Pharmacologic investigation of the anti-inflammatory activity of cryogenine and selected benzoquinolizine derivatives

It has become apparent in recent years that many centrally active agents possess potential anti-inflammatory capabilities. The central or peripheral mechanisms of action for these agents have not been delineated nor has their clinical efficacy baan established or refuted. The centrally active drugs, cryogenine and tetrabenazine (a benzoquinolizine derivative), previously have been shown in this laboratory to inhibit certain models of induced inflammation. The present study in rats verifies the anti-inflammatory properties of cryogenic and established that a structurally related series of benzoquinolizine derivatives possessed the capability of inhibiting both exudative (carrageenan-induced pedal edema) and proliferative (cotton pellet granuloma) models of inflammation when administered orally

Software Performance Modeling in PC Clusters

Execution of course grain parallel programs in PC clusters promises super-computer performance in low cost hardware environments. However the overhead associated with data distribution, synchronization, and peripheral access can easily eliminate any performance gain promised by the individual cluster capacity. Application specific system performance analysis is required both to engineer PC cluster hardware and evaluate the cost effectiveness of parallelizing software components. This paper presents a distributed system performance model and software analysis methodology suitable for estimating the execution times of large grain parallel application programs in clusters of PC hardware. The performance model emphasizes the use of application hardware performance results readily available in most systems. These are combined with single thread application software resource requirements in order to estimate the achievable execution rates in target clusters. A case study of the analysis of a video realistic battlefield simulator implementation in a PC cluster running under Linux is presented. Benchmark results and performance estimates for specific candidate hardware configurations are calculated and compared with actual results

Ground vibrations produced by surface and near-surface explosions

Measurements of seismic signatures produced by airborne, near-surface detonations of explosive charges over a variety of ground types show two distinct ground vibration arrivals. In all cases, the earlier arrival (precursor), has a time of arrival consistent with a predominantly underground path and coupling of blast sound to the ground close to the source and is always much smaller than the later vibration, the time of arrival of which is consistent with coupling from the air blast arrival at the receiver. The ratio of the seismic particle velocity to the acoustic pressure at the surface for the air-coupled seismic wave is constant with respect to distance and maximum pressure at a given location, but varies from site to site, with values usually between 1 and 13 μm s-1 Pa-1. For the precursor seismic wave, a coupling coefficient of 0.16 μm s-1 Pa-1 was measured. A numerical code enabling calculations of the fields due to an impulsive source above a layered poroelastic ground is described. Predictions of the air pressure spectrum above ground and the vertical and radial components of solid particle velocity near the ground surface are found to compare tolerably well with the measured spectra and waveforms of acoustic and seismic pulses at about 100 m range in seismically- hard and -soft soils and with a snow cover present. The predicted seismic responses in ‘soft’ soil confirm that the existence of a near-surface S-wave speed less than that in air is responsible for the observed ‘ringing’, i.e. a long low-frequency wavetrain associated with coupling to the dispersive Rayleigh wave. The predicted seismic pulses in the presence of the shallow snow cover explain the observed phenomenon whereby a high frequency ground vibration is modulated by a lower frequency layer resonance. An empirical equation relating ground vibration from explosions to distance predicts that the commonly- used vibrational damage peak velocity criterion of 12 or 25 mm s-1 will be exceeded when the peak positive pressure exceeds 480 Pa (147.6 dB) or 1 kPa (154.0 dB), respectively. Either of these levels is much higher than the current U.S. Army overpressure damage criterion of 159 Pa (138 dB). Thus in most situations damage from blast overpressure will occur long before damaging levels of ground vibration are reached, so it is likely that civilian perceptions of vibration are produced by coupling from the airblast

Is a Two-Day Cardiopulmonary Exercise Test a Valid Tool for The Diagnosis of Post-Exertional Malaise in Long COVID?

A two-day cardiopulmonary exercise testing (CPET) protocol (maximal ramp-incremental cycle test repeated 24hr apart) in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients has suggested that day-2 performance is decreased relative to day-1. This difference has been attributed to post-exertional malaise (PEM), suggesting the two-day CPET as a protocol to investigate PEM in Long COVID (LC) patients. PURPOSE: We aimed to investigate any effects of PEM on exercise performance and cardiorespiratory and perceptual responses to a two-day CPET in LC patients to determine whether the day-1 CPET would impair performance, cardiorespiratory responses or perceptions of exercise at day-2. METHODS: Fifteen LC patients with one or more symptoms persisting for more than three months after their initial infection [n=7 females; n=1 hospitalized; mean(SD); age 53(11) yrs; body mass index 32.2(8.5) kg/m2; time between COVID-19 onset and CPET 13(7) months; forced expiratory volume in 1 second 89(15) %pred; forced vital capacity 92(14) %pred; diffusing capacity of the lungs for carbon monoxide 92(15) %pred; total lung capacity 86(12) %pred] were studied. Prior to any exercise testing, PEM was assessed relative to the past six months using the modified DePaul Symptom Questionnaire (mDSQ) (0-4 symptoms frequency and severity scores). Each performed a two-day CPET protocol; ramp was 10-20 W/min, with the same ramp rate used for the day-1 and day-2 CPET. Peak oxygen uptake, peak work rate, and gas exchange threshold were measured using standard techniques. Ratings of perceived dyspnea and leg effort during cycling were recorded at peak exercise using the modified Borg’s Scale (0-10). One-sample t-tests were used to assess significance of test-retest mean difference. RESULTS: The mDSQ indicated the presence of PEM symptoms in 80% of participants. However, no significant differences between day-1 and day-2 CPET were found in any of the variables assessed. CONCLUSION: The absence of any difference in cardiorespiratory and perceptual responses in 2-day CPET testing, despite patient reported presence of PEM symptoms, suggests that the two-day CPET protocol may not be a valid tool for the diagnosis of PEM in LC patients

