The benefits of in silico modeling to identify possible small-molecule drugs and their off-target interactions

Accepted for publication in a future issue of Future Medicinal Chemistry.The research into the use of small molecules as drugs continues to be a key driver in the development of molecular databases, computer-aided drug design software and collaborative platforms. The evolution of computational approaches is driven by the essential criteria that a drug molecule has to fulfill, from the affinity to targets to minimal side effects while having adequate absorption, distribution, metabolism, and excretion (ADME) properties. A combination of ligand- and structure-based drug development approaches is already used to obtain consensus predictions of small molecule activities and their off-target interactions. Further integration of these methods into easy-to-use workflows informed by systems biology could realize the full potential of available data in the drug discovery and reduce the attrition of drug candidates.Peer reviewe

CONTEMPORARY CHALLENGES FACING THE AUSTRALIAN JUDICIARY: AN EMPIRICAL INTERRUPTION

© 2019 Melbourne University Law Review. All rights reserved. The structures that regulate and support the Australian judiciary reflect and serve the traditional judicial values of independence, impartiality and the rule of law. Yet modern society places emphasis on an additional range of values that are expected of government and public institutions. These contemporary values include diversity, transparency, accountability and efficiency. Reforms to introduce regulatory and support structures that prioritise and facilitate these values in the judicial arm has proved challenging and, sometimes, contentious. This article reports on a survey of Australian judicial officers (n = 142) from across different jurisdictions. Participants were asked what they considered to be the most pressing challenges that face the various levels of the Australian judiciary, and whether the current regulatory and support environment achieves international best practice. The responses provide a nuanced picture of the state of the modern Australian judiciary as it appears to those within it. The study facilitates an understanding of the degree to which judicial officers are satisfied with the current legal and regulatory framework and, where they are dissatisfied, the nature of their disquiet. While not seeking to offer complete resolutions to the many issues canvassed, the data and analysis presented in this article serve as an interruption to regulatory and academic studies of the Australian judiciary, with the potential to illuminate and re-orientate the reform conversation in light of the judicial perspective on these various issues

THE INFLUENCE OF POTENTILLA REPTANS EXTRACTS ON THE PHYSIOLOGY OF AGROPYRON REPENS L. PLANTS

During the experiments, the influence of the aqueous extracts obtained from the leaves of Potentilla reptans on the physiology of Agropyron repens was studied.Agropyron repens is a plant of spontaneous flora of Romania, growing on cultivated and uncultivated soils and is one of the most harmful plants in agriculture.In areas where Potentilla reptans grows, couch grass growth is inhibited; this demonstrates that this plant can have an allelopatic action on the couch grass. During these experiments, aqueous extracts from the leaves of Potentilla reptans were used in concentrations of 5 g / l, 10 g / l, 15 g / l and 20 g / l. These extracts were used in order to water the Agropyron repens plants .The experiments focused on the intensity of leaf photosynthesis, leaf respiration intensity, transpiration intensity, leaf water content and chlorophyll content.In the variant with a concentration of 5 g / l, photosynthesis had much lower values, and at 20 g / l the process was reduced by about 50%.Regarding the respiration process, there was an increase, but only at high concentrations of the extracts (15 and 20 g / l). At low concentrations, the differences from the control were undetectable.In the control variant, the intensity of leaf transpiration had the lowest value. In the other variants, it has been found to intensify the transpiration process in proportion to the increase in the concentration of the extracts

Small molecule recognition of mephedrone using an anthracene molecular clip

This document is the Accepted Manuscript version of the following article: Kathryn Kellett, J. Hugh Broome, Mire Zloh, Stewart B. Kirton, Suzanne Fergus, Ute Gerhard, Jacqueline Stair, and Kar J. Wallace, ‘Small molecule recognition of mephedrone using an anthracene molecular clip’, Chemical Communications, Vol. 52(47): 7474-7477, 2016. The version of record is available online at DOI: http://dx.doi.org/10.1039/C6CC03404G. Published by the Royal Society of Chemistry.An anthracene molecular probe has been synthesised and shown to target mephedrone, a stimulant drug from the cathinone class of new psychoactive substances (NPS). A protocol has been developed to detect mephedrone via the probe using NMR spectroscopy in a simulated street sample containing two of the most common cutting agents, benzocaine and caffeine.Peer reviewedFinal Accepted Versio

