Identifying general reaction conditions by bandit optimization.

Reaction conditions that are generally applicable to a wide variety of substrates are highly desired, especially in the pharmaceutical and chemical industries1-6. Although many approaches are available to evaluate the general applicability of developed conditions, a universal approach to efficiently discover these conditions during optimizations is rare. Here we report the design, implementation and application of reinforcement learning bandit optimization models7-10 to identify generally applicable conditions by efficient condition sampling and evaluation of experimental feedback. Performance benchmarking on existing datasets statistically showed high accuracies for identifying general conditions, with up to 31% improvement over baselines that mimic state-of-the-art optimization approaches. A palladium-catalysed imidazole C-H arylation reaction, an aniline amide coupling reaction and a phenol alkylation reaction were investigated experimentally to evaluate use cases and functionalities of the bandit optimization model in practice. In all three cases, the reaction conditions that were most generally applicable yet not well studied for the respective reaction were identified after surveying less than 15% of the expert-designed reaction space.

Bayesian reaction optimization as a tool for chemical synthesis.

Reaction optimization is fundamental to synthetic chemistry, from optimizing the yield of industrial processes to selecting conditions for the preparation of medicinal candidates1. Likewise, parameter optimization is omnipresent in artificial intelligence, from tuning virtual personal assistants to training social media and product recommendation systems2. Owing to the high cost associated with carrying out experiments, scientists in both areas set numerous (hyper)parameter values by evaluating only a small subset of the possible configurations. Bayesian optimization, an iterative response surface-based global optimization algorithm, has demonstrated exceptional performance in the tuning of machine learning models3. Bayesian optimization has also been recently applied in chemistry4-9; however, its application and assessment for reaction optimization in synthetic chemistry has not been investigated. Here we report the development of a framework for Bayesian reaction optimization and an open-source software tool that allows chemists to easily integrate state-of-the-art optimization algorithms into their everyday laboratory practices. We collect a large benchmark dataset for a palladium-catalysed direct arylation reaction, perform a systematic study of Bayesian optimization compared to human decision-making in reaction optimization, and apply Bayesian optimization to two real-world optimization efforts (Mitsunobu and deoxyfluorination reactions). Benchmarking is accomplished via an online game that links the decisions made by expert chemists and engineers to real experiments run in the laboratory. Our findings demonstrate that Bayesian optimization outperforms human decisionmaking in both average optimization efficiency (number of experiments) and consistency (variance of outcome against initially available data). Overall, our studies suggest that adopting Bayesian optimization methods into everyday laboratory practices could facilitate more efficient synthesis of functional chemicals by enabling better-informed, data-driven decisions about which experiments to run.

Coupling-Condensation Strategy for the Convergent Synthesis of an Imidazole-Fused 2-Aminoquinoline NLRP3 Agonist.

The development of a convergent route to the NLRP3 (nucleotide-binding domain and leucine-rich repeat-containing protein 3) agonist BMS-986299 is reported. The synthesis relies on a key Miyaura borylation and a tandem Suzuki-Miyaura coupling between an iodoimidazole and an o-aminochloroarene, followed by acid-mediated cyclization to afford the aminoquinoline core. The subsequent Boc cleavage and regioselective acylation afford the target compound. Two routes to the iodoimidazole intermediate are presented, along with the synthesis of the o-aminochloroarene via Negishi coupling. The convergent six-step route leads to an 80% reduction in process mass intensity compared to the linear enabling synthesis.

A Multi-Objective Active Learning Platform and Web App for Reaction Optimization.

We report the development of an open-source experimental design via Bayesian optimization platform for multi-objective reaction optimization. Using high-throughput experimentation (HTE) and virtual screening data sets containing high-dimensional continuous and discrete variables, we optimized the performance of the platform by fine-tuning the algorithm components such as reaction encodings, surrogate model parameters, and initialization techniques. Having established the framework, we applied the optimizer to real-world test scenarios for the simultaneous optimization of the reaction yield and enantioselectivity in a Ni/photoredox-catalyzed enantioselective cross-electrophile coupling of styrene oxide with two different aryl iodide substrates. Starting with no previous experimental data, the Bayesian optimizer identified reaction conditions that surpassed the previously human-driven optimization campaigns within 15 and 24 experiments, for each substrate, among 1728 possible configurations available in each optimization. To make the platform more accessible to nonexperts, we developed a graphical user interface (GUI) that can be accessed online through a web-based application and incorporated features such as condition modification on the fly and data visualization. This web application does not require software installation, removing any programming barrier to use the platform, which enables chemists to integrate Bayesian optimization routines into their everyday laboratory practices.

