OBJECTIVES/GOALS: Preeclampsia, a hypertensive disorder in pregnancy, disrupts immune cell profiles at birth in both mice and humans. In mice, it affects offspring’s memory and behavior. This study aimed to investigate whether preeclampsia induces lasting immune cell changes after birth and its impact on astrocyte and microglia cell counts in offspring. METHODS/STUDY POPULATION: Preeclampsia was induced in C57BL/6 females by infusion of vasopressin (24 ng/hr) or saline throughout gestation via osmotic minipump. Parturition was allowed to occur naturally. Offspring were euthanized at various timepoints post-delivery for experimental measures. Total urine protein was determined via bicinchoninic acid assay. Single cell suspensions were prepared from thymus spleen, and brain tissue and separated via density gradient. Cell suspensions were stained with fluorochrome-conjugated monoclonal antibodies for flow cytometry. Statistical significance was determined using a two-tailed Student t test or one way ANOVA multiple comparisons test. The minimal level of confidence deemed statistically significant was p<0.05. RESULTS/ANTICIPATED RESULTS: Preeclampsia resulted in lower body and heart masses in offspring. Although T cell populations in the thymus were not altered in preeclampsia offspring, total T cells, Thelper, and cytotoxic T cells were elevated. Total B and isotype-switched B cells were increased in offspring of preeclampsia. Total dendritic cell percentages were not changed in offspring of preeclampsia, however, total anti-inflammatory markers on dendritic cells were reduced. Lastly, offspring of preeclampsia had a reduction in microglia and astrocytes within the brain. DISCUSSION/SIGNIFICANCE: Our study could establish including in utero data in predicting future disease risk, addressing gaps in understanding rising rates of cardiovascular and behavioral diseases. It also uncovers the impact of preeclampsia on early immune programming and reduced glial cell populations, potentially affecting cognitive and behavioral development.

The aim of this study was to assess whether adding Ca2+ to aggregate or native forms of β-lactoglobulin alters gut hormone secretion, gastric emptying rates and energy intake in healthy men and women. Fifteen healthy adults (mean ± sd: 9M/6F, age: 24 ± 5 years) completed four trials in a randomised, double-blind, crossover design. Participants consumed test drinks consisting of 30 g of β-lactoglobulin in a native form with (NATIVE + MINERALS) and without (NATIVE) a Ca2+-rich mineral supplement and in an aggregated form both with (AGGREG + MINERALS) and without the mineral supplement (AGGREG). Arterialised blood was sampled for 120 min postprandially to determine gut hormone concentrations. Gastric emptying was determined using 13C-acetate and 13C-octanoate, and energy intake was assessed with an ad libitum meal at 120 min. A protein × mineral interaction effect was observed for total glucagon-like peptide-1 (GLP-1TOTAL) incremental AUC (iAUC; P < 0·01), whereby MINERALS + AGGREG increased GLP-1TOTAL iAUC to a greater extent than AGGREG (1882 ± 603 v. 1550 ± 456 pmol·l−1·120 min, P < 0·01), but MINERALS + NATIVE did not meaningfully alter the GLP-1 iAUC compared with NATIVE (1669 ± 547 v. 1844 ± 550 pmol·l−1·120 min, P = 0·09). A protein × minerals interaction effect was also observed for gastric emptying half-life (P < 0·01) whereby MINERALS + NATIVE increased gastric emptying half-life compared with NATIVE (83 ± 14 v. 71 ± 8 min, P < 0·01), whereas no meaningful differences were observed between MINERALS + AGGREG v. AGGREG (P = 0·70). These did not result in any meaningful changes in energy intake (protein × minerals interaction, P = 0·06). These data suggest that the potential for Ca2+ to stimulate GLP-1 secretion at moderate protein doses may depend on protein form. This study was registered at clinicaltrials.gov (NCT04659902).