Repeated ovarian stimulation with corifollitropin alfa in patients in a GnRH antagonist protocol: no concern for immunogenicity

BACKGROUND One injection of corifollitropin alfa replaces the first seven daily FSH injections in controlled ovarian stimulation (COS) cycles. Repeated treatment with therapeutic proteins may cause immune responses or hypersensitivity reactions. We assessed the immunogenicity and safety of corifollitropin alfa treatment in up to three COS cycles. METHODS In this multicentre, phase III uncontrolled trial, patients (>60 kg) started treatment with one injection of 150 µg corifollitropin alfa on cycle Day 2 or 3 of menses and 0.25 mg ganielix on stimulation Day 5 or 6. Primary outcome measures were antibody formation against corifollitropin alfa (using highly sensitive radioimmunoprecipitation assay), hypersensitivity reactions, local tolerance and adverse events (AEs). RESULTS First, second and third COS cycles were started by 682, 375 and 198 patients, respectively. No clinically relevant immunogenicity or drug-related hypersensitivity was observed. For 192 patients undergoing their third cycle a post-treatment blood sample was negative in the anti-corifollitropin antibody assay, resulting in an upper limit of the one-sided 95% confidence interval (CI) of 1.5%. Most frequent AEs were procedural pain (17.7%, 95% CI: 14.9–20.8%), headache (9.1%, 95% CI: 7.0–11.5%) and pelvic pain (7.6%, 95% CI: 5.7–9.9%). Cumulative ongoing pregnancy rate after three cycles, including frozen-thawed embryo transfer cycles and spontaneous pregnancies, was 61% (95% CI: 56–65%) after censoring for patients who discontinued. CONCLUSIONS Treatment with corifollitropin alfa can safely and effectively initiate and sustain ovarian stimulation during the first 7 days of COS in normal responder patients undergoing up to three treatment cycles, without concerns of immunogenicity.Robert J. Norman, Fernando Zegers-Hochschild, Bruno S. Salle, Jolanda Elbers, Esther Heijnen, Maya Marintcheva-Petrova, and Bernadette Mannaerts for the Trust Investigator

Evaluation of λ-carrageenan, CpG-ODN, glycine betaine, Spirulina platensis and ergosterol as elicitors for the control of Zymoseptoria tritici in wheat

Wheat crops are constantly challenged by the pathogen Zymoseptoria tritici responsible for Septoria tritici Blotch (STB) disease. The present study reports the identification of five biocontrol compounds (λ-carrageenan, CpG-ODN, glycine betaine, Spirulina platensis and ergosterol) for the protection of wheat against STB in order to offer new alternative tools to farmers for sustainable crop protection. Screening of elicitors of wheat defenses was carried out through a succession of experiments: biocidal in vitro tests enabled to check for any fungicidal activities; glasshouse experiments allowed to determine the efficacy of a given compound in protecting wheat against STB; qRT-PCR biomolecular tests investigated the relative expression of 23 defense genes in treated versus untreated plants. We therefore demonstrated that λ-carrageenan, CpG-ODN, glycine betaine, Spirulina platensis and ergosterol are potential elicitors of wheat defenses. Foliar treatments with these compounds conferred protection of wheat by up to approximately 70 % against Z. tritici under semi-controlled conditions and induced both SA- and/or JA-dependent signaling pathways in the plant. These findings contribute to extend the narrow list of potential elicitors of wheat defenses against Z. tritici

Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth.