An ecological perspective on 'plant carnivory beyond bogs': nutritional benefits of prey capture for the Mediterranean carnivorous plant Drosophyllum lusitanicum.

BACKGROUND AND AIMS: Little is known about the evolutionary and ecological drivers of carnivory in plants, particularly for those terrestrial species that do not occur in typical swamp or bog habitats. The Mediterranean endemic Drosophyllum lusitanicum (Drosophyllaceae) is one of very few terrestrial carnivorous plant species outside of Australia to occur in seasonally dry, fire-prone habitats, and is thus an ecological rarity. Here we assess the nutritional benefits of prey capture for D. lusitanicum under differing levels of soil fertility in situ. METHODS: We measured the total nitrogen and stable nitrogen and carbon isotope ratios of D. lusitanicum leaves, neighbouring non-carnivorous plant leaves, and groups of insect prey in three populations in southern Spain. We calculated trophic enrichment (ε15N) and estimated the proportion of prey-derived nitrogen (%Nprey) in D. lusitanicum leaves, and related these factors to soil chemistry parameters measured at each site. KEY RESULTS: In all three populations studied, D. lusitanicum plants were significantly isotopically enriched compared with neighbouring non-carnivorous plants. We estimated that D. lusitanicum gain ~36 %Nprey at the Puerto de Gáliz site, ~54 %Nprey at the Sierra Carbonera site and ~75 %Nprey at the Montera del Torero site. Enrichment in N isotope (ε15N) differed considerably among sites; however, it was not found to be significantly related to log10(soil N), log10(soil P) or log10(soil K). CONCLUSIONS: Drosophyllum lusitanicum individuals gain a significant nutritional benefit from captured prey in their natural habitat, exhibiting proportions of prey-derived nitrogen that are similar to those recorded for carnivorous plants occurring in more mesic environments. This study adds to the growing body of literature confirming that carnivory is a highly beneficial nutritional strategy not only in mesic habitats but also in seasonally dry environments, and provides insights to inform conservation strategies for D. lusitanicum in situ.

Utilizing Native Directing Groups: Synthesis of a Selective IKur Inhibitor, BMS-919373, via a Regioselective C-H Arylation.

BMS-919373 is a highly functionalized quinazoline under investigation as a selective, potent IKur current blocker. By utilizing the aminomethylpyridine side chain at C-4, a selective C-H functionalization at C-5 was invented, enabling the efficient synthesis of this molecule. The strategy of leveraging this inherent directing group allowed the synthesis of this complex heterocycle in only six steps from commodity chemicals. The scope of the C-H activation was further investigated, and the generality of the transformation across a series of bicyclic aromatic heterocycles was explored.

Ecological niche and bet-hedging strategies for Triodia (R.Br.) seed germination.

Background and Aims: Regeneration dynamics in many arid zone grass species are regulated by innate seed dormancy mechanisms and environmental cues (temperature, moisture and fire) that result in infrequent germination following rainfall. This study investigated bet-hedging strategies associated with dormancy and germination in arid zone Triodia species from north-west Australia, by assessing (1) the effects of the mechanical restriction imposed by the indehiscent floral bracts (i.e. floret) covering the seed and (2) the impact of dormancy alleviation on florets and cleaned seeds (i.e. florets removed) when germinated under water stress. Methods: The initial dormancy status and germination for six species were tested on intact florets and cleaned seeds, across temperatures (10-40 °C) with and without the fire-related stimulant karrikinolide (KAR1), and under alternating light or constant dark conditions. Physiological dormancy alleviation was assessed by wet/dry cycling florets over a period of 10 weeks, and germination was compared against untreated florets, and cleaned seeds across a water potential gradient between 0 and -1.5 MPa. Key Results: Florets restricted germination (<45 %) at all temperatures and, despite partial alleviation of physiological dormancy (wet/dry cycling for 8 weeks), intact florets germinated only at high water potentials. Cleaned seeds showed the highest germination (40-90 %) across temperatures when treated with KAR1, and germinated at much lower water potentials (-0.4 and -0.9 MPa). Triodia pungens was the most responsive to KAR1, with both seeds and florets responding, while for the remaining five species, KAR1 had a positive effect for seeds only. Conclusions: Only after seed dormancy was alleviated by removing florets and when KAR1 was applied did germination under water stress increase. This suggests that seeds of these Triodia species are cued to recruit following fire and during periods of high precipitation. Climate change, driven by large shifts in rainfall patterns, is likely to impact Triodia recruitment further in arid zone grasslands.