Since the release of the revised Appendix A from the Council of Europe for housing of laboratory animals there have been claims that laboratory animals should be housed under more complex conditions; known popularly as enrichment. A number of studies have expressed concerns that this may increase uncontrollable variation in the animals, thereby creating the need for greater numbers of animals. Within neurobiology there would appear to be a scientific basis for such concern. However, even though this may be used as an argument for denying the animal environmental enrichment, it is unclear whether there is any basis for concern within other research areas. The aim of this study, therefore, was to explore whether clinical pathology and cardiovascular parameters were influenced by housing rats under environmentally enriched conditions. Male, Sprague-Dawley rats were housed under three different regimes: non-enriched, standard-enriched (according to the guidelines of the Council of Europe) and extra-enriched with a shelf and higher cages. All housing forms were based upon commercially available, standardised equipment. A total of 41 different parameters were monitored via clinical pathology, telemetry and coagulation tests and virtually no differences were observed in relation to the manner in which the rats were housed. The uncontrollable variation observed in our study was compared to within-strain variation data supplied from the breeder and was relatively low in all three types of housing. We conclude, based upon our studies in male, Sprague-Dawley rats, that so far there is no basis for concern that enriched housing will lead to increased group sizes when using animals for research within this field and, as such, there is no reason not to enrich the environment of such rats.

A high dose of whey protein hydrolysate fed with milk minerals rich in calcium (Capolac®) results in enhanced glucagon-like peptide-1 (GLP-1) concentrations in lean individuals; however, the effect of different calcium doses ingested alongside protein is unknown. The present study assessed the dose response of calcium fed alongside 25 g whey protein hydrolysate on GLP-1 concentrations in individuals with overweight/obesity. Eighteen adults (mean ± sd: 8M/10F, 34 ± 18 years, 28·2 ± 2·9 kgm−2) completed four trials in a randomised, double-blind, crossover design. Participants consumed test solutions consisting of 25 g whey protein hydrolysate (CON), supplemented with 3179 mg (LOW), 6363 mg (MED) or 9547 mg (HIGH) Capolac® on different occasions, separated by at least 48 h. The calcium content of test solutions equated to 65, 892, 1719 and 2547 mg, respectively. Arterialised-venous blood was sampled over 180 min to determine plasma concentrations of GLP-1TOTAL, GLP-17–36amide, insulin, glucose, NEFA, and serum concentrations of calcium and albumin. Ad libitum energy intake was measured at 180 min. Time–averaged incremental AUC (iAUC) for GLP-1TOTAL (pmol·l−1·min−1) did not differ between CON (23 ± 4), LOW (25 ± 6), MED (24 ± 5) and HIGH (24 ± 6). Energy intake (kcal) did not differ between CON (940 ± 387), LOW (884 ± 345), MED (920 ± 334) and HIGH (973 ± 390). Co-ingestion of whey protein hydrolysate with Capolac® does not potentiate GLP-1 release in comparison with whey protein hydrolysate alone. The study was registered at clinical trials (NCT03819972).

In 2019, a 42-year-old African man who works as an Ebola virus disease (EVD) researcher traveled from the Democratic Republic of Congo (DRC), near an ongoing EVD epidemic, to Philadelphia and presented to the Hospital of the University of Pennsylvania Emergency Department with altered mental status, vomiting, diarrhea, and fever. He was classified as a “wet” person under investigation for EVD, and his arrival activated our hospital emergency management command center and bioresponse teams. He was found to be in septic shock with multisystem organ dysfunction, including circulatory dysfunction, encephalopathy, metabolic lactic acidosis, acute kidney injury, acute liver injury, and diffuse intravascular coagulation. Critical care was delivered within high-risk pathogen isolation in the ED and in our Special Treatment Unit until a diagnosis of severe cerebral malaria was confirmed and EVD was definitively excluded.

This report discusses our experience activating a longitudinal preparedness program designed for rare, resource-intensive events at hospitals physically remote from any active epidemic but serving a high-volume international air travel port-of-entry.

