The deep-learning model identified several predictive motifs similar to motifs of RNA-binding proteins. DISCUSSION/SIGNIFICANCE OF FINDINGS: This study demonstrates that MPRAs can be used to evaluate the effect of non-coding variants, and the results can be used to train a machine learning model and interpret its predictions. Together, these can help identify causal variants and further understand the etiology of diseases.
In the treatment of psychosis, agitation and aggression in Alzheimer's disease, guidelines emphasise the need to ‘use the lowest possible dose’ of antipsychotic drugs, but provide no information on optimal dosing.
This analysis investigated the pharmacokinetic profiles of risperidone and 9-hydroxy (OH)-risperidone, and how these related to treatment-emergent extrapyramidal side-effects (EPS), using data from The Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer's Disease study (Clinicaltrials.gov identifier: NCT00015548).
A statistical model, which described the concentration–time course of risperidone and 9-OH-risperidone, was used to predict peak, trough and average concentrations of risperidone, 9-OH-risperidone and ‘active moiety’ (combined concentrations) (n = 108 participants). Logistic regression was used to investigate the associations of pharmacokinetic biomarkers with EPS. Model-based predictions were used to simulate the dose adjustments needed to avoid EPS.
The model showed an age-related reduction in risperidone clearance (P < 0.0001), reduced renal elimination of 9-OH-risperidone (elimination half-life 27 h), and slower active moiety clearance in 22% of patients, (concentration-to-dose ratio: 20.2 (s.d. = 7.2) v. 7.6 (s.d. = 4.9) ng/mL per mg/day, Mann–Whitney U-test, P < 0.0001). Higher trough 9-OH-risperidone and active moiety concentrations (P < 0.0001) and lower Mini-Mental State Examination (MMSE) scores (P < 0.0001), were associated with EPS. Model-based predictions suggest the optimum dose ranged from 0.25 mg/day (85 years, MMSE of 5), to 1 mg/day (75 years, MMSE of 15), with alternate day dosing required for those with slower drug clearance.
Our findings argue for age- and MMSE-related dose adjustments and suggest that a single measure of the concentration-to-dose ratio could be used to identify those with slower drug clearance.
Gravitational waves from coalescing neutron stars encode information about nuclear matter at extreme densities, inaccessible by laboratory experiments. The late inspiral is influenced by the presence of tides, which depend on the neutron star equation of state. Neutron star mergers are expected to often produce rapidly rotating remnant neutron stars that emit gravitational waves. These will provide clues to the extremely hot post-merger environment. This signature of nuclear matter in gravitational waves contains most information in the 2–4 kHz frequency band, which is outside of the most sensitive band of current detectors. We present the design concept and science case for a Neutron Star Extreme Matter Observatory (NEMO): a gravitational-wave interferometer optimised to study nuclear physics with merging neutron stars. The concept uses high-circulating laser power, quantum squeezing, and a detector topology specifically designed to achieve the high-frequency sensitivity necessary to probe nuclear matter using gravitational waves. Above 1 kHz, the proposed strain sensitivity is comparable to full third-generation detectors at a fraction of the cost. Such sensitivity changes expected event rates for detection of post-merger remnants from approximately one per few decades with two A+ detectors to a few per year and potentially allow for the first gravitational-wave observations of supernovae, isolated neutron stars, and other exotica.
Improving geolocation accuracy in text data has long been a goal of automated text processing. We depart from the conventional method and introduce a two-stage supervised machine-learning algorithm that evaluates each location mention to be either correct or incorrect. We extract contextual information from texts, i.e., N-gram patterns for location words, mention frequency, and the context of sentences containing location words. We then estimate model parameters using a training data set and use this model to predict whether a location word in the test data set accurately represents the location of an event. We demonstrate these steps by constructing customized geolocation event data at the subnational level using news articles collected from around the world. The results show that the proposed algorithm outperforms existing geocoders even in a case added post hoc to test the generality of the developed algorithm.
Hippocampal neurogenesis continues throughout adult life and potentially plays a crucial role in mood and cognitive disorders. We summarise the preclinical insights and potential translational steps that could be taken to investigate the role and importance of this phenomenon in disease and health in humans.
Although childhood adversities are known to predict increased risk of post-traumatic stress disorder (PTSD) after traumatic experiences, it is unclear whether this association varies by childhood adversity or traumatic experience types or by age.
To examine variation in associations of childhood adversities with PTSD according to childhood adversity types, traumatic experience types and life-course stage.
Epidemiological data were analysed from the World Mental Health Surveys (n = 27017).
Four childhood adversities (physical and sexual abuse, neglect, parent psychopathology) were associated with similarly increased odds of PTSD following traumatic experiences (odds ratio (OR)=1.8), whereas the other eight childhood adversities assessed did not predict PTSD. Childhood adversity–PTSD associations did not vary across traumatic experience types, but were stronger in childhood-adolescence and early-middle adulthood than later adulthood.
Childhood adversities are differentially associated with PTSD, with the strongest associations in childhood-adolescence and early-middle adulthood. Consistency of associations across traumatic experience types suggests that childhood adversities are associated with generalised vulnerability to PTSD following traumatic experiences.
The drainage of a viscous gravity current into a deep porous medium driven by both the gravitational and capillary forces is considered in two steps. We first study the one-dimensional case where a layer of fluid drains vertically into an infinitely deep porous medium. We determine a transition from the capillary-driven regime to the gravity-driven regime as time proceeds. Second, we solve the coupled spreading and drainage problem. There are no self-similar solutions of the problem for the entire time period, so asymptotic analyses are developed for the height, depth and front location in both the early-time and the late-time periods. In addition, we present numerical results of the governing partial differential equations, which agree well with the self-similar solutions in the appropriate asymptotic limits.
