RESUMO
New Zealand's public insurer for natural hazards, 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 over time and space. The percent change between projected and past damages-the climate change signal-ranges between an increase of 7%-8% in liabilities for the period 2020 to 2040, and between 9% and 25% higher for the period 2080 to 2100. We also provide detail caveats as towhy 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 weatherrelated.
Assuntos
Mudança Climática , Clima Extremo , Previsões , Nova Zelândia , Tempo (Meteorologia)RESUMO
The design, synthesis and assessment of ß-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 Aß 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-Aß 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.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/análise , Antioxidantes/farmacologia , Carbolinas/farmacologia , Inibidores da Colinesterase/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/biossíntese , Antioxidantes/síntese química , Antioxidantes/química , Carbolinas/síntese química , Carbolinas/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Colinesterases/metabolismo , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Sulfonamide linker-based inhibitors with extended linear structure were designed and synthesized with the aim of producing multifunctional agents against several processes involved in the pathology of Alzheimer's disease (AD). The potency of the compounds were assessed in the inhibition of Aß self-assembly (fibril and oligomer formation), in modulating cholinesterase (AChE, BuChE) activity, and scavenging free radicals. Several compounds exhibited promising Aß self-assembly and cholinesterase inhibition and in parallel, showed good free radical scavenging properties. The investigation of the scaffold described in this study resulted in the identification of three compounds (14, 19 and 26) as promising leads for the further design of multifunctional drug candidates for AD.
Assuntos
Inibidores da Colinesterase/química , Sequestradores de Radicais Livres/química , Sulfonamidas/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Sítios de Ligação , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Domínio Catalítico , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/uso terapêutico , Donepezila , Sequestradores de Radicais Livres/metabolismo , Sequestradores de Radicais Livres/uso terapêutico , Humanos , Indanos/química , Indanos/metabolismo , Simulação de Dinâmica Molecular , Piperidinas/química , Piperidinas/metabolismo , Ligação Proteica , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêuticoRESUMO
The design and application of an effective, new class of multifunctional small molecule inhibitors of amyloid self-assembly are described. Several compounds based on the diaryl hydrazone scaffold were designed. Forty-four substituted derivatives of this core structure were synthesized using a variety of benzaldehydes and phenylhydrazines and characterized. The inhibitor candidates were evaluated in multiple assays, including the inhibition of amyloid ß (Aß) fibrillogenesis and oligomer formation and the reverse processes, the disassembly of preformed fibrils and oligomers. Because the structure of the hydrazone-based inhibitors mimics the redox features of the antioxidant resveratrol, the radical scavenging effect of the compounds was evaluated by colorimetric assays against 2,2-diphenyl-1-picrylhydrazyl and superoxide radicals. The hydrazone scaffold was active in all of the different assays. The structure-activity relationship revealed that the substituents on the aromatic rings had a considerable effect on the overall activity of the compounds. The inhibitors showed strong activity in fibrillogenesis inhibition and disassembly, and even greater potency in the inhibition of oligomer formation and oligomer disassembly. Supporting the quantitative fluorometric and colorimetric assays, size exclusion chromatographic studies indicated that the best compounds practically eliminated or substantially inhibited the formation of soluble, aggregated Aß species, as well. Atomic force microscopy was also applied to monitor the morphology of Aß deposits. The compounds also possessed the predicted antioxidant properties; approximately 30% of the synthesized compounds showed a radical scavenging effect equal to or better than that of resveratrol or ascorbic acid.
Assuntos
Amiloide/antagonistas & inibidores , Antioxidantes/farmacologia , Hidrazonas/química , Hidrazonas/farmacologia , Relação Estrutura-Atividade , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/química , Compostos de Bifenilo/química , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Hidrazonas/síntese química , Microscopia de Força Atômica , Estrutura Molecular , Picratos/química , Superóxidos/químicaRESUMO
A series of compounds containing an α,ß-unsaturated carbonyl moiety, such as chalcones and coumarins were designed, synthesized and tested in a variety of assays to assess their potential as anti-Alzheimer's disease (AD) agents. The investigations included the inhibition of cholinesterases (AChE, BuChE), the inhibition of amyloid beta (Aß) self-assembly and the disassembly of preformed Aß oligomers. Several compounds showed excellent potential as multifunctional compounds for AD. Docking studies for 16 that performed well in all the assays gave a clear interpretation of various interactions in the gorge of AChE. Based on the results, the long-chain coumarin scaffold appears to be a promising structural template for further AD drug development.