The present work investigates local flow structures and the downstream evolution of the core of helical tip vortices generated by a three-bladed rotor. Earlier experimental studies have shown that the core of a helical tip vortex exhibits a local helical symmetry with a simple relation between the axial and azimuthal velocities. In the present study, a self-similarity scaling argument further describes the downstream development of the vortex core. Self-similarity has up to now only been investigated for longitudinal vortices and it is the first time that helical vortices have become the subject of such an analysis. Combining symmetry arguments from previous studies on helical vortices with novel experiments and knowledge regarding the self-similarity evolution of the core of longitudinal vortices, a new model describing what is referred to as ‘helical self-similarity’ is proposed. The generality of the model is verified and supported by experimental data. The proposed model is important for fundamental understanding of the behaviour of helical vortices, with a range of applications in both industry and nature. Examples of this are tip vortices behind aerodynamic devices, such as vortex generators, and fixed and rotary aircraft, and in combustion chambers and cyclone separators.

Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that selectively infects dividing cancer cells, integrates into the genome and replicates due to immune defects in tumors. Toca 511 spreads through tumors and stably delivers the gene encoding an optimized yeast cytosine deaminase that converts the prodrug Toca FC (investigational, extended-release of 5-fluorocytosine) into 5-fluorouracil. In preclinical models, 5-fluorouracil kills infected dividing cancer cells, myeloid derived suppressor cells and tumor associated macrophages, enabling immune activation against the tumor. In this dose ascending Ph1 trial (NCT01470794), Toca 511 was injected into the resection cavity wall of patients with rHGG, followed by courses of oral Toca FC. Additional cohorts included combination with bevacizumab or lomustine. Across the Ph1 program, the safety profile remains favorable. Objective responses (ORs) were assessed by IRR using MRI scans prior to Toca FC treatment as baseline. ORs occurred 6-19 months after Toca 511 administration, suggesting an immunologic mechanism. The ORs were observed in 4 patients with IDH1-wildtype and 2 patients with IDH1-mutant tumors, including 5 complete responses (CRs) with the investigational therapy alone, and 1 CR in combination with bevacizumab. The median duration of response (mDoR) was 35.1+ months. As of AUG2017, all responders were CR and remain alive. In a 23-patient subgroup who received high doses of Toca 511 and met Ph3 trial criteria, mOS was 14.4 months, 3-year survival rate was 26.1%, and mDoR was 35.7+ months with a durable response rate of 21.7%. Data suggest a positive association of durable response with OS.

The Greenland ice sheet is experiencing dramatic melt that is likely to continue with rapid Arctic warming. However, the proportion of meltwater stored before reaching the global ocean remains difficult to quantify. We use NASA MODIS surface reflectance data to estimate river discharge from two West Greenland rivers – the Watson River near Kangerlussuaq and the Naujat Kuat River near Nuuk – over the summers of 2000–12. By comparison with in situ river discharge observations, ‘inundation–discharge’ relations were constructed for both rivers. MODIS-based total annual discharges agree well with total discharge estimated from in situ observations (86% of summer discharge in 2009 to 96% in 2011 at the Watson River, and 106% of total discharge in 2011 to 104% in 2012 at the Naujat Kuat River). We find, however, that a time-lapse camera, deployed at the Watson River in summer 2012, better captures the variations in observed discharge, benefiting from fewer data gaps due to clouds. The MODIS-derived estimates indicate that summer discharge has not significantly increased over the last decade, despite a strong warming trend. Also, meltwater runoff estimates derived from the regional climate model RACMO2/GR for the drainage basins are higher than our reconstructions of river discharge. These results provide indirect evidence for a considerable component of water storage within the glacio-hydrological system.

