Knowledge graphs have become a common approach for knowledge representation. Yet, the application of graph methodology is elusive due to the sheer number and complexity of knowledge sources. In addition, semantic incompatibilities hinder efforts to harmonize and integrate across these diverse sources. As part of The Biomedical Translator Consortium, we have developed a knowledge graph–based question-answering system designed to augment human reasoning and accelerate translational scientific discovery: the Translator system. We have applied the Translator system to answer biomedical questions in the context of a broad array of diseases and syndromes, including Fanconi anemia, primary ciliary dyskinesia, multiple sclerosis, and others. A variety of collaborative approaches have been used to research and develop the Translator system. One recent approach involved the establishment of a monthly “Question-of-the-Month (QotM) Challenge” series. Herein, we describe the structure of the QotM Challenge; the six challenges that have been conducted to date on drug-induced liver injury, cannabidiol toxicity, coronavirus infection, diabetes, psoriatic arthritis, and ATP1A3-related phenotypes; the scientific insights that have been gleaned during the challenges; and the technical issues that were identified over the course of the challenges and that can now be addressed to foster further development of the prototype Translator system. We close with a discussion on Large Language Models such as ChatGPT and highlight differences between those models and the Translator system.

Annual bluegrass is a troublesome weed in turfgrass, with reported resistance to at least 12 herbicide sites of action. The mitotic-inhibiting herbicide pronamide has both preemergence and postemergence activity on susceptible annual bluegrass populations. Previous studies suggest that postemergence activity may be compromised due to lack of root uptake, as well as target-site- and translocation-based mechanisms. Research was conducted to determine the effects of spray droplet spectra on spray coverage and control of annual bluegrass with pronamide, flazasulfuron, and a mixture of pronamide plus flazasulfuron. Herbicides were delivered to annual bluegrass plants having two to three leaves via five different spray spectra based on volume median diameters (VMD) of 200, 400, 600, 800, and 1,000 µm. Fluorescent tracer dye was added to each treatment solution to quantify the effects of herbicide and spray droplet spectra on herbicide deposition. In another experiment, the efficacy of 0.58, 1.16, and 2.32 kg pronamide ha−1; 0.022, 0.044, and 0.088 kg flazasulfuron ha−1, or a combination of the two, were assessed in iteration with droplet spectrum sprays of 400 and 1,000 µm on two pronamide-resistant and two pronamide-susceptible annual bluegrass populations. Spray droplet spectrum affected the deposition of pronamide and flazasulfuron, applied alone and in combination. Pronamide foliar deposition decreased with increasing droplet spectra. Pronamide efficacy was affected by droplet spectrum, with the largest (1,000 µm) exhibiting improved control. Flazasulfuron efficacy and pronamide plus flazasulfuron efficacy were not affected by droplet spectra. Pronamide plus flazasulfuron mixture controlled all four populations more effectively than pronamide alone, regardless of droplet spectra. A mixture of pronamide plus flazasulfuron applied with relatively large droplets may be optimal for annual bluegrass control, which offers valuable insights for optimizing herbicide application and combatting herbicide resistance. However, applications in this controlled-growth pot study may not mimic conditions in which thatch and turfgrass canopy limit the soil deposition of pronamide.

Severe acute respiratory coronavirus virus 2 (SARS-CoV-2) real-time reverse-transcription polymerase chain reaction (rRT-PCR) strand-specific assay can be used to identify active SARS-CoV-2 viral replication. We describe the characteristics of 337 hospitalized patients with at least 1 minus-strand SARS-CoV-2 assay performed >20 days after illness onset. This test is a novel tool to identify high-risk hospitalized patients with prolonged SARS-CoV-2 replication.

