Biology subjects

Bennett, J.

Publications and source records attributed to Bennett, J..

5 recordsLinked to original sources

bioRxiv2018

Rapid covalent-probe discovery by electrophile fragment screening

Covalent probes can display unmatched potency, selectivity and duration of action, however, their discovery is challenging. In principle, fragments that can irreversibly bind their target can overcome the low affinity that limits reversible fragment screening. Such electrophilic fragments were considered non-selective and were rarely screened. We hypothesized that mild electrophiles might overcome the selectivity challenge, and constructed a library of 993 mildly electrophilic fragments. We characterized this library by a new high-throughput thiol-reactivity assay and screened them against ten cysteine-containing proteins. Highly reactive and promiscuous fragments were rare and could be easily eliminated. By contrast, we found selective hits for most targets. Combination with high-throughput crystallography allowed rapid progression to potent and selective probes for two enzymes, the deubiquitinase OTUB2, and the pyrophosphatase NUDT7. No inhibitors were previously known for either. This study highlights the potential of electrophile fragment screening as a practical and efficient tool for covalent ligand discovery.

biochemistry↗

bioRxiv2018

Prioritize diversity or declining species? Trade-offs and synergies in spatial planning for the conservation of migratory birds

Stemming biodiversity loss requires strategic conservation guided by well-articulated and achievable targets, whether they be proactive (e.g., protect diverse places) or reactive (e.g., protect threatened species). Both types of targets can be effective, but there are trade-offs, especially for broadly-distributed ecosystems or taxa, such as migratory species, a group for which conservation has been challenged by limited knowledge of distributions throughout the annual cycle. We combined novel spatiotemporal distribution models with population trend data to first examine focal areas for the conservation of Neotropical migratory birds (n=112 species) during the non-breeding period in the Western Hemisphere based on a proactive approach (highest diversity) versus a reactive approach (strongest declines) to conservation. For the focal areas, we then assessed the extent of recent anthropogenic impact, protected area status and projected future changes in land cover using three shared socioeconomic pathways (Sustainability=SSP1, Business-as-usual=SSP2, Regional nationalism=SSP3). Spatial priorities were strikingly different when targeting areas of high species diversity, emphasizing southern Mexico and northern Central America, versus areas with more severe declines across species, emphasizing the Andean cordilleras of South America. Only a fraction of the non-breeding region (1.4%) met targets for diversity and decline, mostly in southern Central America. Current levels of protection were similar for the two targets. Areas prioritized to conserve high species diversity have experienced less recent anthropogenic impact than areas prioritized for decline but are predicted to experience more rapid land conversion to less suitable open, agricultural landscapes in the next three decades under both an SSP1 and SSP2 scenario. Only the SSP3 scenario projected similar conversion rates for the two targets. Our findings indicate how even within taxa, efficient conservation efforts will depend on the careful consideration of desired targets combined with reliable predictions about the locations and types of land cover change under alternative socioeconomic futures.

ecology↗

bioRxiv2018

Biodiversity on Indigenous lands equals that in protected areas

Declines in global biodiversity due to land conversion and habitat loss are driving a \"Sixth Mass Extinction\" and many countries currently fall short of meeting even nominal land protection targets to mitigate this crisis. Here, we quantify the potential contribution of Indigenous lands to biodiversity conservation using case studies of Australia, Brazil and Canada. Indigenous lands in each country are slightly more species rich than existing protected areas and, in Brazil and Canada, support more threatened species than existing protected areas or random sites. These results indicate that Indigenous lands and existing protected areas are similar in biodiversity. Enhanced partnerships between Indigenous communities and federal or state governments could help ameliorate current shortfalls in global biodiversity protection by facilitating protection for native species, helping to stem global biodiversity loss.

ecology↗

bioRxiv2018

Optimizing conservation of migratory species over their full annual cycle in the Western Hemisphere

Limited knowledge of the distribution, abundance, and habitat associations of migratory species introduces uncertainty about the most effective conservation actions. We used Neotropical migratory birds as a model group to evaluate contrasting approaches to land prioritization to support [≥]30% of the global abundances of 117 species throughout the annual cycle in the Western hemisphere. Conservation targets were achieved in 43% less land area in plans based on annual vs. weekly optimizations. Plans agnostic to population structure required comparatively less land area to meet targets, but at the expense of representation. Less land area was also needed to meet conservation targets when human-dominated lands were included rather than excluded from solutions. Our results point to key trade-offs between efforts minimizing the opportunity costs of conservation vs. those ensuring spatiotemporal representation of populations, and demonstrate a novel approach to the conservation of migratory species based on leading-edge abundance models and linear programming to identify portfolios of priority landscapes and inform conservation planners.

ecology↗

bioRxiv2018

AAK1 inhibits WNT signaling by promoting clathrin-mediated endocytosis of LRP6

{beta}-catenin-dependent WNT signal transduction governs normal development and adult tissue homeostasis. Inappropriate pathway activity mediates a vast array of human diseases, including bone density disorders, neurodegeneration and cancer. Although several WNT-directed therapeutics are in clinical trials, new targets, compounds and strategies are needed. We performed a gain-of-function screen of the human kinome to identify new druggable regulators of {beta}-catenin-dependent transcription. We found that over-expression of the AP2 Associated Kinase 1 (AAK1) strongly inhibited WNT signaling. Reciprocally, silencing of AAK1 expression or pharmacological inhibition of AAK1 kinase activity using a new, selective and potent small molecule inhibitor activated WNT signaling. This small molecule is a cell active dual AAK1/BMP2K inhibitor that represents the best available tool to study AAK1-dependent signaling pathways. We report that AAK1 and the WNT co-receptor LRP6 physically co-complex and that AAK1 promotes clathrin-mediated endocytosis of LRP6. Collectively, our data support a WNT-induced negative feedback loop mediated by AAK1-driven, clathrin-mediated endocytosis of LRP6.\n\nSummary StatementA gain-of-function screen of the human kinome revealed AAK1 as a negative regulator of WNT signaling. We show that AAK1 promotes clathrin-mediated endocytosis of LRP6, resulting in downregulation of WNT signaling. We use a new selective and potent AAK1/BMP2K small molecule probe to validate our findings.

cell biology↗