Assuntos
Chalconas/química , Inibidores da Colinesterase/síntese química , Cumarínicos/química , Desenho de Fármacos , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Sítios de Ligação , Domínio Catalítico , Chalconas/síntese química , Chalconas/uso terapêutico , Inibidores da Colinesterase/química , Inibidores da Colinesterase/uso terapêutico , Cumarínicos/síntese química , Cumarínicos/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
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 IC50. Interestingly, the inhibitors identified from the screen do not inhibit phosphoprotein phosphatase 2A, a member of the serine/threonine phosphatase family that shares 43% sequence identity with the CaN active site. The pharmacophore model that we developed and validated in this work may help to accelerate the development of specific CaN inhibitors.
RESUMO
A potential therapeutic approach for Alzheimer's disease is to reduce the amount of toxic amyloid-beta oligomers and fibrillar amyloid plaques. In order to contribute to this approach the ability of small organofluorine compounds that were previously reported as successful inhibitors of fibrillogenesis to destabilize preformed fibrils of the amyloid-beta peptide was studied. These organofluorine molecules including chiral compounds were tested in vitro using standard methods based on Thioflavin-T (THT) fluorescence spectroscopy, atomic force microscopy (AFM) and Fourier-transform infrared spectroscopy (FTIR). It was observed that 5'-halogen substituted 3,3,3-trifluoromethyl-2-hydroxyl-(indol-3-yl)-propionic acid esters showed significant activity in the disassembly of the preformed fibrils. Since the same compounds were identified as strong fibrillogenesis inhibitors as well, this dual action makes them promising candidates for further drug development.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Flúor/metabolismo , Fluorescência , Microscopia de Força Atômica , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
A highly diastereoselective microwave-assisted three component synthesis of azabicyclo[2.2.2]octan-5-ones by a silicotungstic acid-catalyzed aza-Diels-Alder cyclization is described. The one-pot process involves the formation of the in situ generated Schiff base and its immediate cyclization with cyclohex-2-enone. The short reaction times, good yields and excellent diastereoselectivity make this annulation a practical and environmentally attractive method for the synthesis of the target compounds. Preliminary assays were carried out to determine the activity of the products in AChE as well as in amyloid ß fibrillogenesis inhibition.
Assuntos
Ácidos/química , Doença de Alzheimer/metabolismo , Compostos Aza/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Catálise , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Ciclização , Humanos , Micro-Ondas , Estrutura Molecular , EstereoisomerismoRESUMO
Climate change has already been affecting the regional suitability of grapevines with significant advances in phenology being observed globally in the last few decades. This has significant implications for New Zealand, where the wine industry represents a major share of the horticultural industry revenue. We modeled key crop phenological stages to better understand temporal and spatial shifts in three important regions of New Zealand (Marlborough, Hawke's Bay, Central Otago) for three dominant cultivars (Merlot, Pinot noir, and Sauvignon blanc) and one potential new and later ripening cultivar (Grenache). Simulations show an overall advance in flowering, véraison, and sugar ripeness by mid-century with more pronounced advance by the end of the century. Results show the magnitude of changes depends on the combination of greenhouse gas emission pathway, grape cultivar, and region. By mid-century, in the Marlborough region for instance, the four cultivars would flower 3 to 7 days earlier and reach sugar ripeness 7 to 15 days earlier depending on the greenhouse gas emission pathway. For growers to maintain the same timing of key phenological stages would require shifting planting of cultivars to more Southern parts of the country or implement adaptation strategies. Results also show the compression of time between flowering and véraison for all three dominant cultivars is due to a proportionally greater advance in véraison, particularly for Merlot in the Hawke's Bay and Pinot noir in Central Otago. Cross-regional analysis also raises the likelihood of the different regional cultivars ripening within a smaller window of time, complicating harvesting schedules across the country. However, considering New Zealand primarily accommodates cool climate viticulture cultivars, our results suggest that late ripening cultivars or extended ripening window in cooler regions may be advantageous in the face of climate change. These insights can inform New Zealand winegrowers with climate change adaptation options for their cultivar choices.