The mitotic-inhibiting herbicide pronamide controls susceptible annual bluegrass (Poa annua L.) pre- and postemergence, but in some resistant populations, postemergence activity is compromised, hypothetically due to a target-site mutation, lack of root uptake, or an unknown resistance mechanism. Three suspected pronamide-resistant (LH-R, SC-R, and SL-R) and two pronamide-susceptible (BS-S and HH-S) populations were collected from Mississippi golf courses. Dose–response experiments were conducted to confirm and quantify pronamide resistance, as well as resistance to flazasulfuron and simazine. Target sites known to confer resistance to mitotic-inhibiting herbicides were sequenced, as were target sites for herbicides inhibiting acetolactate synthase (ALS) and photosystem II (PSII). Pronamide absorption and translocation were investigated following foliar and soil applications. Dose–response experiments confirmed pronamide resistance of LH-R, SC-R, and SL-R populations, as well as instances of multiple resistance to ALS- and PSII-inhibiting herbicides. Sequencing of the α-tubulin gene confirmed the presence of a mutation that substituted isoleucine for threonine at position 239 (Thr-239-Ile) in LH-R, SC-R, SL-R, and BS-S populations. Foliar application experiments failed to identify differences in pronamide absorption and translocation between the five populations, regardless of harvest time. All populations had limited basipetal translocation—only 3% to 13% of the absorbed pronamide—across harvest times. Soil application experiments revealed that pronamide translocation was similar between SC-R, SL-R, and both susceptible populations across harvest times. The LH-R population translocated less soil-applied pronamide than susceptible populations at 24, 72, and 168 h after treatment, suggesting that reduced acropetal translocation may contribute to pronamide resistance. This study reports three new pronamide-resistant populations, two of which are resistant to two modes of action (MOAs), and one of which is resistant to three MOAs. Results suggest that both target site– and translocation-based mechanisms may be associated with pronamide resistance. Further research is needed to confirm the link between pronamide resistance and the Thr-239-Ile mutation of the α-tubulin gene.

OBJECTIVES/GOALS: Adolescence represents a critical period for substance use initiation. Various factors may contribute to trying a sip or single puff of a substance, that could lead to more frequent use. However, less is known about how predictors from multiple domains converge to impact risk for general substance use initiation. METHODS/STUDY POPULATION: The Adolescent Brain Cognitive Development (ABCD) study is a multi-site longitudinal study following youth into early adulthood. The present study included 7,644 ABCD children who reported no lifetime substance use (including any experimentation) at baseline (ages 9–10). Our primary aim was to use a random forest classification model to predict binary substance use initiation, defined as trying any non-prescribed substance (e.g., alcohol, tobacco, cannabis, non-prescribed medications), during a 2-year follow-up after baseline. A total of 402 variables from the following categories were examined as predictors: demographics, peer substance use and availability, mental and physical health, culture and environment, biospecimens, neurocognitive functioning, and structural neuroimaging variables. RESULTS/ANTICIPATED RESULTS: Over a two-year follow-up, 751 (9.8%) of substance-naïve children reported trying a substance by age 11. The most common substance was alcohol, followed by cannabis and tobacco. Mean Decrease Accuracy (MDA) values were used to assess the relative importance of each predictor. The overall accuracy of the model in accurately predicting group membership (no substance use initiation vs. substance use initiation) was 57.66%. Of the top 5 predictors, the most important predictor was intent to use alcohol (MDA = .002). The following top predictors were structural neuroimaging variables: volume and surface area of right lateral occipital lobe (MDA = .0009 and .0008, respectively), surface area of right inferior temporal lobe (MDA = .0007), and surface area of left superior frontal lobe (MDA = .0007). DISCUSSION/SIGNIFICANCE: A combination of intent to use alcohol and structural neuroimaging indices were among the top predictors of substance use initiation. Understanding predictors of early substance use experimentation is important for identifying at-risk youth that may require targeted intervention approaches.