Characterization of universal features of partially methylated domains across tissues and species

Abstract: Background: Partially methylated domains (PMDs) are a hallmark of epigenomes in reproducible and specific biological contexts, including cancer cells, the placenta, and cultured cell lines. Existing methods for deciding whether PMDs exist in a sample, as well as their identification, are few, often tailored to specific biological questions, and require high coverage samples for accurate identification. Results: In this study, we outline a set of axioms that take a step towards a functional definition for PMDs, describe an improved method for comparable PMD detection across samples with substantially differing sequencing depths, and refine the decision criteria for whether a sample contains PMDs using a data-driven approach. Applying our method to 267 methylomes from 7 species, we corroborated recent results regarding the general association between replication timing and PMD state, and report identification of several reproducibly “escapee” genes within late-replicating domains that escape the reduced expression and hypomethylation of their immediate genomic neighborhood. We also explored the discordant PMD state of orthologous genes between human and mouse, and observed a directional association of PMD state with gene expression and local gene density. Conclusions: Our improved method makes low sequencing depth, population-level studies of PMD variation possible and our results further refine the model of PMD formation as one where sequence context and regional epigenomic features both play a role in gradual genome-wide hypomethylation

DNA methylation dynamics during intestinal stem cell differentiation reveals enhancers driving gene expression in the villus

Background: DNA methylation is of pivotal importance during development. Previous genome-wide studies identified numerous differentially methylated regions upon differentiation of stem cells, many of them associated with transcriptional start sites. Results: We present the first genome-wide, single-base-resolution view into DNA methylation dynamics during differentiation of a mammalian epithelial stem cell: the mouse small intestinal Lgr5+ stem cell. Very little change was observed at transcriptional start sites and our data suggest that differentiation-related genes are already primed for expression in the stem cell. Genome-wide, only 50 differentially methylated regions were identified. Almost all of these loci represent enhancers driving gene expression in the differentiated part of the small intestine. Finally, we show that binding of the transcription factor Tcf4 correlates with hypo-methylation and demonstrate that Tcf4 is one of the factors contributing to formation of differentially methylated regions. Conclusions: Our results reveal limited DNA methylation dynamics during small intestine stem cell differentiation and an impact of transcription factor binding on shaping the DNA methylation landscape during differentiation of stem cells in vivo

DNA Methylation Divergence and Tissue Specialization in the Developing Mouse Placenta

The placental epigenome plays a vital role in regulating mammalian growth and development. Aberrations in placental DNA methylation are linked to several disease states, including intrauterine growth restriction and preeclampsia. Studying the evolution and development of the placental epigenome is critical to understanding the origin and progression of such diseases. Although high-resolution studies have found substantial variation between placental methylomes of different species, the nature of methylome variation has yet to be characterized within any individual species. We conducted a study of placental DNA methylation at high resolution in multiple strains and closely related species of house mice (Mus musculus musculus, Mus m. domesticus, and M. spretus), across developmental timepoints (embryonic days 15-18), and between two distinct layers (labyrinthine transport and junctional endocrine). We observed substantial genome-wide methylation heterogeneity in mouse placenta compared with other differentiated tissues. Species-specific methylation profiles were concentrated in retrotransposon subfamilies, specifically RLTR10 and RLTR20 subfamilies. Regulatory regions such as gene promoters and CpG islands displayed cross-species conservation, but showed strong differences between layers and developmental timepoints. Partially methylated domains exist in the mouse placenta and widen during development. Taken together, our results characterize the mouse placental methylome as a highly heterogeneous and deregulated landscape globally, intermixed with actively regulated promoter and retrotransposon sequences.Funding was provided by an EU COST ACTION grant and Erasmus Traineeship (J.L.T.), a Royal Society Dorothy Hodgkin Fellowship (A.N.S.P.), and National Insitutes of Health grants GM098536 (M.D.D.) and HG005238 (A.D.S.)

Rapid Microwave-Assisted Shape Controlled Synthesis of Silver Nanoparticles

Color poster with text, diagrams, charts, images, graphs, and tables.The majority of procedures for shape-controlled silver nanoparticle synthesis report the use of a common set of reagents: a source of silver ions, a reducing agent, a shape directing agent, and a capping/protective agent. Associated reaction times are long, typically ranging from 24-72 hours. The purpose of this study was to develop a rapid microwave-assisted synthesis that includes only water, silver ions, and polyvinylpyrrolidone (PVP), producing predictable sizes and shapes of silver nanoparticles in 20 minutes.University of Wisconsin--Eau Claire Office of Research and Sponsored Programs

Pharmacologic investigation of the anti-inflammatory activity of cryogenine and selected benzoquinolizine derivatives

It has become apparent in recent years that many centrally active agents possess potential anti-inflammatory capabilities. The central or peripheral mechanisms of action for these agents have not been delineated nor has their clinical efficacy baan established or refuted. The centrally active drugs, cryogenine and tetrabenazine (a benzoquinolizine derivative), previously have been shown in this laboratory to inhibit certain models of induced inflammation. The present study in rats verifies the anti-inflammatory properties of cryogenic and established that a structurally related series of benzoquinolizine derivatives possessed the capability of inhibiting both exudative (carrageenan-induced pedal edema) and proliferative (cotton pellet granuloma) models of inflammation when administered orally