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

Factors associated with foreign body infection in methicillin-resistant Staphylococcus aureus bacteremia

BackgroundWe aimed to compare patient characteristics, MRSA sequence types, and biofilm production of MRSA strains that did and did not cause a foreign body infection in patients with MRSA bloodstream infections (BSI)MethodsAll adult patients with MRSA BSI hospitalized in two hospitals were identified by clinical microbiology laboratory surveillance. Only patients who had at least one implanted foreign body during the episode of BSI were included.ResultsIn July 2018 - March 2022, of 423 patients identified with MRSA BSI, 118 (28%) had ≥1 foreign body. Among them, 51 (43%) had one or more foreign body infections. In multivariable analysis, factors associated with foreign body infection were history of MRSA infection in the last year (OR=4.7 [1.4-15.5], p=0.012) community-associated BSI (OR=68.1 [4.2-1114.3], p=0.003); surgical site infection as source of infection (OR=11.8 [2-70.4], p=0.007); presence of more than one foreign body (OR=3.4 [1.1-10.7], p=0.033); interval between foreign body implantation and infection <18 months (OR=3.3 [1.1-10], p=0.031); and positive blood culture ≥48h (OR=16.7 [4.3-65.7], p<0.001). The most prevalent sequence type was ST8 (39%), followed by ST5 (29%), and ST105 (20%) with no significant difference between patients with or without foreign body infection. Only 39% of MRSA isolates formed a moderate/strong biofilm. No significant difference was observed between patients with foreign body infection and those without foreign body infection. In multivariable analysis, subjects infected with a MRSA isolate producing moderate/strong in vitro biofilm were more likely to have a history of MRSA infection in the last year (OR=3.41 [1.23-9.43]), interval between foreign body implantation and MRSA BSI <18 months (OR=3.1 [1.05-9.2]) and ST8 (OR=10.64 [2-57.3]).ConclusionMost factors associated with foreign body infection in MRSA BSI were also characteristic of persistent infections. Biofilm-forming isolates were not associated with a higher risk of foreign-body infection but appeared to be associated with MRSA genetic lineage, especially ST8

A Global lake ecological observatory network (GLEON) for synthesising high-frequency sensor data for validation of deterministic ecological models

A Global Lake Ecological Observatory Network (GLEON; www.gleon.org) has formed to provide a coordinated response to the need for scientific understanding of lake processes, utilising technological advances available from autonomous sensors. The organisation embraces a grassroots approach to engage researchers from varying disciplines, sites spanning geographic and ecological gradients, and novel sensor and cyberinfrastructure to synthesise high-frequency lake data at scales ranging from local to global. The high-frequency data provide a platform to rigorously validate processbased ecological models because model simulation time steps are better aligned with sensor measurements than with lower-frequency, manual samples. Two case studies from Trout Bog, Wisconsin, USA, and Lake Rotoehu, North Island, New Zealand, are presented to demonstrate that in the past, ecological model outputs (e.g., temperature, chlorophyll) have been relatively poorly validated based on a limited number of directly comparable measurements, both in time and space. The case studies demonstrate some of the difficulties of mapping sensor measurements directly to model state variable outputs as well as the opportunities to use deviations between sensor measurements and model simulations to better inform process understanding. Well-validated ecological models provide a mechanism to extrapolate high-frequency sensor data in space and time, thereby potentially creating a fully 3-dimensional simulation of key variables of interest

Lake-size dependency of wind shear and convection as controls on gas exchange

High-frequency physical observations from 40 temperate lakes were used to examine the relative contributions of wind shear (u*) and convection (w*) to turbulence in the surface mixed layer. Seasonal patterns of u* and w* were dissimilar; u* was often highest in the spring, while w * increased throughout the summer to a maximum in early fall. Convection was a larger mixed-layer turbulence source than wind shear (u */w*-1 for lakes* and w* differ in temporal pattern and magnitude across lakes, both convection and wind shear should be considered in future formulations of lake-air gas exchange, especially for small lakes. © 2012 by the American Geophysical Union.Jordan S. Read, David P. Hamilton, Ankur R. Desai, Kevin C. Rose, Sally MacIntyre, John D. Lenters, Robyn L. Smyth, Paul C. Hanson, Jonathan J. Cole, Peter A. Staehr, James A. Rusak, Donald C. Pierson, Justin D. Brookes, Alo Laas, and Chin H. W

Design and Synthesis of Brain Penetrant Trypanocidal N-Myristoyltransferase Inhibitors