Direct Lewis Acid Catalyzed Conversion of Enantioenriched N-Acyloxazolidinones to Chiral Esters, Amides, and Acids.

The identification of Yb(OTf)3 through a multivariable high-throughput experimentation strategy has enabled a unified protocol for the direct conversion of enantioenriched N-acyloxazolidinones to the corresponding chiral esters, amides, and carboxylic acids. This straightforward and catalytic method has shown remarkable chemoselectivity for substitution at the acyclic N-acyl carbonyl for a diverse array of N-acyloxazolidinone substrates. The ionic radius of the Lewis acid catalyst was demonstrated as a key driver of catalyst performance that led to the identification of a robust and scalable esterification of a pharmaceutical intermediate using catalytic Y(OTf)3.

Improving Robustness: In Situ Generation of a Pd(0) Catalyst for the Cyanation of Aryl Bromides.

Conditions have been developed for the palladium-catalyzed cyanation of aryl bromides utilizing the air-stable XantPhos-PdCl2 precatalyst. By employing a trialkylamine as a reducing agent, the active Pd(0) species is generated in situ, alleviating the need to employ the air-sensitive Pd2(dba)3. Twenty-two substituted benzonitriles have been synthesized using this method.

Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation.

Many globular and natively disordered proteins can convert into amyloid fibrils. These fibrils are associated with numerous pathologies as well as with normal cellular functions, and frequently form during protein denaturation. Inhibitors of pathological amyloid fibril formation could be useful in the development of therapeutics, provided that the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibrils as templates, we have designed and characterized an all-D-amino-acid inhibitor of the fibril formation of the tau protein associated with Alzheimer's disease, and a non-natural L-amino-acid inhibitor of an amyloid fibril that enhances sexual transmission of human immunodeficiency virus. Our results indicate that peptides from structure-based designs can disrupt the fibril formation of full-length proteins, including those, such as tau protein, that lack fully ordered native structures. Because the inhibiting peptides have been designed on structures of dual-ß-sheet 'steric zippers', the successful inhibition of amyloid fibril formation strengthens the hypothesis that amyloid spines contain steric zippers.

Spatio-temporal water dynamics in mature Banksia menziesii trees during drought.

Southwest Australian Banksia woodlands are highly diverse plant communities that are threatened by drought- or temperature-induced mortality due to the region's changing climate. We examined water relations in dominant Banksia menziesii R. Br. trees using magnetic leaf patch clamp pressure (ZIM-) probes that allow continuous, real-time monitoring of leaf water status. Multiple ZIM-probes across the crown were complemented by traditional ecophysiological measurements. During summer, early stomatal downregulation of transpiration prevented midday balancing pressures from exceeding 2.5 MPa. Diurnal patterns of ZIM-probe and pressure chamber readings agreed reasonably well, however, ZIM-probes recorded short-term dynamics, which are impossible to capture using a pressure chamber. Simultaneous recordings of three ZIM-probes evenly spaced along leaf laminas revealed intrafoliar turgor gradients, which, however, did not develop in a strictly basi- or acropetal fashion and varied with cardinal direction. Drought stress manifested as increasing daily signal amplitude (low leaf water status) and occasionally as rising baseline at night (delayed rehydration). These symptoms occurred more often locally than across the entire crown. Microclimate effects on leaf water status were strongest in crown regions experiencing peak morning radiation (East and North). Extreme spring temperatures preceded the sudden death of B. menziesii trees, suggesting a temperature- or humidity-related tipping point causing rapid hydraulic failure as evidenced by collapsing ZIM-probe readings from an affected tree. In a warmer and drier future, increased frequency of B. menziesii mortality will result in significantly altered community structure and ecosystem function.