Structural microtubule associated proteins (MAPs) stabilize microtubules, a property that was thought to be essential for development, maintenance and function of neuronal circuits. However, deletion of the structural MAPs in mice does not lead to major neurodevelopment defects. Here we demonstrate a role for MAP6 in brain wiring that is independent of microtubule binding. We find that MAP6 deletion disrupts brain connectivity and is associated with a lack of post-commissural fornix fibres. MAP6 contributes to fornix development by regulating axonal elongation induced by Semaphorin 3E. We show that MAP6 acts downstream of receptor activation through a mechanism that requires a proline-rich domain distinct from its microtubule-stabilizing domains. We also show that MAP6 directly binds to SH3 domain proteins known to be involved in neurite extension and semaphorin function. We conclude that MAP6 is critical to interface guidance molecules with intracellular signalling effectors during the development of cerebral axon tracts

Recombinant Vesicular Stomatitis Virus Vaccine Vectors Expressing Filovirus Glycoproteins Lack Neurovirulence in Nonhuman Primates

The filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with high mortality in humans and nonhuman primates. Among the most promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV) that expresses an individual filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). The main concern with all replication-competent vaccines, including the rVSV filovirus GP vectors, is their safety. To address this concern, we performed a neurovirulence study using 21 cynomolgus macaques where the vaccines were administered intrathalamically. Seven animals received a rVSV vector expressing the Zaire ebolavirus (ZEBOV) GP; seven animals received a rVSV vector expressing the Lake Victoria marburgvirus (MARV) GP; three animals received rVSV-wild type (wt) vector, and four animals received vehicle control. Two of three animals given rVSV-wt showed severe neurological symptoms whereas animals receiving vehicle control, rVSV-ZEBOV-GP, or rVSV-MARV-GP did not develop these symptoms. Histological analysis revealed major lesions in neural tissues of all three rVSV-wt animals; however, no significant lesions were observed in any animals from the filovirus vaccine or vehicle control groups. These data strongly suggest that rVSV filovirus GP vaccine vectors lack the neurovirulence properties associated with the rVSV-wt parent vector and support their further development as a vaccine platform for human use

Surface Plasmon Resonance Reveals a Different Pattern of Proinsulin Autoantibodies Concentration and Affinity in Diabetic Patients

Type 1 diabetes mellitus (DM) is characterized by autoimmune aggression against pancreatic beta cells resulting in absolute deficiency of insulin secretion. The first detectable sign of emerging autoimmunity during the preclinical asymptomatic period is the appearance of diabetes-related autoantibodies. In children at risk for type 1 DM, high-affinity Insulin autoantibodies reactive to proinsulin, are associated with diabetes risk. Autoantibodies are usually measured by radioligand binding assay (RBA) that provides quasi-quantitative values reflecting potency (product between concentration and affinity) of specific autoantibodies. Aiming to improve the characterization of the specific humoral immune response, we selected surface plasmon resonance (SPR) as an alternative method to measure proinsulin autoantibodies (PAA). This novel technology has allowed real time detection of antibodies interaction and kinetic analysis. Herein, we have employed SPR to characterize the PAA present in sera from 28 childhood-onset (mean age 8.31±4.20) and 23 adult-onset diabetic patients (≥65 years old, BMI<30) in terms of concentration and affinity. When evaluating comparatively samples from both groups, childhood-onset diabetic patients presented lower PAA concentrations and higher affinities (median 67.12×10−9 M and 3.50×107 M−1, respectively) than the adults (median 167.4×10−9 M and 0.84×107 M−1, respectively). These results are consistent with those from the reference method RBA (Standard Deviation score median 9.49 for childhood-onset group and 5.04 for adult-onset group) where the binding can be directly related to the intrinsic affinity of the antibody, suggesting that there is a different etiopathogenic pathway between both types of clinical presentation of the disease. This technology has shown to be a useful tool for the characterization of PAAs parameters as an alternative to radioimmunoassay, with high versatility and reproducibility associated to low occupational and environmental risk. However, this technology is not eligible for routine marker screening, but this is a powerful technique for a fine description of the thermodynamic parameters of antigen-antibody interaction