Merino ewes have been selected, over 18 generations, for calm (C) or nervous (N) temperament using using an arena test and an isolation box test. We investigated the relative contributions of genotype versus the post-partum behaviour of the dam on the temperament of the lambs using a cross-fostering procedure. Forty-eight multiparous calm and 52 nervous ewes were artificially inseminated with the semen of a sire of the same temperament. At birth, 32 lambs of a given temperament line were cross fostered to ewes from the other line (16 N × C, 16 C × N), 34 lambs were cross fostered to ewes from the same line (15 C × C, 19 N × N) and 30 lambs were left with their birth mother (15 C, 15 N), to control for the effect of cross fostering. The temperament of the progeny was assessed at two occasions, one week after birth by measuring locomotor activity during an open-field test and at weaning (16 weeks) by measuring locomotor activity during an arena test and agitation score measured during an isolation box test. There was a genotype effect but no maternal or fostering effect on the lamb temperament at one week. This may be because the maternal behaviour of the foster ewes did not differ considerably between the calm and nervous mothers during adoption or within the first week, post partum. Similarly, at weaning, only a genotype effect was found on the locomotor and agitation score. Therefore, it appears that temperament in Merino sheep is mainly determined by the genetic transmission of the trait across generations rather than behaviours learned from the mother.

Plasmodium coatneyi has been proposed as an animal model for human Plasmodium falciparum malaria as it appears to replicate many aspects of pathogenesis and clinical symptomology. As part of the ongoing evaluation of the rhesus macaque model of severe malaria, a detailed ultrastructural analysis of the interaction between the parasite and both the host erythrocytes and the microvasculature was undertaken. Tissue (brain, heart and kidney) from splenectomized rhesus macaques and blood from spleen-intact animals infected with P. coatneyi were examined by electron microscopy. In all three tissues, similar interactions (sequestration) between infected red blood cells (iRBC) and blood vessels were observed with evidence of rosette and auto-agglutinate formation. The iRBCs possessed caveolae similar to P. vivax and knob-like structures similar to P. falciparum. However, the knobs often appeared incompletely formed in the splenectomized animals in contrast to the intact knobs exhibited by spleen intact animals. Plasmodium coatneyi infection in the monkey replicates many of the ultrastructural features particularly associated with P. falciparum in humans and as such supports its use as a suitable animal model. However, the possible effect on host–parasite interactions and the pathogenesis of disease due to the use of splenectomized animals needs to be taken into consideration.

The first demonstration of laser action in ruby was made in 1960 by T. H. Maiman of Hughes Research Laboratories, USA. Many laboratories worldwide began the search for lasers using different materials, operating at different wavelengths. In the UK, academia, industry and the central laboratories took up the challenge from the earliest days to develop these systems for a broad range of applications. This historical review looks at the contribution the UK has made to the advancement of the technology, the development of systems and components and their exploitation over the last 60 years.

ABSTRACT IMPACT: Melanoma leptomeningeal disease (LMD) is a devastating subtype of central nervous system (CNS) metastatic disease that is associated with limited treatment options and an extremely poor prognosis, thus requiring the development of preclinical models of LMD for therapeutic development. OBJECTIVES/GOALS:

1. 1. Develop an immunocompetent murine model of melanoma LMD with tumors bearing genetic mutations commonly found in patients, specifically BRAF(V600E)/PTEN-/-

2. 2. Assess the safety of intrathecal (IT) immunotherapy, specifically anti-PD1 antibody (aPD1)