Spatiotemporal variation in ecophysiological traits align with high resolution niche modelling in the short-range banded ironstone endemic Aluta quadrata.

Defining plant ecophysiological responses across natural distributions enables a greater understanding of the niche that plants occupy. Much of the foundational knowledge of species' ecology and responses to environmental change across their distribution is often lacking, particularly for rare and threatened species, exacerbating management and conservation challenges. Combining high-resolution species distribution models (SDMs) with ecophysiological monitoring characterized the spatiotemporal variation in both plant traits and their interactions with their surrounding environment for the range-restricted Aluta quadrata Rye & Trudgen, and a common, co-occurring generalist, Eremophila latrobei subsp. glabra (L.S.Sm.) Chinnock., from the semi-arid Pilbara and Gascoyne region in northwest Western Australia. The plants reflected differences in gas exchange, plant health and plant water relations at sites with contrasting suitability from the SDM, with higher performance measured in the SDM-predicted high-suitability site. Seasonal differences demonstrated the highest variation across ecophysiological traits in both species, with higher performance in the austral wet season across all levels of habitat suitability. The results of this study allow us to effectively describe how plant performance in A. quadrata is distributed across the landscape in contrast to a common, widespread co-occurring species and demonstrate a level of confidence in the habitat suitability modelling derived from the SDM in predicting plant function determined through intensive ecophysiology monitoring programmes. In addition, the findings also provide a baseline approach for future conservation actions, as well as to explore the mechanisms underpinning the short-range endemism arid zone systems.

Limited efficacy of a commercial microbial inoculant for improving growth and physiological performance of native plant species.

Soil microbial inoculants are increasingly being explored as means to improve soil conditions to facilitate ecological restoration. In southwestern Western Australia, highly biodiverse Banksia woodland plant communities are increasingly threatened by various factors including climate change, land development and mining. Banksia woodland restoration is necessary to conserve this plant community. The use of microbial inoculation in Banksia woodland restoration has not yet been investigated. Here, we evaluated the efficacy of a commercial microbial inoculant (GOGO Juice, Neutrog Australia Pty Ltd) for improving the performance of 10 ecologically diverse Banksia woodland plant species in a pot experiment. Plants were subjected to one of two watering regimes (well-watered and drought) in combination with microbial inoculation treatments (non-inoculated and inoculated). Plants were maintained under these two watering treatments for 10 weeks, at which point plants in all treatments were subjected to a final drought period lasting 8 weeks. Plant performance was evaluated by plant biomass and allocation, gas exchange parameters, foliar carbon and nitrogen and stable isotope (δ15N and δ13C) compositions. Plant xylem sap phytohormones were analysed to investigate the effect of microbial inoculation on plant phytohormone profiles and potential relationships with other observed physiological parameters. Across all investigated plant species, inoculation treatments had small effects on plant growth. Further analysis within each species revealed that inoculation treatments did not result in significant biomass gain under well-watered or drought-stressed conditions, and effects on nitrogen nutrition and photosynthesis were variable and minimal. This suggests that the selected commercial microbial inoculant had limited benefits for the tested plant species. Further investigations on the compatibility between the microorganisms (present in the inoculant) and plants, timing of inoculation, viability of the microorganisms and concentration(s) required to achieve effectiveness, under controlled conditions, and field trials are required to test the feasibility and efficacy in actual restoration environments.

Enantioselective α-alkenylation of aldehydes with boronic acids via the synergistic combination of copper(II) and amine catalysis.

The enantioselective α-alkenylation of aldehydes has been accomplished using boronic acids via the synergistic combination of copper and chiral amine catalysis. The merger of two highly utilized and robust catalytic systems has allowed for the development of a mild and operationally trivial protocol for the direct formation of α-formyl olefins employing common building blocks for organic synthesis.

