Timed Insemination vs. Modified Estrus Detection in Beef Heifers

Th e objective of this study was to compare a modified estrus detection and fixed time AI vs. no estrus detection and fixed time AI on subsequent pregnancy rates. Yearling heifers were estrus synchronized and AI at 72 ± 2 h after prostaglandin injection. In one group estrus was not detected and all heifers received gonadotropin releasing hormone at the fixed- time AI; in the other group estrus was detected at 58 ± 2 and 70 ± 2 h after prostaglandin and inseminated in the following order at 72 ± 2 h: heifers in estrus at 58 h, heifers in estrus at 70 h, and heifers not appearing in estrus at either observation. Similar AI conception and final pregnancy rates were achieved without the added labor of estrus detection

NOX1 and NOX4 are required for the differentiation of mouse F9 cells into extraembryonic endoderm

Mouse F9 cells differentiate to primitive endoderm (PrE) when treated with retinoic acid (RA). Differentiation is accompanied by increased reactive oxygen species (ROS) levels, and while treating F9 cells with antioxidants attenuates differentiation, H2O2 treatment alone is sufficient to induce PrE. We identified the NADPH oxidase (NOX) complexes as candidates for the source of this endogenous ROS, and within this gene family, and over the course of differentiation, Nox1 and Nox 4 show the greatest upregulation induced by RA. Gata6, encoding a master regulator of extraembryonic endoderm is also up-regulated by RA and we provide evidence that NOX1 and NOX4 protein levels increase in F9 cells overexpressing Gata6. Pan-NOX and NOX1-specific inhibitors significantly reduced the ability of RA to induce PrE, and this was recapitulated using a genetic approach to knockdown Nox1 and/or Nox4 transcripts. Interestingly, overexpressing either gene in untreated F9 cells did not induce differentiation, even though each elevated ROS levels. Thus, the data suggests that ROS produced during PrE differentiation is dependent in part on increased NOX1 and NOX4 levels, which is under the control of GATA6. Furthermore, these results suggest that the combined activity of multiple NOX proteins is necessary for the differentiation of F9 cells to primitive endoderm

Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study

BACKGROUND: Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span. METHODS:We conducted a genome wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models (Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate [greater than or equal to]80%, minor allele frequency [greater than or equal to]10%, Hardy-Weinberg test p [greater than or equal to] 0.001).RESULTS:In family-based association test (FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73, 527,652) were associated with age at death (p-value < 10-5). The two sets of SNPs were in high linkage disequilibrium (minimum r2 = 0.58). The top 30 SNPs for generalized estimating equation (GEE) tests of association with age at death included rs10507486 (p = 0.0001) and rs4943794 (p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes, SNP associations (FBAT or GEE p-value < 0.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. Top ranked SNP associations in the GEE model for age at natural menopause included rs6910534 (p = 0.00003) near FOXO3a and rs3751591 (p = 0.00006) in CYP19A1. Results of all longevity phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. CONCLUSION: Longevity and aging traits are associated with SNPs on the Affymetrix 100K GeneChip. None of the associations achieved genome-wide significance. These data generate hypotheses and serve as a resource for replication as more genes and biologic pathways are proposed as contributing to longevity and healthy aging

Predicting and Manipulating Cardiac Drug Inactivation by the Human Gut Bacterium Eggerthella lenta

Despite numerous examples of the effects of the human gastrointestinal microbiome on drug efficacy and toxicity, there is often an incomplete understanding of the underlying mechanisms. Here, we dissect the inactivation of the cardiac drug digoxin by the gut Actinobacterium Eggerthella lenta. Transcriptional profiling, comparative genomics, and culture-based assays revealed a cytochrome-encoding operon up-regulated by digoxin, inhibited by arginine, absent in nonmetabolizing E. lenta strains, and predictive of digoxin inactivation by the human gut microbiome. Pharmacokinetic studies using gnotobiotic mice revealed that dietary protein reduces the in vivo microbial metabolism of digoxin, with significant changes to drug concentration in the serum and urine. These results emphasize the importance of viewing pharmacology from the perspective of both our human and microbial genomes.Chemistry and Chemical Biolog

Effect of Small-Molecule-Binding Affinity on Tumor Uptake In Vivo: A Systematic Study Using a Pretargeted Bispecific Antibody

Small-molecule ligands specific for tumor-associated surface receptors have wide applications in cancer diagnosis and therapy. Achieving high-affinity binding to the desired target is important for improving detection limits and for increasing therapeutic efficacy. However, the affinity required for maximal binding and retention remains unknown. Here, we present a systematic study of the effect of small-molecule affinity on tumor uptake in vivo with affinities spanning a range of three orders of magnitude. A pretargeted bispecific antibody with different binding affinities to different DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-based small molecules is used as a receptor proxy. In this particular system targeting carcinoembryonic antigen, a small-molecule–binding affinity of 400 pmol/L was sufficient to achieve maximal tumor targeting, and an improvement in affinity to 10 pmol/L showed no significant improvement in tumor uptake at 24 hours postinjection. We derive a simple mathematical model of tumor targeting using measurable parameters that correlates well with experimental observations. We use relations derived from the model to develop design criteria for the future development of small-molecule agents for targeted cancer therapeutics.National Science Foundation (U.S.). Graduate Research Fellowship ProgramNational Institutes of Health (U.S.) (Grant R01-CA-101830

GNSS Spoof Detection Using Shipboard IMU Measurements

A variety of approaches have been proposed in the literature to detect spooing of Global Navigation Satellite Systems (GNSS). These approaches vary widely based upon the assumed capabilities and a priori knowledge of the spoofer. This paper considers a method to detect spoofing based on comparing the relative (not absolute) platform trajectory estimated by the GNSS receiver to the relative trajectory developed from IMU measurements (specifically pitch and roll from a gyro compass). The primary contribution of this paper is the development and analysis of a GNSS spoofing detection algorithm that exploits the unknown (to the spoofer) “high” frequency pitch/roll motion of the ship as seen by a commercial-off-the-shelf (COTS) receiver and an inertial measurement unit (IMU) that may already be in use onboard ships. We focus on generalized likelihood ratio tests using simple models of the GNSS and gyro measurements. Further, we avoid using a navigation filter, such as the extended Kalman filter, on the measurements; instead, the algorithm directly employs the instantaneous trajectories. Experimental results are shown using a commercial GNSS receiver with data from a GNSS simulator with IMU capability. The length of time and amount of motion required to achieve low probabilities of false alarm and missed detection are analyzed

Transmission Dynamics of COVID-19 in Ghana and the Impact of Public Health Interventions

This study characterized COVID-19 transmission in Ghana in 2020 and 2021 by estimating the time-varying reproduction number (Rt) and exploring its association with various public health interventions at the national and regional levels. Ghana experienced four pandemic waves, with epidemic peaks in July 2020 and January, August, and December 2021. The epidemic peak was the highest nationwide in December 2021 with Rt ≥ 2. Throughout 2020 and 2021, per-capita cumulative case count by region increased with population size. Mobility data suggested a negative correlation between Rt and staying home during the first 90 days of the pandemic. The relaxation of movement restrictions and religious gatherings was not associated with increased Rt in the regions with fewer case burdens. Rt decreased from \u3e 1 when schools reopened in January 2021 to \u3c 1 after vaccination rollout in March 2021. Findings indicated most public health interventions were associated with Rt reduction at the national and regional levels