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Calcineurin (CaN) is a calcium/calmodulin-dependent serine/threonine phosphatase with a crucial role in cellular homeostasis. It is also the target of the Food and Drug Administration (FDA) approved immunosuppressant drugs FK506 and cyclosporine A. Recent work from our group and others indicated that an uncontrolled increase in CaN activity causes synaptic dysfunction and neuronal death in various models of neurodegenerative diseases associated with calcium dysregulation. Furthermore, pharmacological normalization of CaN activity can prevent disease progression in animal models. However, none of the FDA-approved CaN inhibitors bind CaN directly, leading to adverse side effects. The development of direct CaN inhibitors is required to reduce off-target effects, but its highly conserved active site and similar mechanism of action with other protein serine/threonine phosphatases impose a significant challenge. In this work, we developed a novel pharmacophore model to screen for CaN-specific inhibitors. Then, we performed a virtual screen for molecules having the pharmacophore model. We also show that the molecules identified in this screen can inhibit CaN with a low micromolar IC

New Zealand’s public insurer, the Earthquake Commission (EQC), provides residential insurance for some weather-related damage. Climate change and the expected increase in intensity and frequency of extreme weather-related events are likely to translate into higher damages and thus an additional financial liability for the EQC. We project future insured damages from extreme precipitation events associated with future projected climatic change. We first estimate the empirical relationship between extreme precipitation events and the EQC’s weather-related insurance claims based on a complete dataset of all claims from 2000 to 2017. We then use this estimated relationship, together with climate projections based on future greenhouse gases concentration scenarios from six different dynamically downscaled Regional Climate Models, to predict the impact of future extreme precipitation events on EQC liabilities for different time horizons up to the year 2100. Our results show predicted adverse impacts that vary — increase or decrease over time and space. The percent change between projected and past damages — the climate change signal — ranges between an increase of 7% and 8% higher in the period 2020 to 2040, and between 9% and 25% higher in the period 2080 to 2100. We also provide detail caveats as to why these quantities might be mis-estimated. The projected increase in the public insurer’s liabilities could also be used to inform private insurers, regulators, and policymakers who are assessing the future performance of both the public and private insurers that cover weather-related risks in the face of climatic change.

The design, synthesis and assessment of β-carboline core-based compounds as potential multifunctional agents against several processes that are believed to play a significant role in Alzheimer's disease (AD) pathology, are described. The activity of the compounds was determined in Aβ self-assembly (fibril and oligomer formation) and cholinesterase (AChE, BuChE) activity inhibition, and their antioxidant properties were also assessed. To obtain insight into the mode of action of the compounds, HR-MS studies were carried out on the inhibitor-Aβ complex formation and molecular docking was performed on inhibitor-BuChE interactions. While several compounds exhibited strong activities in individual assays, compound 14 emerged as a promising multi-target lead for the further structure-activity relationship studies.

The effect of enantiomeric trifluoromethyl-indolyl-acetic acid ethyl esters on the fibrillogenesis of Alzheimer's amyloid beta (Abeta) peptide is described. These compounds have been previously identified as effective inhibitors of the Abeta self-assembly in their racemic form. Thioflavin-T Fluorescence Spectroscopy and Atomic Force Microscopy were applied to assess the potency of the chiral target compounds. Both enantiomers showed significant inhibition in the in vitro assays. The potency of the enantiomeric inhibitors appeared to be very similar to each other suggesting the lack of the stereospecific binding interactions between these small molecule inhibitors and the Abeta peptide.

In the SU(3) Einstein-Yang-Mills system sequences of static spherically symmetric regular solutions and black hole solutions exist for both the SU(2) and the SO(3) embedding. We construct the lowest regular solutions of the SO(3) embedding, missed previously, and the corresponding black holes. The SO(3) solutions are classified according to their boundary conditions and the number of nodes of the matter functions. Both, the regular and the black hole solutions are unstable., Comment: LATEX, 16 pages, 5 figures

A significant enhancement (7–8 fold) of monophenolase activity by GA 3 was observed in de-embryonated half-seeds of wheat after 2 hr of imbibition. This early response to GA 3 (2–12 hr) was apparent only after lowering the endogenous levels of phytohormone in wheat half-seeds by leaching. Cycloheximide (CHI, 20 μg/ml) failed to inhibit GA 3 -stimulated (GA 3 , 10 μM) monophenolase activity. This ruled out the requirement of de novo protein synthesis for the hormone-regulated activity of monophenolase. Abscisic acid (100 μM) effectively stopped the GA 3 -mediated activation of monophenolase. Curiously, the early stimulatory response to GA 3 of monophenolase activity was completely mimicked by the administration of phosphate ions (Pi, 75 mM). Simultaneous addition of GA 3 and Pi to wheat half-seeds, however, showed no cumulative effect on the activation of monophenolase. Both GA 3 and Pi activated monophenolase exhibited altered molecular properties, in terms of shift in the pH optimum of enzyme activity towards alkalinity (pH 9.0) and relatively increased thermostability of the enzyme at 50°. Molecular sieving of the enzyme fraction on Sephacryl S-200 revealed a single molecular form of monophenolase ( M r 45 000) both in control and GA 3 -treated wheat half-seeds during the first 12 hr of imbibition. This indicated that the activation of monophenolase by GA 3 is due to some structural modification of the enzyme without its oligomerization. We envisage that the modulation of monophenolase activity by GA 3 during early imbibition of wheat half-seeds is a true primary response to the phytohormone.