Patterns of salivary analytes provide diagnostic capacity for distinguishing chronic adult periodontitis from health.

Salivary biomarker discovery requires identification of analytes with high discriminatory capacity to distinguish disease from health, including day-to-day variations that occur in analyte levels. In this study, seven biomarkers associated with inflammatory and tissue destructive processes of periodontal disease were investigated. In a prospective cohort study design, analyte expression levels were determined in unstimulated whole saliva samples collected on multiple occasions from 30 healthy adults (i.e., orally and systemically) and 50 chronic adult periodontitis patients. Salivary levels of IL-1ß, IL-6, MMP-8, and albumin were significantly elevated (5.4 to 12.6X) and levels of IFNα were consistently lower (8.7X) in periodontitis patients compared with the daily variation observed in healthy adults. ROC analyses of IL-1ß, IL-6 and MMP-8 yielded areas under the curves of 0.963-0.984 for discriminating periodontitis from health. These results demonstrate that levels of salivary bioanalytes of patients who have periodontitis are uniquely different from normal levels found in healthy subjects, and a panel consisting of IL-1ß, MMP-8 and IL-6 shows particular diagnostic potential.

Seeds of Brassicaceae weeds have an inherent or inducible response to the germination stimulant karrikinolide.

BACKGROUND AND AIMS: Karrikinolide (KAR(1)) is a smoke-derived chemical that can trigger seeds to germinate. A potential application for KAR(1) is for synchronizing the germination of weed seeds, thereby enhancing the efficiency of weed control efforts. Yet not all species germinate readily with KAR(1), and it is not known whether seemingly non-responsive species can be induced to respond. Here a major agronomic weed family, the Brassicaceae, is used to test the hypothesis that a stimulatory response to KAR(1) may be present in physiologically dormant seeds but may not be expressed under all circumstances. METHODS: Seeds of eight Brassicaceae weed species (Brassica tournefortii, Raphanus raphanistrum, Sisymbrium orientale, S. erysimoides, Rapistrum rugosum, Lepidium africanum, Heliophila pusilla and Carrichtera annua) were tested for their response to 1 µm KAR(1) when freshly collected and following simulated and natural dormancy alleviation, which included wet-dry cycling, dry after-ripening, cold and warm stratification and a 2 year seed burial trial. KEY RESULTS: Seven of the eight Brassicaceae species tested were stimulated to germinate with KAR(1) when the seeds were fresh, and the remaining species became responsive to KAR(1) following wet-dry cycling and dry after-ripening. Light influenced the germination response of seeds to KAR(1), with the majority of species germinating better in darkness. Germination with and without KAR(1) fluctuated seasonally throughout the seed burial trial. CONCLUSIONS: KAR(1) responses are more complex than simply stating whether a species is responsive or non-responsive; light and temperature conditions, dormancy state and seed lot all influence the sensitivity of seeds to KAR(1), and a response to KAR(1) can be induced. Three response types for generalizing KAR(1) responses are proposed, namely inherent, inducible and undetected. Given that responses to KAR(1) were either inherent or inducible in all 15 seed lots included in this study, the Brassicaceae may be an ideal target for future application of KAR(1) in weed management.

Seed encrusting with salicylic acid: A novel approach to improve establishment of grass species in ecological restoration.

To achieve global ambitions in large scale ecological restoration, there is a need for approaches that improve the efficiency of seed-based interventions, particularly in overcoming the bottleneck in the transition from germination to seedling establishment. In this study, we tested a novel seed-based application of the plant stress modulator compound salicylic acid as a means to reduce seedling losses in the seed-to-seedling phase. Seed coating technology (encrusting) was developed as a precursor for optimising field sowing for three grass species commonly used in restoration programs, Austrostipa scabra, Microlaena stipoides, and Rytidosperma geniculatum. Salicylic acid (SA, 0.1mM) was delivered to seeds via imbibition and seed encrusting. The effects of SA on seed germination were examined under controlled water-limited conditions (drought resilience) in laboratory setting and on seed germination, seedling emergence, seedling growth and plant survival in field conditions. Salicylic acid did not impact germination under water stress in controlled laboratory conditions and did not affect seedling emergence in the field. However, seedling survival and growth were improved in plants grown from SA treated seeds (imbibed and encrusted) under field conditions. When SA delivery methods of imbibing and coating were compared, there was no significant difference in survival and growth, showing that seed coating has potential to deliver SA. Effect of intraspecific competition as a result of seedling density was also considered. Seedling survival over the dry summer season was more than double at low seedling density (40 plants/m2) compared to high seedling density (380 plants/m2). Overall, adjustment of seeding rate according to expected emergence combined with the use of salicylic acid via coating could improve seed use efficiency in seed-based restoration.