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The Problem: Global environmental stressors of human health include, but are not limited to, conflict, migration, war, natural disasters, climate change, pollution, trauma, and pandemics. In combination with other factors, these stressors influence physical and mental as well as reproductive health. Maternal stress is a known factor for adverse pregnancy outcomes such as preterm birth (PTB); however, environmental stressors are less well-understood in this context and the problem is relatively under-researched. According to the WHO, major Indian cities including New Delhi are among the world's 20 most polluted cities. It is known that maternal exposure to environmental pollution increases the risk of premature births and other adverse pregnancy outcomes which is evident in this population. Response to the Problem: Considering the seriousness of this problem, an international and interdisciplinary group of researchers, physicians, and organizations dedicated to the welfare of women at risk of adverse pregnancy outcomes launched an international program named Optimal Pregnancy Environment Risk Assessment (OPERA). The program aims to discover and disseminate inexpensive, accessible tools to diagnose women at risk for PTB and other adverse pregnancy outcomes due to risky environmental factors as early as possible and to promote effective interventions to mitigate these risks. OPERA has been supported by the Worldwide Universities Network, World Health Organization (WHO) and March of Dimes USA. Addressing the Problem: This review article addresses the influence of environmental stressors on maternal-fetal health focusing on India as a model population and describes the role of OPERA in helping local practitioners by sharing with them the latest risk prediction and mitigation tools. The consequences of these environmental stressors can be partially mitigated by experience-based interventions that build resilience and break the cycle of inter- and-transgenerational transmission. The shared knowledge and experience from this collaboration are intended to guide and facilitate efforts at the local level in India and other LMIC to develop strategies appropriate for the jurisdiction for improving pregnancy outcomes in vulnerable populations.
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Winter cover crops are sown in between main spring crops (e.g. cash and forage crops) to provide a range of benefits, including the reduction of nitrogen (N) leaching losses to groundwater. However, the extent by which winter cover crops will remain effective under future climate change is unclear. We assess variability and uncertainty of climate change effects on the reduction of N leaching by winter oat cover crops. Field data were collected to quantify ranges of cover crop above-ground biomass (7 to 10 t DM/ha) and N uptake (70 to 180 kg N/ha) under contrasting initial soil conditions. The data were also used to evaluate the APSIM-NextGen model (R2 from 62 to 96% and RMSEr from 7 to 50%), which was then applied to simulate cover crop and fallow conditions across four key agricultural locations in New Zealand, under baseline and future climate scenarios. Cover crops reduced N leaching risks for all location/scenario combinations but with large variability in space and time (e.g. 21 to 47% of fallow) depending on the climate change scenario. For instance, end-of-century estimates for northern (warmer) locations mostly showed non-significant effects of climate change on cover crop effectiveness and N leaching. In contrast for southern (colder) locations, there was a systematic increase in N leaching risks with climate change intensity despite a concomitant, but less than proportional, increase in cover crop effectiveness (up to ~5% of baseline) due to higher winter yields and N uptake. This implies that climate change may not only modify the geography of N leaching hotspots, but also the extent by which cover crops can locally reduce pollution risks, in some cases requiring complementary adaptive measures. The patchy- and threshold-nature of leaching events indicates that fine spatio-temporal resolutions are better suited to evaluate cover crop effectiveness under climate change.