3. 3. Evaluate the therapeutic efficacy of IT aPD1 checkpoint blockade in murine melanoma LMD METHODS/STUDY POPULATION: To develop BRAF(V600E)/PTEN-/- LMD models, we acquired BP, D4M, and D4M-UV2 (irradiated) murine melanoma cell lines and luciferase-tagged them. 1.5x10^4 cells were suspended in 10 uL serum-free media and injected into the cisterna magna of female C57BL/6 mice. Brain and spinal cord were harvested for histologic assessment once mice were moribund. To assess safety of IT aPD1, we injected IT control IgG or IT aPD1 (13 ug, 26 ug, 39 ug) and monitored weights or harvested at days 7 or 14 for IHC staining of inflammation markers. To evaluate therapeutic efficacy of IT aPD1, BP cells were directly injected as above. After 3 days, mice underwent imaging to confirm tumor uptake and randomization to receive 13 ug IT control IgG or aPD1 once + 200 ug systemic (Sys) control IgG or aPD1 (days 0, 3, and 5), and then monitored for survival. RESULTS/ANTICIPATED RESULTS: For LMD development, all mice survived cisternal injection of BP, D4M, and D4M-UV2 cells and median survival was 17, 19, and 30 days, respectively. Presence of leptomeningeal deposits was confirmed for all tumor-bearing mice by IHC for MART1. For safety of IT aPD1, all mice survived the procedure and no mice displayed morbidity or >10% weight loss over 14 days of observation. IHC assessment of brain and spinal cord samples from mice treated with 13 ug aPD1 revealed focal ischemia related to injection site and no other signs of neurological damage or inflammation. IT aPD1 treatment of mice with BP leptomeningeal tumors demonstrated no significant survival advantage, although both IT aPD1 +/- Sys aPD1 had mice live up to days 29 and 26, respectively, compared to both IT control IgG +/- Sys aPD1, for which all mice died by day 22. DISCUSSION/SIGNIFICANCE OF FINDINGS: We demonstrate that cisternal injection of murine BRAF(V600E)/PTEN-/- melanoma cell lines yield LMD with reproducible survival and that treatment with IT aPD1 in this model is feasible and safe. Together these findings establish a new model to facilitate the development of more effective immunotherapy strategies for melanoma patients with LMD.

Accurate and timely data are essential for identifying populations at risk for undernutrition due to poor-quality diets, for implementing appropriate interventions and for evaluating change. Life-logging wearable cameras (LLWC) have been used to prospectively capture food/beverage consumed by adults in high-income countries. This study aimed to evaluate the concurrent criterion validity, for assessing maternal and child dietary diversity scores (DDS), of a LLWC-based image-assisted recall (IAR) and 24-h recall (24HR). Direct observation was the criterion method. Food/beverage consumption of rural Eastern Ugandan mothers and their 12–23-month-old child (n 211) was assessed, for the same day for each method, and the IAR and 24HR DDS were compared with the weighed food record DDS using the Bland–Altman limits of agreement (LOA) method of analysis and Cohen’s κ. The relative bias was low for the 24HR (–0·1801 for mothers; –0·1358 for children) and the IAR (0·1227 for mothers; 0·1104 for children), but the LOA were wide (–1·6615 to 1·3012 and –1·6883 to 1·4167 for mothers and children via 24HR, respectively; –2·1322 to 1·8868 and –1·7130 to 1·4921 for mothers and children via IAR, respectively). Cohen’s κ, for DDS via 24HR and IAR, was 0·68 and 0·59, respectively, for mothers, and 0·60 and 0·59, respectively, for children. Both the 24HR and IAR provide an accurate estimate of median dietary diversity, for mothers and their young child, but non-differential measurement error would attenuate associations between DDS and outcomes, thereby under-estimating the true associations between DDS – where estimated via 24HR or IAR – and outcomes measured.

College athletes across north America are often known on their respective college campuses for their athleticism, and spend a considerable amount of hours weekly engaging in their respective sport through practices, meetings, travelling and meals, to name a few. It is no wonder it is difficult for these students to feel fully engaged and connected on university campuses as students. Female college athletes in particular, who often are not athletes in revenue-generating sports, often feel left behind as students and isolated as athletes. The purpose of the current study was to examine female collegiate athletes’ experience with belonging in a university setting. This qualitative inquiry utilised consensual qualitative research to explore 14 female student athletes’ experience of belonging on a university campus. The results of the data analysis yielded the following domains or themes: athletic team culture, athletic department culture, campus support and involvement, female athlete identity, and individual athlete experience. The most salient finding was that these female athletes suggested that their sense of belonging on campus was almost exclusively related to their experience as an athlete and their athletic team.