We present satellite-derived velocity patterns for the two contrasting melt seasons of 2009–10 across Russell Glacier catchment, a western, land-terminating sector of the Greenland ice sheet which encompasses the K(angerlussuaq)-transect. Results highlight great spatial heterogeneity in flow, indicating that structural controls such as bedrock geometry govern ice discharge into individual outlet troughs. Results also reveal strong seasonal flow variability extending 57 km up-glacier to 1200 m elevation, with the largest acceleration (100% over 11 days) occurring within 10 km of the margin coincident with spring melt. By late July 2010, 2 weeks before peak melt and runoff, 48 % of the 2400 km2 catchment had slowed to less than the winter mean. This observation supports the hypothesis that the subglacial hydrological system evolves from an inefficient distributed to an efficient drainage system, regulating flow dynamics. Despite this, the cumulative surface flux over the record melt year of 2010 was still greater compared with the perturbation over the average melt year of 2009. This study supports the proposition that local surface meltwater runoff couples to basal hydrology driving ice-sheet dynamics, and although the effect is nonlinear, our observations indicate that greater meltwater runoff yields increased net flux over this sector of the ice sheet.

Large crabgrass is a problem weed in horticultural crops, particularly in turfgrass in the southeastern United States. If growth of large crabgrass could be suppressed via soil pH or calcium levels, control of this weed in turfgrass might be improved while minimizing herbicide usage. To determine the effect of soil calcium and pH on germination and growth of large crabgrass, seeds were sown in a loamy sand soil amended with calcium carbonate (CaCO3) or magnesium carbonate (MgCO3) that established a range of soil pH from 4.8 to 7.8. Seeds were also sown in soil amended similarly with calcium sulfate (CaSO4), which does not affect pH, that established a range of exchangeable Ca levels corresponding to the Ca range in CaCO3 from pH 4.8 to 7.8. Seed germination of large crabgrass was unaffected by pH when soil was amended with CaCO3, whereas seed germination decreased with increasing pH when soil was amended with MgCO3. Crabgrass germination was not affected by Ca (CaSO4) independent of pH changes. Increasing soil pH reduced shoot and root dry weights of seedlings regardless of material used to raise pH. Maximum shoot dry weights occurred at pH 4.8 in the unamended soil, whereas maximum root dry weights occurred at ranges from pH 5.8 to 6.3 for CaCO3 and pH 5.3 to 5.8 for MgCO3. Shoot and root dry weights were not affected by Ca when soil was amended with CaSO4. By raising soil pH levels, the growth of large crabgrass and its ability to compete with turfgrass may be reduced. Raising exchangeable Ca does not appear to be an effective management tool for control of this weed species.

Recurrent glioblastoma (GBM) has an unmet need for effective therapies. Toca 511 (vocimagene amiretrorepvec), a retroviral replicating vector with the transgene cytosine deaminase, selectively infects, persists and spreads in tumor. Subsequent oral administration of 5-fluorocytosine (Toca FC) produces 5-fluorouracil (5-FU) within infected cells. 5-FU kills cancer cells and myeloid derived suppressor cells, inducing robust antitumor immune responses in animal models. In 2 Phase 1 studies, Toca 511 was administered into the cavity wall after surgical resection (NCT01470794) or intratumoral injection by biopsy needle (NCT01156584). To provide context to the results observed, subjects were compared to an external lomustine treated control (Courtesy Denovo Biopharma; Wick 2010). Treatment with Toca 511/Toca FC from 2 Phase I studies showed significant improvement in OS HR equals to 0.48, p less than 0.001, with similar effect in the surgical resection (OS HR 0.45, p equals to 0.003) and intratumoral injection (OS HR 0.56, p equals to 0.060). Fewer related greater or equal to Grade 3 adverse events (AEs) were reported for Toca 511/Toca FC (2.5 percent) vs. lomustine (36.9 percent). There was a virtual absence of hematologic toxicity for Toca 511/Toca FC vs. lomustine (Grade greater or equal to 3 thrombocytopenia 23.8 percent). Discontinuations for AEs occurred in 0percent for Toca 511/Toca FC vs. 4.8 percent for lomustine. Toca 511 is surgically delivered and treatment-emergent AEs regardless of attribution included incision site pain (20 percent), procedural pain (12.5 percent), and wound infection (5 percent) vs. 0percent, 1.2 percent, 1.2 percent respectively for lomustine. Toca 511/Toca FC significantly improved survival and safety relative to lomustine. A Phase 2/3 trial has launched (NCT02414165).