Ability of CIDRs or Melengestrol Acetate to Initiate Estrous Cycles in Early Postpartum Beef Cows

Postpartum anestrous interval in beef cows is a major factor contributing to reproductive failure during a defined breeding season. Our objectives were to determine the ability of a controlled internal drug-releasing device (CIDR), or melengestrol acetate (MGA) to induce ovulation and to eliminate short estrous cycles. Multiparous beef cows (n = 75) were equally assigned by age, days postpartum, body condition, and body weight to one of three treatments: CIDR, MGA, or control. All cows were fed carrier (2 lbs•cow-1•day-1) with MGA (0.25 mg/lb) or without MGA for 7 days (day -6 to 0). On day -6, CIDR were inserted and were removed on d 0. Estrous behavior was monitored continuously from day -6 until 29 using HeatWatch electronic mount detectors. Blood was collected three times weekly from day -6 to 29. Treatment influenced (P = 0.03) the percentage of cows that were detected in standing estrus. Beginning on d 2, more CIDR-treated cows had exhibited standing estrus compared to control cows, but CIDR- and MGA-treated cows did not differ. The percentage of CIDR-treated cows that had ovulated was greater (P \u3c 0.05) than the percentage of MGA-, or control-treated cows beginning on day 4. The percentage of cows that exhibited standing estrus before the first postpartum ovulation (CIDR = 65%, MGA = 57%, control = 30%) did not differ (P = 0.09) among treatments. Luteal lifespan following the first ovulation postpartum and the percentage of cows with a normal luteal lifespan (progesterone \u3e 1 ng/mL for ≥ 10 d) was greater (P \u3c 0.01) in CIDR-treated cows (14.0 ± 0.8 days; 20/20, 100%) compared with MGA- (6.2 ± 1.0 days; 3/13, 23%), or control-treated cows (6.1 ± 0.9 days; 4/17, 24%). In the present study, treatment of early postpartum suckled beef cows with CIDR-induced ovulation and initiated estrous cycles with a normal luteal lifespan in more cows than treatment with MGA, and treatment with MGA did not induce ovulation earlier than control cows

Whole-organism phenotypic screening methods used in early-phase anthelmintic drug discovery

Diseases caused by parasitic helminths (worms) represent a major global health burden in both humans and animals. As vaccines against helminths have yet to achieve a prominent role in worm control, anthelmintics are the primary tool to limit production losses and disease due to helminth infections in both human and veterinary medicine. However, the excessive and often uncontrolled use of these drugs has led to widespread anthelmintic resistance in these worms - particularly of animals - to almost all commercially available anthelmintics, severely compromising control. Thus, there is a major demand for the discovery and development of new classes of anthelmintics. A key component of the discovery process is screening libraries of compounds for anthelmintic activity. Given the need for, and major interest by the pharmaceutical industry in, novel anthelmintics, we considered it both timely and appropriate to re-examine screening methods used for anthelmintic discovery. Thus, we reviewed current literature (1977-2021) on whole-worm phenotypic screening assays developed and used in academic laboratories, with a particular focus on those employed to discover nematocides. This review reveals that at least 50 distinct phenotypic assays with low-, medium- or high-throughput capacity were developed over this period, with more recently developed methods being quantitative, semi-automated and higher throughput. The main features assessed or measured in these assays include worm motility, growth/development, morphological changes, viability/lethality, pharyngeal pumping, egg hatching, larval migration, CO2- or ATP-production and/or enzyme activity. Recent progress in assay development has led to the routine application of practical, cost-effective, medium- to high-throughput whole-worm screening assays in academic or public-private partnership (PPP) contexts, and major potential for novel high-content, high-throughput platforms in the near future. Complementing this progress are major advances in the molecular data sciences, computational biology and informatics, which are likely to further enable and accelerate anthelmintic drug discovery and development

The Metabolic Inhibition Model Which Predicts the Intestinal Absorbability and Metabolizability of Drug: Theory and Experiment

The intestinal absorption of analgesic peptides (leucine enkephalin and kyotorphin) and modified peptides in rat were studied. Although these peptides were not absorbed, the absorbability (absorption clearance) of these peptides were increased in the presence of peptidase inhibitors. In order to kinetically analyze these phenomena, we proposed the metabolic inhibition model, which incorporated the metabolic clearance (metabolizability) with the absorption clearance. Metabolic activity was determined with intestinal homogenates. The higher the metabolic clearance was, the lower was the absorption clearance. The relationships between the absorption clearance and the metabolic clearance of the experimental data as well as of the theoretical values were hyperbolic. This model predicted the maximum absorption clearances of cellobiose-coupled leucine enkephalin (0.654 μl/min/cm) and kyotorphin (0.247 μl/min/cm). Details of the experimental methods are described

Kepler-47: A Transiting Circumbinary Multi-Planet System

We report the detection of Kepler-47, a system consisting of two planets orbiting around an eclipsing pair of stars. The inner and outer planets have radii 3.0 and 4.6 times that of the Earth, respectively. The binary star consists of a Sun-like star and a companion roughly one-third its size, orbiting each other every 7.45 days. With an orbital period of 49.5 days, eighteen transits of the inner planet have been observed, allowing a detailed characterization of its orbit and those of the stars. The outer planet's orbital period is 303.2 days, and although the planet is not Earth-like, it resides within the classical "habitable zone", where liquid water could exist on an Earth-like planet. With its two known planets, Kepler-47 establishes that close binary stars can host complete planetary systems.Comment: To appear on Science Express August 28, 11 pages, 3 figures, one table (main text), 56 pages, 28 figures, 10 table

WormAssay: A Novel Computer Application for Whole-Plate Motion-based Screening of Macroscopic Parasites

Lymphatic filariasis is caused by filarial nematode parasites, including Brugia malayi. Adult worms live in the lymphatic system and cause a strong immune reaction that leads to the obstruction of lymph vessels and swelling of the extremities. Chronic disease leads to the painful and disfiguring condition known as elephantiasis. Current drug therapy is effective against the microfilariae (larval stage) of the parasite, but no drugs are effective against the adult worms. One of the major stumbling blocks toward developing effective macrofilaricides to kill the adult worms is the lack of a high throughput screening method for candidate drugs. Current methods utilize systems that measure one well at a time and are time consuming and often expensive. We have developed a low-cost and simple visual imaging system to automate and quantify screening entire plates based on parasite movement. This system can be applied to the study of many macroparasites as well as other macroscopic organisms

A repurposing strategy for Hsp90 inhibitors demonstrates their potency against filarial nematodes

Novel drugs are required for the elimination of infections caused by filarial worms, as most commonly used drugs largely target the microfilariae or first stage larvae of these infections. Previous studies, conducted in vitro, have shown that inhibition of Hsp90 kills adult Brugia pahangi. As numerous small molecule inhibitors of Hsp90 have been developed for use in cancer chemotherapy, we tested the activity of several novel Hsp90 inhibitors in a fluorescence polarization assay and against microfilariae and adult worms of Brugia in vitro. The results from all three assays correlated reasonably well and one particular compound, NVP-AUY922, was shown to be particularly active, inhibiting Mf output from female worms at concentrations as low as 5.0 nanomolar after 6 days exposure to drug. NVP-AUY922 was also active on adult worms after a short 24 h exposure to drug. Based on these in vitro data, NVP-AUY922 was tested in vivo in a mouse model and was shown to significantly reduce the recovery of both adult worms and microfilariae. These studies provide proof of principle that the repurposing of currently available Hsp90 inhibitors may have potential for the development of novel agents with macrofilaricidal properties