Halogenated indole-3-acetic acids as oxidatively activated prodrugs with potential for targeted cancer therapy

Peer reviewe

In silico and in vitro approaches to develop Dimethylarginine dimethylaminohydrolase-1 inhibitors

Introduction: Dimethylarginine dimethylaminohydrolases (DDAH) metabolise the endogenous nitric oxide synthase (NOS) inhibitors: asymmetric dimethylarginine (ADMA) and monomethylarginine1. In sepsis excessive nitric oxide partially contributes to acute circulatory failure, and pharmacological DDAH1 inhibition has been proposed in order to increase methylarginines and reduce NO levels 2. The SR257 arginine analogue, with NG-methoxyethyl substituent, inhibits DDAH1 with an IC50 22 µM without directly inhibiting NOSs1,3. Methods: Acyclic and cyclic NG,NG-disubstituted arginines were made as previously described4 using Katritzky’s synthesis preparing trisubstituted guanidines from di-(benzotriazol-1-yl)methanimine5. Molecular docking was employed to explore interactions of these NG,NG-disubstituted arginines with human DDAH1 (PDB 2JAJ) using Glide (Schroedinger6) and Autodock47. The published SR257 ligand was used to define the binding site with both software tools. Recombinant human DDAH1 activity was measured using colorometric citrulline assay8 containing ADMA (100 µM), sodium phosphate (10 mM pH7.4); with symmetric dimethylarginine (100 µM), not a substrate for DDAH1, as blank. Experiments were carried out in duplicate, and repeated on at least 3 separate occasions. Results: Recombinant DDAH1 activity was reduced to less than 25% of control (ADMA substrate, 100 µM) in the presence of 100 µM piperidinyl, methoxyethyl/methyl, N-methylpiperazinyl, with morpholinyl and pyrrolidinyl substituents reducing activity to less than 10% of control. The in silico Glide docking score and predicted Autodock4 binding energy for human DDAH1 (PDB, 2JAJ) for the known SR257 DDAH1 inhibitor and NG,NG-disubstituted arginines are shown in the table: Conclusion: Both Autodock4 and Glide docking predicted higher binding energies for morpholinyl, pyrrolidinyl and piperinyl than the known SR257 compound. In vitro assays confirmed these NG,NG-disubstituted arginines reduced DDAH1 activity. There was variation between Glide and Autodock4 in the docking predictions for methoxyethyl/methyl and N-methylpiperazinyl. In silico prediction of DDAH1-ligand interactions may assist in the future design and development of novel NG,NG-disubstituted arginines. References: 1 Leiper, J. et al. (2007) Nat Med. 13:198-203. 2 Wang, Z et al. (2014) Biochem J. 460:309 3 Rossiter, S. et al. (2005) J Med Chem. 48:4670-4678. 4 Morfill, C et al. (2012) http://www.pA2online.org/abstracts/Vol10Issue4abst197P.pdf 5 Katritzky, A et al. (2000) J. Org. Chem. 65: 8080-8082. 6 Friesner, RA et al. (2006) J Med Chem. 49:6177-6196. 7 Morris, GM et al. (2009) J. Comp. Chem. 16:2785-91. 8 Knipp, M & Vasak, M (2000) Anal Biochem 286:257-64

Napanee : A Song Founded On Actual Facts

https://digitalcommons.library.umaine.edu/mmb-vp/4801/thumbnail.jp

Small Scale Hoop Structures for Market Swine

In the mid-1990s, amid concerns and realities surrounding the shift to large industrial-style swine confinement production units in Iowa, an alternative swine production system was introduced to the Midwest from Canada−hoop structures or hoops. Hoops are large tentlike structures that are deep bedded with cornstalks or straw. The pigs are kept in the hoop usually as one large group (\u3e150 head). The hoop is naturally ventilated. Bedding is added as the pigs grow. The hoop is cleaned after the pigs are marketed. Typical size for hoops is 30 ft × 84 ft for 200 market pigs. Wider hoops with steel truss arches are now on the market. Wider and longer hoops often have ridge vents to improve ventilation. Several companies are now marketing small-scale hoops of widths less than 20 ft These are often called utility shelters. The objective of this project was to demonstrate a small-scale hoop structure for swine. Low cost, small scale, versatility and quasitemporary status were emphasized

Modifying an Outdoor Farrowing Hut for Alternative Indoor Farrowing During Summer and Winter

The objective of this project was to modify an outdoor farrowing hut for winter and summer farrowing indoors to meet niche pork market requirements. Typical modified A-frame plywood outdoor farrowing huts were used to farrow sows indoors in summer and winter. The farrowing occurred in an insulated lean-to shed of a larger machine shed. During summer, the huts were fitted with a common 20-inch box fan positioned in the hut roof blowing down on the sow (Figures 2 and 3). This helped keep air moving over the sow during hot weather. At night when the temperature dropped, a thermostat in the fan would switch the fan off. A hover was built for the back of each hut and fitted with two heat lamps (Figure 4). This attachment provided a warm draft-free area for the piglets away from the sow. Also, the heat lamps were inaccessible to the sow to minimize risk of fire. These simple modifications helped keep the sows comfortable and piglets warm in a bedded alternative farrowing arrangement

A Comparison of Alternative Winter Farrowing Systems

The purpose of this demonstration was to compare two alternative winter farrowing systems that meet niche pork production criteria. The demonstration was conducted at the ISU Armstrong Research Farm, Lewis, IA, and the ISU Allee Demonstration Farm, Newell, IA. A group of 18 second parity gestating sows from the Allee Farm were randomly divided into two groups of nine sows. One group was farrowed during January 2007 at each farm. Each group farrowing was completed in 5 to 6 days. One farm had swing-side farrowing pens and the other farm had farrowing huts, all in bedded, heated rooms. The two systems had virtually identical performance results. For both systems the average number of pigs born alive was 13 pigs per litter with an average birth weight of 3.8 lb per pig. Weaning occurred at 44.9 days of age with 10.2 pigs per litter weighing an average of 34.2 lb each. The pre-wean mortality was 21.8%. Although this is high, it is approximately 1/4 less than the pre-wean mortality recorded during our earlier demonstration of the bedded Swedish free-stall farrowing system. The larger number of pigs born live and the lower pre-wean mortality resulted in 10.2 pigs weaned per litter in this demonstration compared with 8.1 pigs per litter in the Swedish cubicle system. This is about a 26% improvement. Again, the bedded group lactation worked well with few mortalities and good pig growth. Overall about 80% of the piglet mortalities occurred on day 1. The swing-side pens had fewer losses on day 1, but more losses later

Fatigue detection using computer vision

Long duration driving is a significant cause of fatigue related accidents of cars, airplanes, trains and other means of transport. This paper presents a design of a detection system which can be used to detect fatigue in drivers. The system is based on computer vision with main focus on eye blink rate. We propose an algorithm for eye detection that is conducted through a process of extracting the face image from the video image followed by evaluating the eye region and then eventually detecting the iris of the eye using the binary image. The advantage of this system is that the algorithm works without any constraint of the background as the face is detected using a skin segmentation technique. The detection performance of this system was tested using video images which were recorded under laboratory conditions. The applicability of the system is discussed in light of fatigue detection for drivers