Bee species visiting Medicago sativa differ in pollen deposition curves with consequences for gene flow.

PREMISE: Pollinator foraging behavior can influence pollen dispersal and gene flow. In many plant species a pollinator trips a flower by applying pressure to release its sexual organs. We propose that differences in tripping rate among grooming pollinators could generate distinct pollen deposition curves, the pattern of pollen deposition over successive flowers visited. This study compares the pollen deposition curves of two grooming pollinators, a social bumble bee and a solitary leafcutting bee, with distinct tripping rates on Medicago sativa flowers. We predict a steeper deposition curve for pollen moved by leafcutting bees, the pollinator with the higher tripping rate. METHODS: Medicago sativa plants carrying a gene (GUS) whose product is easily detected by staining, were used as pollen donors. After visiting the GUS plants, a bee was released on a linear array of conventional M. sativa plants. The number of GUS pollen grains deposited over successive flowers visited or over cumulative distances was examined. Distinct mixed effect Poisson regression models, illustrating different rates of decay in pollen deposition, were fitted to the pollen data for each bee species. RESULTS: Pollen decay was steeper for leafcutting bees relative to bumble bees for both models of flowers visited and cumulative distance, as predicted by their higher tripping rate. CONCLUSIONS: This is the first report of a difference in pollen deposition curves between two bee species, both grooming pollinators. Such differences could lead to distinct impacts of bee species on gene flow, genetic differentiation, introgression, and ultimately speciation.

Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1.

Herein, we disclose a new series of TYK2/ JAK1 inhibitors based upon a 3.1.0 azabicyclic substituted pyrimidine scaffold. We illustrate the use of structure-based drug design for the initial design and subsequent optimization of this series of compounds. One advanced example 19 met program objectives for potency, selectivity and ADME, and demonstrated oral activity in the adjuvant-induced arthritis rat model.

Intraguild predation decreases predator fitness with potentially varying effects on pathogen transmission in a herbivore host.

Predators and pathogens often regulate the population dynamics of their prey or hosts. When species interact with both their predators and their pathogens, understanding each interaction in isolation may not capture the system's dynamics. For instance, predators can influence pathogen transmission via consumptive effects, such as feeding on infected prey, or non-consumptive effects, such as changing the prey's susceptibility to infection. A prey species' infection status can, in turn, influence predator's choice of prey and have negative fitness consequences for the predator. To test how intraguild predation (IGP), when predator and pathogen share the same prey/host, affects pathogen transmission, predator preference, and predator fitness, we conducted a series of experiments using a crop pest (Pseudoplusia includens), a generalist predator (Podisus maculiventris), and a generalist pathogen (Autographa californica multicapsid nuclear polyhedrovirus, AcMNPV). Using a field experiment, we quantified the effects of consumptive and non-consumptive predators on pathogen transmission. We found that a number of models provided similar fits to the data. These models included null models showing no effects of predation and models that included a predation effect. We also found that predators consumed infected prey more often when choosing between live infected or live healthy prey. Infected prey also reduced predator fitness. Developmental times of predators fed infected prey increased by 20% and longevity decreased by 45%, compared with those that consumed an equivalent number of non-infected prey. While this research shows an effect of the pathogen on intraguild predator fitness, we found no support that predators affected pathogen transmission.

Intraspecific variation in indirect plant-soil feedbacks influences a wetland plant invasion.

Plant-soil feedbacks (PSFs) influence plant competition via direct interactions with pathogens and mutualists or indirectly via apparent competition/mutualisms (i.e., spillover to co-occurring plants) and soil legacy effects. It is currently unknown how intraspecific variation in PSFs interacts with the environment (e.g., nutrient availability) to influence competition between native and invasive plants. We conducted a fully crossed multi-factor greenhouse experiment to determine the effects of Phragmites australis rhizosphere soil biota, interspecific competition, and nutrient availability on biomass of replicate populations from one native and two invasive lineages of common reed (P. australis) and a single lineage of native smooth cordgrass (Spartina alterniflora). Harmful soil biota consistently dominated PSFs involving all three P. australis lineages, reducing biomass by 10%. Indirect PSFs (i.e., soil biota spillover) from the two invasive P. australis lineages reduced S. alterniflora biomass by 7%, whereas PSFs from the native P. australis lineage increased S. alterniflora biomass by 6%. Interestingly, interspecific competition and PSFs interacted to weaken their respective impacts on S. alterniflora, whereas they exerted synergistic negative effects on P. australis. Phragmites australis soil biota decreased S. alterniflora biomass when grown alone (i.e., a soil legacy), but increased S. alterniflora biomass when grown with P. australis, suggesting that P. australis recruits harmful generalist soil biota or facilitates S. alterniflora via spillover (i.e., apparent mutualism). Soil biota also reduced interspecific competition impacts on S. alterniflora, although it remained competitively inferior to P. australis across all treatments. Competitive interactions and responses to nutrients did not differ among P. australis lineages, indicating that interspecific competition and nutrient deposition may not be key drivers of P. australis invasion in North America. Although soil biota, interspecific competition, and nutrient availability appear to have no direct impact on the success of invasive P. australis lineages in North America, intraspecific lineage variation in indirect spillover and soil legacies from P. australis occur and may have important implications for co-occurring native species and restoration of invaded habitats. Our study integrates multiple factors linked to plant invasions, highlighting that indirect interactions are likely commonplace in influencing plant community dynamics and invasion success and impacts.