Metal oxide-based transistors can be fabricated by low-cost, large-area solution processing methods, but involve a trade-off between low processing temperature, facile charge transport and high-capacitance/low-voltage transistor gates. We achieve these simultaneously by fabricating zinc oxide and sodium-incorporated alumina (SA) thin films with temperature not exceeding 200 to 250 °C using aqueous and combustion precursors, respectively. X-ray reflectivity shows a compositionally distinct SA boundary layer forming near the substrate and that a portion of the SA is chemically removed during the subsequent semiconductor deposition. Improved etch resistance and reduced dielectric leakage was obtained when (3-glycidoxypropyl) trimethoxysilane was included in the SA precursor.
Despite being well versed in scientific and technical concepts, engineering students often struggle with technical writing and communication. The CLEAR (Communication, Leadership, Ethics and Research) program at the University of Utah prepares engineering undergraduates for success in their careers through coursework aimed to improve oral and written communication skills, teamwork and ethical understanding. Along with an evaluation of ongoing CLEAR curricula in engineering laboratory and design classes, we are developing tools to assess student outcomes as defined by ABET criteria. These outcomes will inform how best to implement CLEAR curricula at the University of Utah, and ensure our graduates are better prepared to join the engineering workforce.
Complementing a multitude of activities around the International Year of Crystallography, we report here on a few resources that are helpful for integrating basic crystallography into interdisciplinary college education. We concentrate on four resources with which we are directly involved. The Crystallography Open Database (COD) features currently more than 295,000 entries and has over the last decade developed into the world’s premier open-access source for the structures of small molecules and small to medium sized unit cell crystals. ‘Educational offshoots’ of the COD with approximately a thousand entries combined provide structural information on small molecules, selected macromolecules, crystal structures, grain boundaries, and crystal morphologies in the well documented Crystallographic Information Framework (CIF) file format. This information can be displayed interactively on the website http://nanocrystallography.research.pdx.edu and freely downloaded. Files that allow for the printing of selected database entries on any 3D printer have been added to this site and are also freely downloadable. These files were created with the programs Cif2VRML and WinXMorph that convert CIF files directly into 3D printing files. Interested college educators are invited to visit our open access crystallography resource portal and suggest other resources that should receive wider exposure over this portal.
The Capstone Design course in the Department of Mechanical Engineering at Northeastern University requires students to build a physical prototype by the end of the two semester sequence. Although students have long been required to take an introductory materials science course as part of their curriculum, there was concern that materials selection was a weakness in the design process. Beginning in Fall 2011, the CES Edupack materials selection software was introduced into the Capstone Design class. The current work means to investigate: 1) how to assess designs for effective materials selection 2) whether the new software was actually used by the student teams and 3) whether there was evidence of improved materials selection in the projects that occurred after the new software was introduced. Final capstone design reports from 10 previous terms were examined to look for evidence of systematic materials selection procedures and clear discussion of materials properties as the basis for selecting a material. References to the software were also noted. Results show that 24% of the groups used the CES Edupack software in the first three terms that the software was available. In addition, there was an increase in the number of groups that used a systematic selection process based on research into published materials properties rather than choosing materials based on rough experimentation or convenience. Finally, there has been an increase in the number of projects which consider or incorporate composites, high temperature alloys, and advanced polymers as the software has increased awareness of these options.
The Center for Functional Nanoscale Materials (CFNM), an NSF Center for Research Excellence in Science and Technology, at Clark Atlanta University has partnered with ACS (American Chemical Society) Project SEED. The ACS project SEED program is recognized nationally as providing hands-on research opportunities to disadvantaged high school students who historically lack exposures to scientific careers. The University is a minority serving institution (MSI) and has an excellent relationship with Atlanta area school systems, which serve the African American community. Students entering their junior and senior years in high school were selected based on their academic performance, an essay and letters of recommendation for participation the Center’s eight week summer nanoscholar Program. Professors served as advisors and/or mentors and graduate students and doctoral fellows served as mentors. The Program included a variety of enrichment activities. All summer nanoscholars had personal research projects that were integral to the research programs of their advisors, and they presented their work in the form of a symposium at the end of the Program. We have completed three summers as an ACS Project SEED site. So far we have had one SEED scholar submit a major manuscript, two were invited to present at ACS National Meetings and one was awarded an eight year Gates-Millennium fellowship. Evaluation of the project strongly suggests that our approach is effective for opening doors for the economically disadvantaged students and tapping the best and the brightest for careers in the sciences and engineering. In the words of one of our young scholars “I realized that research is a continuous learning process. You can never know everything. Even a professor has credentials but they’re still continuing to learn.”
In this paper, the kinematic workspace characteristics of
a crab-like legged vehicle are investigated using a 2-D model.
The alternative kinematic configurations and their corresponding workspace constraints are
discussed, and the vehicle configuration of most interest identified. It
is shown that, for constant vehicle body attitude, only two
parameters affect the kinematic workspace, foot overlap and thigh length.
Analytical methods for calculating the workspace characteristics are presented and,
using these methods, the effects of the design geometry on
the kinematic workspace are investigated.
Interest in the synthesis of semiconductor nanoparticles has been generated by their unusual optical and electronic properties arising from quantum confinement effects. We have synthesized silicon and germanium nanoclusters by reacting Zintl phase precursors with either silicon or germanium tetrachloride in various solvents. Strategies have been investigated to stabilize the surface, including reactions with RLi and MgBrR (R = alkyl). This synthetic method produces group IV nanocrystals with passivated surfaces. These nanoparticle emit over a very large range in the visible region. These particles have been characterized using HRTEM, FTIR, UV-Vis, solid state NMR, and fluorescence. The synthesis and characterization of these nanoclusters will be presented.
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