Uterine and placental infections are the leading cause of abortion, stillbirth, and preterm delivery in the mare. Whereas uterine and placental infections in women have been studied extensively, a comprehensive examination of the pathogenic processes leading to this unsatisfactory pregnancy outcome in the mare has yet to be completed. Most information in the literature relating to late-term pregnancy loss in mares is based on retrospective studies of clinical cases submitted for necropsy. Here we report the development and application of a novel approach, whereby transgenically modified bacteria transformed with lux genes of Xenorhabdus luminescens or Photorhabdus luminescens origin and biophotonic imaging are utilized to better understand pathogen-induced preterm birth in late-term pregnant mares. This technology uses highly sensitive bioluminescence imaging camera systems to localize and monitor pathogen progression during tissue invasion by measuring the bioluminescent signatures emitted by the lux-modified pathogens. This method has an important advantage in that it allows for the potential tracking of pathogens in vivo in real time and over time, which was hitherto impossible. Although the application of this technology in domestic animals is in its infancy, investigators were successful in identifying the fetal lungs, sinuses, nares, urinary, and gastrointestinal systems as primary tissues for pathogen invasion after experimental infection of pregnant mares with lux-modified Escherichia coli. It is important that pathogens were not detected in other vital organs, such as the liver, brain, and cardiac system. Such precision in localizing sites of pathogen invasion provides potential application for this novel approach in the development of more targeted therapeutic interventions for pathogen-related diseases in the equine and other domestic species.
Microglia are the resident immune cell of the brain involved in the development and progression of Alzheimer’s disease (AD). Modulation of microglia activity represents a potential mechanism for treating AD. Herein, the compound NNC 26–9100 (NNC) was evaluated in toxicity, nitric oxide release, Aβ1–42 uptake and cytosolic calcium assays during lipopolysaccharide (LPS)-activated conditions using mouse BV2 microglia cells. After 24 hours, LPS increased cell toxicity in the alamar blue and lactate dehydrogenase assays, increased nitrite release, and increase cytoplasmic calcium. Addition of NNC decreased the LPS-induce lactate dehydrogenase release, had no effect in the alamar blue assay, decreased nitrite release and decreased cytosolic calcium. In the absence of LPS, NNC increased uptake of FITC-tagged Aβ1–42. These data demonstrate that NNC treatment decreases nitrosative stress and microglia cell damage during LPS-induced activation and enhances phagocytosis of Aβ1–42 during non-inflammatory conditions. Thus, NNC 26–9100 may have beneficial effects in AD and in inflammatory diseases of the brain through enhancement of microglial Aβ clearance, and cell protective effects through prevention of elevated cytosolic calcium and inhibition of nitric oxide release.
In a well-managed beef herd, heifers should represent the most valuable genetics in the herd and be an improvement on the previous generation of females. Recent economic conditions have brought forth a trend in which heifers are developed in “low input” management scenarios where they typically achieve 50-55% of projected mature body weight at breeding as opposed to the more traditional 65-70%. Seasonal differences in calf performance and heifer reproductive efficiency have also been observed. The uterine environment during gestation is known to have lifelong epigenetic effects on offspring. This is often achieved by imposing suboptimal conditions or nutrition prior to breeding or during gestation, and the effects may be translated to the developing calf by altered patterns of uteroplacental blood flow. Thus, it was hypothesized that low input heifer development protocols resulting in light weight heifers at breeding may cause decreased uteroplacental blood flow during pregnancy compared to traditionally developed females even when nutrition during gestation is equivalent. Furthermore, it was posited that calving season may also alter uteroplacental hemodynamics. Therefore, the objective of the present study was to evaluate the effects of heifer development practices and season on uteroplacental hemodynamics during mid to late gestation of nulliparous beef females.
This research evaluated the somatostatin receptor subtype‐4 (SSTR4) agonist, NNC 26‐9100, on microglial amyloid‐beta 1‐42 (Aβ42) uptake with inflammatory stimulation. Microglia mediated events have been identified as critical to Alzheimer's disease (AD) progression. Considering microglia have been shown to express SSTR4 and have the capacity to take up and degrade hallmark Aβ isoforms, we hypothesized that a SSTR4 agonist may increase beta amyloid uptake dependent upon the level of inflammation. The effect of NNC 26‐9100 was evaluated in immortalized BV2 microglia cells against inflammatory activation using lipopolysaccharide (LPS). BV2 cells were plated at a density of 62,500 cells/cm2 in 12 well plates for 24hrs. FITC‐Aβ42 (100nM) uptake was then assessed following 24hr NNC 26‐9100 treatment (0, 1μM) against increasing concentrations of LPS (0, 0.83, 8.3 ng/mL) by flow cytometry. A two‐way ANOVA with Tukey post‐hoc tests were utilized to assess the impact of NNC 26‐9100, LPS and their interaction on FITC‐Aβ42 uptake. Both LPS (p<0.0001) and NNC 26‐9100 (p=0.0004) significantly affected mean FITCA‐β42 uptake by BV2 cells. While no significant interaction was found between LPS and NNC 26‐9100 on mean FITC‐Aβ42 uptake (p=0.2963), FITC‐Aβ42 uptake significantly increased with each additional increase in LPS (p<0.0001, Tukey). Moreover, FITC‐Aβ42 uptake significantly increased with 1 μM NNC 26‐9100 treatment when compared to vehicle control (p=0.0004, Tukey). In conclusion, the SSTR4 agonist NNC 26‐9100 and LPS significantly increased microglial uptake of Aβ42. These results identify a novel mechanism for enhancing microglial uptake of Aβ42 by an SSTR4 agonist under inflammatory conditions. Support or Funding Information This work is supported by the National Institutes of Health, National Institute of Aging (R01AG047858) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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