Cannibalism and Infectious Disease: Friends or Foes?

Cannibalism occurs in a majority of both carnivorous and noncarnivorous animal taxa from invertebrates to mammals. Similarly, infectious parasites are ubiquitous in nature. Thus, interactions between cannibalism and disease occur regularly. While some adaptive benefits of cannibalism are clear, the prevailing view is that the risk of parasite transmission due to cannibalism would increase disease spread and, thus, limit the evolutionary extent of cannibalism throughout the animal kingdom. In contrast, surprisingly little attention has been paid to the other half of the interaction between cannibalism and disease, that is, how cannibalism affects parasites. Here we examine the interaction between cannibalism and parasites and show how advances across independent lines of research suggest that cannibalism can also reduce the prevalence of parasites and, thus, infection risk for cannibals. Cannibalism does this by both directly killing parasites in infected victims and by reducing the number of susceptible hosts, often enhanced by the stage-structured nature of cannibalism and infection. While the well-established view that disease should limit cannibalism has held sway, we present theory and examples from a synthesis of the literature showing how cannibalism may also limit disease and highlight key areas where conceptual and empirical work is needed to resolve this debate.

Synthetic approaches to the 2014 new drugs.

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition and also serve as leads for designing future new drugs. This annual review covers the synthesis of thirty-seven NCEs that were approved for the first time in 2014 and one drug which was approved in 2013 and was not covered in a previous edition of this review.

Synthetic approaches to the 2013 new drugs.

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition and also serve as leads for designing future new drugs. This annual review covers the synthesis of twenty-four NCEs that were approved for the first time in 2013 and two 2012 drugs which were not covered during the previous edition of this review.

Synthetic approaches to the 2012 new drugs.

New drugs introduced to the market every year represent a privileged structure for a particular biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of twenty-six NCEs that were launched or approved worldwide in 2012 and two additional drugs which were launched at the end of 2011.

Synthetic Approaches to the New Drugs Approved During 2022.

In 2022, 23 new small molecule chemical entities were approved as drugs by the United States FDA, European Union EMA, Japan PMDA, and China NMPA. This review describes the synthetic approach demonstrated on largest scale for each new drug based on patent or primary literature. The synthetic routes highlight practical methods to construct molecules, sometimes on the manufacturing scale, to access the new drugs. Ten additional drugs approved in 2021 and one approved in 2020 are included that were not covered in the previous year's review.

Design and Discovery of a Potent and Selective Inhibitor of Integrin αvß1.

Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvß1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, in silico modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvß1 relative to several other integrin isoforms measured. Azabenzimidazolone 25 demonstrated antifibrotic efficacy in an in vivo rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvß1 inhibition.

Synthetic approaches to the 2011 new drugs.

New drugs are introduced to the market every year and each represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of 26 NCEs that were launched in the world in 2011.

Macrocyclic Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonists.

Macrocyclic retinoic acid receptor-related orphan receptor C2 (RORC2) inverse agonists have been designed with favorable properties for topical administration. Inspired by the unanticipated bound conformation of an acyclic sulfonamide-based RORC2 ligand from cocrystal structure analysis, macrocyclic linker connections between the halves of the molecule were explored. Further optimization of analogues was accomplished to maximize potency and refine physiochemical properties (MW, lipophilicity) best suited for topical application. Compound 14 demonstrated potent inhibition of interleukin-17A (IL-17A) production by human Th17 cells and in vitro permeation through healthy human skin achieving high total compound concentration in both skin epidermis and dermis layers.

