From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

The orexin system is responsible for regulating the sleep-wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}methanone ( 6 ), a compound which emerged from our in-house research program. Compound 6 was shown to be a potent, brain-penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (f_u brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above-mentioned shortcomings resulted in the identification of (4-chloro-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-methyl-2-[5-(2-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone ( 42 ), a DORA with improved in vivo efficacy compared to 6 .     

Indoor boundary layer chemistry modeling

Ozone (O₃) chemistry is thought to dominate the oxidation of indoor surfaces. We consider the hypothesis that reactions taking place within indoor boundary layers result in greater than anticipated hydroxyl radical (OH) deposition rates. We develop models that account for boundary layer mass‐transfer phenomena, O₃‐terpene chemistry and OH formation, removal, and deposition; we solve these analytically and by applying numerical methods. For an O₃‐limonene system, we find that OH flux to a surface with an O₃ reaction probability of 10^?8 is 4.3 × 10^?5 molec/(cm² s) which is about 10 times greater than predicted by a traditional boundary layer theory. At very low air exchange rates the OH surface flux can be as much as 10% of that for O₃. This effect becomes less pronounced for more O₃‐reactive surfaces. Turbulence intensity does not strongly influence the OH concentration gradient except for surfaces with an O₃ reaction probability >10^?4. Although the O₃ flux dominates OH flux under most conditions, OH flux can be responsible for as much as 10% of total oxidant uptake to otherwise low‐reactivity surfaces. Further, OH chemistry differs from that for ozone; therefore, its deposition is important in understanding the chemical evolution of some indoor surfaces and surface films.     

A Symmetrical Diester as the Sex Attractant Pheromone of the North American Click Beetle Parallelostethus attenuatus (Say) (Coleoptera: Elateridae)

Hexanoic acid, 1-octanol, 1,8-octanediol, octyl hexanoate, 1,8-octanediol monohexanoate, and 1,8-octanediol dihexanoate were identified in headspace volatiles collected from the crushed abdomen of a female click beetle of the species Parallelostethus attenuatus (Say) (Elaterinae, tribe Elaterini). In field trials carried out in Illinois, South Carolina, North Carolina, and Virginia, adult male beetles were strongly attracted to 1,8-octanediol dihexanoate alone. Blends of the dihexanoate with one or more of the other compounds proved to be less attractive than the dihexanoate alone, suggesting that the pheromone of this species may consist of a single compound. The symmetrical diester structure of the pheromone is a novel natural product and appears to be structurally unique among insect pheromones.

     

A boronic acid-based fluorescent hydrogel for monosaccharide detection

A boronic acid-based anthracene fluorescent probe was functionalised with an acrylamide unit to incorporate into a hydrogel system for monosaccharide detection. In solution, the fluorescent probe displayed a strong fluorescence turn-on response upon exposure to fructose, and an expected trend in apparent binding constants, as judged by a fluorescence response where D-fructose>D-galactose>D-mannose>D-glucose. The hydrogel incorporating the boronic acid monomer demonstrated the ability to detect monosaccharides by fluorescence with the same overall trend as the monomer in solution with the addition of D-fructose resulting in a 10-fold enhancement (≤0.25 mol/L).     

An enhanced deterministic beacon advertising algorithm for building TSCH networks

In this paper, we focus first on the time needed by a node to join a Time Slotted Channel Hopping (TSCH) network, this time is called joining time. Second, we are also interested in the network building time. Since the data generated by a sensor node remain unavailable as long as this node has not yet joined the wireless sensor network, these times are of prime importance for applications having strong latency requirements on data gathering. The joining time depends on the beacon advertising policy that has been left unspecified by the standard. The contribution of this paper is triple. First, we propose an Enhanced Deterministic Beacon Advertising algorithm, called EDBA, that ensures a collision-free advertising of beacons and minimizes the average joining time. Second, we model the behavior of a joining node by a Markov chain, validated by NS3 simulations, and compute the average joining time. Third, we compare the performance of EDBA with this of MBS, considered as the best beacon advertising algorithm in the literature.     

Colostrum source and passive immunity transfer in dairy bull calves

Colostrum is essential for good neonate health; however, it is not known whether different calves absorb the nutrients from colostrum equally well. In this study, the absorption of protein, IgG, and γ-glutamyl transferase was compared in newborn dairy bull calves for 1 wk after feeding colostrum from different sources. Thirty-five Holstein-Friesian bull calves were randomly allocated into 3 groups and fed colostrum within 4 h after birth. Group A calves (n = 12) were bottle fed colostrum from their own dam for 3 d. Colostrum from these group A cows was also used as foster cow colostrum for the group B calves (n = 12), such that each group A and B calf pair received identical colostrum from each milking of the respective group A dam (10% of birth weight per day). The group C calves (n = 11) were fed 1 bottle (2 L) of pooled colostrum and transition milk (referred to as pooled colostrum), as was the standard practice on the dairy farm. The pooled colostrum was collected from the other dairy cows on the farm 0 to 4 d postpartum and stored at 4°C for less than 12 h. Blood was sampled from calves before the first feeding and at 1, 2, 3, and 7 d after birth. Levels of total solids, total protein, and IgG were higher in the dam colostrum than in the pooled colostrum. At birth, there were no differences between the calf groups for any measurements, and all calves had very low IgG levels. After receiving colostrum, the glucose, plasma γ-glutamyl transferase, serum total protein, and IgG concentrations increased significantly in all calves. There were no differences in any blood measurements at any time point between the pairs of group A and group B calves that received colostrum from the same cow except for the IgG concentration 2 d after birth. However, the group A calves had a higher total serum protein level and IgG concentration than the group C calves for all the time points after the first feeding. The group B calves had a higher IgG concentration than the group C calves on d 1, 2, and 7 after birth. Compared with groups A and B, there was no difference in the proportion of calves in group C that failed to have passive immunity transferred adequately based on the IgG threshold (<10 g/L). Thus, the calves receiving identical colostrum from the same cow had the same levels of IgG, and even the pooled colostrum provided sufficient transfer of IgG as the calves were fed within 4 h after birth.     

Role network measures to assess healthcare team adaptation to complex situations: the case of venous thromboembolism prophylaxis

Hospitals are complex environments that rely on clinicians working together to provide appropriate care to patients. These clinical teams adapt their interactions to meet changing situational needs. Venous thromboembolism (VTE) prophylaxis is a complex process that occurs throughout a patient’s hospitalisation, presenting five stages with different levels of complexity: admission, interruption, re-initiation, initiation, and transfer. The objective of our study is to understand how the VTE prophylaxis team adapts as the complexity in the process changes; we do this by using social network analysis (SNA) measures. We interviewed 45 clinicians representing 9 different cases, creating 43 role networks. The role networks were analysed using SNA measures to understand team changes between low and high complexity stages. When comparing low and high complexity stages, we found two team adaptation mechanisms: (1) relative increase in the number of people, team activities, and interactions within the team, or (2) relative increase in discussion among the team, reflected by an increase in reciprocity.

 

Practitioner Summary: The reason for this study was to quantify team adaptation to complexity in a process using social network analysis (SNA). The VTE prophylaxis team adapted to complexity by two different mechanisms, by increasing the roles, activities, and interactions among the team or by increasing the two-way communication and discussion throughout the team. We demonstrated the ability for SNA to identify adaptation within a team.