Assuntos
Mudança Climática , Produtos Agrícolas , Agricultura , Nova Zelândia , Nitrogênio , SoloRESUMO
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.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Flúor/farmacologia , Propionatos/farmacologia , Peptídeos beta-Amiloides/metabolismo , Flúor/química , Humanos , Microscopia de Força Atômica , Propionatos/química , Espectrometria de Fluorescência , EstereoisomerismoRESUMO
One of the most promising methods of unveiling the pharmacology of marketed drugs is to screen them against new biological targets. In an attempt to find inhibitors for acetylcholinesterase (AChE), the Drug Bank Database and natural alkaloids with other known medicinal values were screened through a four-point pharmacophore built in this study. The development of the pharmacophore was based on a structurally diverse set of reported AChE inhibitors and was validated using a separate set of known inhibitors. The developed pharmacophore indicated that the presence of one H-acceptor motif, one H-donor motif, one positively charged group and one aromatic ring is needed for AChE inhibition. Selected hits were further investigated by molecular docking and in vitro testing. The assays revealed that the majority of these compounds showed reasonable inhibition, indicating that the developed pharmacophore can indeed reliably screen molecules for potential AChE inhibitors. It appears that several commercially available marketed drugs have further potential as AChE inhibitors. To extend our study the same compounds have been tested in the fibrillogenesis inhibition of amyloidß (Aß) peptide to explore the possibility of their dual-function therapeutic activity in Alzheimer's disease.
Assuntos
Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Desenho Assistido por Computador , Desenho de Fármacos , Alcaloides/química , Alcaloides/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Bases de Dados de Produtos Farmacêuticos , Humanos , Simulação de Acoplamento Molecular , TorpedoRESUMO
An undergraduate laboratory exercise is described to demonstrate the biochemical applications of electron paramagnetic resonance (EPR) spectroscopy. The ß93 cysteine residue of hemoglobin is labeled by the covalent binding of 3-maleimido-proxyl (5-MSL) and 2,2,5,5-tetramethyl-1-oxyl-3-methyl methanethiosulfonate (MTSL), respectively. The excess spin label is removed by gel-exclusion chromatography. Changes in the mobility of the reporter groups attached to the protein are monitored by EPR spectroscopy. While the spectral parameters of the rigidly attached 5-MSL provide information on the rotation of the whole spin labeled protein, MTSL bound by a more flexible linkage describes the local environment of the cysteine residue in the interior of the protein structure. Students can study the known crystal structure of hemoglobin in comparison to the results they obtain by analyzing the EPR spectra. Overall, the exercise introduces them to laboratory techniques such as protein labeling, gel filtration, EPR spectroscopy, as well as familiarizes them with the online Protein Data Bank as a research resource and PyMOL software as a structure visualization tool.
Assuntos
Currículo , Óxidos N-Cíclicos/química , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Hemoglobinas/química , Marcadores de Spin , Estudantes , Sítios de Ligação , Humanos , Modelos Moleculares , Ligação Proteica , Conformação ProteicaRESUMO
A broad group of structurally diverse small organofluorine compounds were synthesized and evaluated as inhibitors of ß-amyloid (Aß) self-assembly. The main goal was to generate a diverse library of compounds with the same functional group and to observe general structural features that characterize inhibitors of Aß oligomer and fibril formation, ultimately identifying structures for further focused inhibitor design. The common structural motifs in these compounds are CF(3) -C-OH and CF(3) -C-NH groups that were proposed to be binding units in our previous studies. A broad range of potential small-molecule inhibitors were synthesized by combining various carbocyclic and heteroaromatic rings with an array of substituents, generating a total of 106 molecules. The compounds were tested by standard methods such as thioflavin-T fluorescence spectroscopy for monitoring fibril formation, biotinyl Aß(1-42) single-site streptavidin-based assays for observing oligomer formation, and atomic force microscopy for morphological studies. These assays revealed a number of structures that show significant inhibition against either Aß fibril or oligomer formation. A detailed analysis of the structure-activity relationship of anti-fibril and -oligomer properties is provided. These data present further experimental evidence for the distinct nature of fibril versus oligomer formation and indicate that the interaction of the Aß peptide with chiral small molecules is not stereospecific in nature.