Design,synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics

Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH₂-imidazole or CH₂-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC?=?12.5?μg/mL, 17a 50?μg/mL). Crystal structures were determined for CYP121A1 bound to series A compounds 6a and 6b that show the imidazole groups positioned directly above the haem iron with binding between the haem iron and imidazole nitrogen of both compounds at a distance of 2.2?Å. A model generated from a 1.5?Å crystal structure of CYP121A1 in complex with compound 10a showed different binding modes in agreement with the heterogeneous binding observed. Although the crystal structures of 6a and 6b would indicate binding with CYP121A1, the binding assays themselves did not allow confirmation of CYP121A1 as the target.     

Improving biocontrol of black vine weevil (<Emphasis Type="Italic">Otiorhynchus sulcatus</Emphasis>) with entomopathogenic fungi in growing media by incorporating spent mushroom compost

Amending a peat-based growing medium with 10% v/v spent mushroom compost, a source of fungal chitin and other nutrients, prolonged the persistence of entomopathogenic fungi (Metarhizium brunneum Petsch and Beauveria bassiana (Balsamo) Vuillemin; Hypocreales: Clavicipitaceae). This resulted in improved efficacy of M. brunneum against black vine weevil, Otiorhynchus sulcatus F. (Coleoptera: Curculionidae) larvae compared with using inoculum without spent mushroom compost. B. bassiana only controlled larvae when used in combination with spent mushroom compost (75?±?7% reduction in live larvae). Mixing entomopathogenic fungal inoculum with spent mushroom compost and growing medium was as effective in controlling black vine weevil larvae as using spent mushroom compost colonised with M. brunneum or B. bassiana in the growing medium (80?±?12% reduction in live larvae). The former method is preferable since it does not require production and storage of colonised spent mushroom compost, or registration of new substrate formulations of M. brunneum or B. bassiana.     

The nutritional value of feeding on crops: Diets of vervet monkeys in a humanized landscape

Anthropogenic influences have dramatically altered the environments with which primates interact. In particular, the introduction of anthropogenic food sources to primate groups has implications for feeding behaviour, social behaviour, activity budgets, demography and life history. While the incorporation of anthropogenic foods can be beneficial to primates in a variety of nutritional ways including increased energetic return, they also carry risks associated with proximity to humans, such as risk of being hunted, disease risk and risk of conflict. Given such risks, we initiated a 3‐year study where we sought to understand the underlying nutritional motivations for anthropogenic food resource use by vervet monkeys (Cercopithecus aethiops) in the humanized matrix surrounding the Nabugabo Field Station in central Uganda. Feeding effort, defined as proportion of feeding scans spent on anthropogenic food, was not associated with ripe fruit availability nor with crop availability as determined by phenological monitoring. Likewise, there was no difference in the protein, fibre, or lipid composition of crop food items compared to wild food items. Individuals spent less time feeding overall in months over the 3 years with a higher proportion of time spent feeding on crop foods, suggesting a potential benefit in terms of accessibility (reduction in the proportion of activity budget devoted to feeding).     

Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1

The oral S1PR1 agonist ponesimod demonstrated substantial efficacy in a phase II clinical trial of psoriasis. Unfortunately, systemic side effects were observed, which included lymphopenia and transient bradycardia. We sought to develop a topical soft-drug S1PR1 agonist with an improved therapeutic index. By modifying ponesimod, we discovered an ester series of S1PR agonists. To increase metabolic instability in plasma we synthesised esters described as specific substrates for paraoxonase and butyrylcholinesterases, esterases present in human plasma.     

Integrating thin film microfluidics in developing a concise synthesis of DGJNAc: A potent inhibitor of α-N-acetylgalctosaminidases

A simple synthesis, which utilizes a thin film microfluidic reactor for a problematic step, of a potent inhibitor of α-N-acetylhexosaminidases, DGJNAc, has been developed.     

Mechanisms,resources, and background conditions

Distinguishing mechanistic components from mere causally relevant background conditions remains a difficulty for mechanistic accounts of explanation. By distinguishing resources from mechanical parts, I argue that we can more effectively draw this boundary. Further, the distinction makes obvious that there are distinctive resource explanations which are not captured by a traditional part-based mechanistic account. While this suggests a straightforward extension of the mechanistic model, I argue that incorporating resources and resource explanations requires moving beyond the purely local account of levels that some mechanists advocate.