<i>N</i>-Myristoyltransferase (NMT) represents a promising drug target within the parasitic protozoa <i>Trypanosoma brucei</i> (<i>T. brucei</i>), the causative agent for human African trypanosomiasis (HAT) or sleeping sickness. We have previously validated <i>T. brucei</i> NMT as a promising druggable target for the treatment of HAT in both stages 1 and 2 of the disease. We report on the use of the previously reported DDD85646 (<b>1</b>) as a starting point for the design of a class of potent, brain penetrant inhibitors of <i>T. brucei</i> NMT

Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism

A key step in drug discovery, common to many disease areas, is preclinical demonstration of efficacy in a mouse model of disease. However, this demonstration and its translation to the clinic can be impeded by mouse-specific pathways of drug metabolism. Here we show that a mouse line extensively humanized for the cytochrome P450 gene superfamily (“8HUM”) can circumvent these problems. The pharmacokinetics, metabolite profiles and magnitude of drug-drug interactions of a test set of approved medicines were in much closer alignment with clinical observations than in wild-type mice. Infection with Mycobacterium tuberculosis, Leishmania donovani and Trypanosoma cruzi was well tolerated in 8HUM, permitting efficacy assessment. During such assessments, mouse-specific metabolic liabilities were bypassed while the impact of clinically relevant active metabolites and DDI on efficacy were well-captured. Removal of species differences in metabolism by replacement of wild-type mice with 8HUM therefore reduces compound attrition while improving clinical translation, accelerating drug discovery

Angiosperm symbioses with non-mycorrhizal fungal partners enhance N acquisition from ancient organic matter in a warming maritime Antarctic

In contrast to the situation in plants inhabiting most of the world’s ecosystems, mycorrhizal fungi are usually absent from roots of the only two native vascular plant species of maritime Antarctica, Deschampsia antarctica and Colobanthus quitensis. Instead, a range of ascomycete fungi, termed dark septate endophytes (DSEs), frequently colonise the roots of these plant species. We demonstrate that colonisation of Antarctic vascular plants by DSEs facilitates not only the acquisition of organic nitrogen as early protein breakdown products, but also as non-proteinaceous D-amino acids and their short peptides, accumulated in slowly-decomposing organic matter, such as moss peat. Our findings suggest that, in a warming maritime Antarctic, this symbiosis has a key role in accelerating the replacement of formerly dominant moss communities by vascular plants, and in increasing the rate at which ancient carbon stores laid down as moss peat over centuries or millennia are returned to the atmosphere as CO2.Additional co-authors: Richard D Bardgett, David W Hopkins and Davey L Jone

Discovery of Soft-Drug Topical Tool Modulators of Sphingosine-1-phosphate Receptor 1 (S1PR1)

In order to study the role of S1PRs in inflammatory skin disease, S1PR modulators are dosed orally and topically in animal models of disease. The topical application of S1PR modulators in these models may, however, lead to systemic drug concentrations, which can complicate interpretation of the observed effects. We set out to design soft drug S1PR modulators as topical tool compounds to overcome this limitation. A fast follower approach starting from the drug ponesimod allowed the rapid development of an active phenolic series of soft drugs. The phenols were, however, chemically unstable. Protecting the phenol as an ester removed the instability and provided a compound that is converted by enzymatic hydrolysis in the skin to the phenolic soft drug species. In simple formulations, topical dosing of these S1PR modulators to mice led to micromolar skin concentrations but no detectable blood concentrations. These topical tools will allow researchers to investigate the role of S1PR in skin, without involvement of systemic S1PR biology

Sperm Toolbox-A selection of small molecules to study human spermatozoa

Male contraceptive options and infertility treatments are limited, and almost all innovation has been limited to updates to medically assisted reproduction protocols and methods. To accelerate the development of drugs that can either improve or inhibit fertility, we established a small molecule library as a toolbox for assay development and screening campaigns using human spermatozoa. We have profiled all compounds in the Sperm Toolbox in several automated high-throughput assays that measure stimulation or inhibition of sperm motility or the acrosome reaction. We have assayed motility under non-capacitating and capacitating conditions to distinguish between pathways operating under these different physiological states. We also assayed cell viability to ensure any effects on sperm function are specific. A key advantage of our studies is that all compounds are assayed together in the same experimental conditions, which allows quantitative comparisons of their effects in complementary functional assays. We have combined the resulting datasets to generate fingerprints of the Sperm Toolbox compounds on sperm function. The data are included in an on-line R-based app for convenient querying.</p