Synthetic Approaches to the New Drugs Approved During 2021.

Each year, new drugs are introduced to the market, representing structures that have affinity for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and serve as potential leads for the design of future medicines. This annual review is part of a continuing series highlighting the most likely process-scale synthetic approaches to 35 NCEs that were first approved anywhere in the world during 2021.

Synthetic approaches to the 2010 new drugs.

New drugs are introduced to the market every year and each represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of 15 NCEs that were launched anywhere in the world in 2010.

Synthetic Approaches to the New Drugs Approved During 2020.

New drugs introduced to the market are privileged structures that have affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates (ADCs), provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This Review is part of a continuing series presenting the most likely process-scale synthetic approaches to 44 new chemical entities approved for the first time anywhere in the world during 2020.

Discovery of a Series of Pyrimidine Carboxamides as Inhibitors of Vanin-1.

A diaryl ketone series was identified as vanin-1 inhibitors from a high-throughput screening campaign. While this novel scaffold provided valuable probe 2 that was used to build target confidence, concerns over the ketone moiety led to the replacement of this group. The successful replacement of this moiety was achieved with pyrimidine carboxamides derived from cyclic secondary amines that were extensively characterized using biophysical and crystallographic methods as competitive inhibitors of vanin-1. Through optimization of potency and physicochemical and ADME properties, and guided by co-crystal structures with vanin-1, 3 was identified with a suitable profile for advancement into preclinical development.

Synthetic approaches to the 2009 new drugs.

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the syntheses of 21 NCEs marketed in 2009.

Synthetic Approaches to the New Drugs Approved during 2019.

New drugs introduced to the market are privileged structures having affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This review is part of a continuing series presenting the most likely process-scale synthetic approaches to 40 NCEs approved for the first time anywhere in the world in 2019.

2,3-Bis(phenylsulfonyl)-1,3-butadiene as a reagent for the synthesis of the azatricyclic core of (+/-)-halichlorine.

An efficient stereocontrolled route to the azatricyclic core of an advanced halichlorine intermediate is described. Reaction of the oxime derived from 2-(oxo-cyclopentyl)acetic acid ethyl ester with 2,3-bis(phenylsulfonyl)-1,3-butadiene gives rise to a 7-oxa-1-azanorbornane cycloadduct in high yield. The formation of the bicyclic isoxazolidine arises from conjugate addition of the oxime onto the diene to afford a transient nitrone that then undergoes an intramolecular dipolar cycloaddition. Treatment of the cycloadduct with 5% Na/Hg results in reductive nitrogen-oxygen bond cleavage to furnish a spirocyclic piperidinone, which was further elaborated to an advanced intermediate employed in an earlier synthesis of halichlorine.

Phenotypic Selection on Flower Color and Floral Display Size by Three Bee Species.

Plants exhibit a wide array of floral forms and pollinators can act as agent of selection on floral traits. Two trends have emerged from recent reviews of pollinator-mediated selection in plants. First, pollinator-mediated selection on plant-level attractants such as floral display size is stronger than on flower-level attractant such as flower color. Second, when comparing plant species, distinct pollinators can exert different selection patterns on floral traits. In addition, many plant species are visited by a diverse array of pollinators but very few studies have examined selection by distinct pollinators. In the current study, we examined phenotypic selection on flower color and floral display size by three distinct bee species, the European honey bee, Apis mellifera, the common eastern bumble bee, Bombus impatiens, and the alfalfa leafcutting bee, Megachile rotundata, foraging on Medicago sativa. To estimate phenotypic selection by each bee species and for all bees combined simultaneously and on the same group of plants, we introduce a new method that combines pollinator visitation data to seed set and floral trait measurements data typical of phenotypic selection study. When comparing floral traits, all bee species selected on the number of racemes per stem and the number of stems per plant, two components of floral display size. However, only leafcutting bees selected on hue or flower color and only bumble bees selected on chroma or darkness of flowers. Selection on chroma occurred via correlational selection between chroma and number of open flowers per raceme and we examine how correlational selection may facilitate the evolution of flower color in plant populations. When comparing bee species, the three bee species exerted similar selection pattern on some floral traits but different patterns on other floral traits and differences in selection patterns were observed between flower-level and plant-level attractants. The trends detected were consistent with previous studies and we advocate the approach introduced here for future studies examining the impact of distinct pollinators on floral trait evolution.