Global change impacts on arid zone ecosystems: Seedling establishment processes are threatened by temperature and water stress.

Recruitment for many arid-zone plant species is expected to be impacted by the projected increase in soil temperature and prolonged droughts associated with global climate change. As seed dormancy is considered a strategy to avoid unfavorable conditions, understanding the mechanisms underpinning vulnerability to these factors is critical for plant recruitment in intact communities, as well as for restoration efforts in arid ecosystems. This study determined the effects of temperature and water stress on recruitment processes in six grass species in the genus Triodia R.Br. from the Australian arid zone. Experiments in controlled environments were conducted on dormant and less-dormant seeds at constant temperatures of 25°C, 30°C, 35°C, and 40°C, under well-watered (Ψsoil = -0.15 MPa) and water-limited (Ψsoil = -0.35 MPa) conditions. Success at three key recruitment stages-seed germination, emergence, and survival-and final seed viability of ungerminated seeds was assessed. For all species, less-dormant seeds germinated to higher proportions under all conditions; however, subsequent seedling emergence and survival were higher in the more dormant seed treatment. An increase in temperature (35-40°C) under water-limited conditions caused 95%-100% recruitment failure, regardless of the dormancy state. Ungerminated seeds maintained viability in dry soil; however, when exposed to warm (30-40°C) and well-watered conditions, loss of viability was greater from the less-dormant seeds across all species. This work demonstrates that the transition from seed to established seedling is highly vulnerable to microclimatic constraints and represents a critical filter for plant recruitment in the arid zone. As we demonstrate temperature and water stress-driven mortality between seeds and established seedlings, understanding how these factors influence recruitment in other arid-zone species should be a high priority consideration for management actions to mitigate the impacts of global change on ecosystem resilience. The knowledge gained from these outcomes must be actively incorporated into restoration initiatives.

Initiating pedogenesis of magnetite tailings using Lupinus angustifolius (narrow-leaf lupin) as an ecological engineer to promote native plant establishment.

Mine tailings pose physical and chemical challenges for plant establishment. Our aim was to learn from natural processes in long-term soil and ecosystem development to use tailings as novel parent materials and pioneer ecological-engineering plant species to ameliorate extreme conditions of tailings, and facilitate the establishment of subsequent native plants. A glasshouse trial was conducted using magnetite tailings containing various amendments, investigating the potential of the nitrogen (N)-fixing, non-native pioneer species Lupinus angustifolius (Fabaceae), narrow-leaf lupin, as a potential eco-engineer to promote soil formation processes, and whether amendment type or the presence of pioneer vegetation improved the subsequent establishment and growth of 40 species of native plants. We found that L. angustifolius eco-engineered the mine tailings, by enhancing the N status of tailings and mobilising primary mineral P into organic P via a carboxylate-exudation strategy, thereby enabling subsequent growth of native species. The substantial increases of the soil organic P (from ca. 10 to 150 mg kg-1) pool and organo-bound Al minerals (from 0 to 2 mg kg-1) were particularly evident, indicating the initiation of pedogenesis in mine tailings. Our findings suggest that the annual legume L. angustifolius has eco-engineering potential on mine tailings through N-fixation and P-mobilisation, promoting the subsequent growth of native plants. We proposed Daviesia (Fabaceae) species as native species alternatives for the non-native L. angustifolius in the Western Australian context. Our findings are important for restoration practitioners tasked with mine site restoration in terms of screening pioneer eco-engineering plant species, where native plants are required to restore after mine operations.