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  • 1
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 47 ( 2020-11-24), p. 29937-29947
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 47 ( 2020-11-24), p. 29937-29947
    Abstract: Analysis of the presynaptic action potential’s (AP syn ) role in synaptic facilitation in hippocampal pyramidal neurons has been difficult due to size limitations of axons. We overcame these size barriers by combining high-resolution optical recordings of membrane potential, exocytosis, and Ca 2+ in cultured hippocampal neurons. These recordings revealed a critical and selective role for K v 1 channel inactivation in synaptic facilitation of excitatory hippocampal neurons. Presynaptic K v 1 channel inactivation was mediated by the K v β1 subunit and had a surprisingly rapid onset that was readily apparent even in brief physiological stimulation paradigms including paired-pulse stimulation. Genetic depletion of K v β1 blocked all broadening of the AP syn during high-frequency stimulation and eliminated synaptic facilitation without altering the initial probability of vesicle release. Thus, using all quantitative optical measurements of presynaptic physiology, we reveal a critical role for presynaptic K v channels in synaptic facilitation at presynaptic terminals of the hippocampus upstream of the exocytic machinery.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
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  • 2
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 15 ( 2022-04-12)
    Abstract: Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub ( https://covid19forecasthub.org/ ) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
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  • 3
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 375, No. 6586 ( 2022-03-18), p. 1275-1281
    Abstract: A widespread adaptive change in antiherbivore response is seen in a common plant species in urban environments across 160 cities.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2022
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  • 4
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 378, No. 6623 ( 2022-12-02)
    Abstract: Madagascar is one of the world’s foremost biodiversity hotspots. Its unique assemblage of plants, animals, and fungi—the majority of which evolved on the island and occur nowhere else—is both diverse and threatened. After human arrival, the island’s entire megafauna became extinct, and large portions of the current flora and fauna may be on track for a similar fate. Conditions for the long-term survival of many Malagasy species are not currently met because of multiple anthropogenic threats. ADVANCES We review the extinction risk and threats to biodiversity in Madagascar, using available international assessment data as well as a machine learning analysis to predict the extinction risks and threats to plant species lacking assessments. Our compilation of global International Union for Conservation of Nature (IUCN) Red List assessments shows that overexploitation alongside unsustainable agricultural practices affect 62.1 and 56.8% of vertebrate species, respectively, and each affects nearly 90% of all plant species. Other threats have a relatively minor effect today but are expected to increase in coming decades. Because only one-third (4652) of all Malagasy plant species have been formally assessed, we carried out a neural network analysis to predict the putative status and threats for 5887 unassessed species and to evaluate biases in current assessments. The percentage of plant species currently assessed as under threat is probably representative of actual numbers, except in the case of the ferns and lycophytes, where significantly more species are estimated to be threatened. We find that Madagascar is home to a disproportionately high number of Evolutionarily Distinct and Globally Endangered (EDGE) species. This further highlights the urgency for evidence-based and effective in situ and ex situ conservation. Despite these alarming statistics and trends, we find that 10.4% of Madagascar’s land area is protected and that the network of protected areas (PAs) covers at least part of the range of 97.1% of terrestrial and freshwater vertebrates with known distributions (amphibians, freshwater fishes, reptiles, birds, and mammal species combined) and 67.7% of plant species (for threatened species, the percentages are 97.7% for vertebrates and 79.6% for plants). Complementary to this, ex situ collections hold 18% of vertebrate species and 23% of plant species. Nonetheless, there are still many threatened species that do not occur within PAs and are absent from ex situ collections, including one amphibian, three mammals, and seven reptiles, as well as 559 plants and more yet to be assessed. Based on our updated vegetation map, we find that the current PA network provides good coverage of the major habitats, particularly mangroves, spiny forest, humid forest, and tapia, but subhumid forest and grassland-woodland mosaic have very low areas under protection (5.7 and 1.8% respectively). OUTLOOK Madagascar is among the world’s poorest countries, and its biodiversity is a key resource for the sustainable future and well-being of its citizens. Current threats to Madagascar’s biodiversity are deeply rooted in historical and present social contexts, including widespread inequalities. We therefore propose five opportunities for action to further conservation in a just and equitable way. First, investment in conservation and restoration must be based on evidence and effectiveness and be tailored to meet future challenges through inclusive solutions. Second, expanded biodiversity monitoring, including increased dataset production and availability, is key. Third, improving the effectiveness of existing PAs—for example through community engagement, training, and income opportunities—is more important than creating new ones. Fourth, conservation and restoration should not focus solely on the PA network but should also include the surrounding landscapes and communities. And finally, conservation actions must address the root causes of biodiversity loss, including poverty and food insecurity. In the eyes of much of the world, Madagascar’s biodiversity is a unique global asset that needs saving; in the daily lives of many of the Malagasy people, it is a rapidly diminishing source of the most basic needs for subsistence. Protecting Madagascar’s biodiversity while promoting social development for its people is a matter of the utmost urgency Visual representation of five key opportunities for conserving and restoring Madagascar’s rapidly declining biodiversity identified in this Review. The dashed lines point to representative vegetation types where these recommendations could have tangible effects, but the opportunities are applicable across Madagascar. ILLUSTRATION: INESSA VOET
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2022
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  • 5
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 378, No. 6623 ( 2022-12-02)
    Abstract: The Republic of Madagascar is home to a unique assemblage of taxa and a diverse set of ecosystems. These high levels of diversity have arisen over millions of years through complex processes of speciation and extinction. Understanding this extraordinary diversity is crucial for highlighting its global importance and guiding urgent conservation efforts. However, despite the detailed knowledge that exists on some taxonomic groups, there are large knowledge gaps that remain to be filled. ADVANCES Our comprehensive analysis of major taxonomic groups in Madagascar summarizes information on the origin and evolution of terrestrial and freshwater biota, current species richness and endemism, and the utilization of this biodiversity by humans. The depth and breadth of Madagascar’s biodiversity—the product of millions of years of evolution in relative isolation —is still being uncovered. We report a recent acceleration in the scientific description of species but many remain relatively unknown, particularly fungi and most invertebrates. DIGITIZATION Digitization efforts are already increasing the resolution of species richness patterns and we highlight the crucial role of field- and collections-based research for advancing biodiversity knowledge in Madagascar. Phylogenetic diversity patterns mirror that of species richness and endemism in most of the analyzed groups. Among the new data presented, our update on plant numbers estimates 11,516 described vascular plant species native to Madagascar, of which 82% are endemic, in addition to 1215 bryophyte species, of which 28% are endemic. Humid forests are highlighted as centers of diversity because of their role as refugia and centers of recent and rapid radiations, but the distinct endemism of other areas such as the grassland-woodland mosaic of the Central Highlands and the spiny forest of the southwest is also important despite lower species richness. Endemism in Malagasy fungi remains poorly known given the lack of data on the total diversity and global distribution of species. However, our analysis has shown that ~75% of the fungal species detected by environmental sequencing have not been reported as occurring outside of Madagascar. Among the 1314 species of native terrestrial and freshwater vertebrates, levels of endemism are extremely high (90% overall)—all native nonflying terrestrial mammals and native amphibians are found nowhere else on Earth; further, 56% of the island’s birds, 81% of freshwater fishes, 95% of mammals, and 98% of reptile species are endemic. Little is known about endemism in insects, but data from the few well-studied groups on the island suggest that it is similarly high. The uses of Malagasy species are many, with much potential for the uncovering of useful traits for food, medicine, and climate mitigation. OUTLOOK Considerable work remains to be done to fully characterize Madagascar’s biodiversity and evolutionary history. The multitudes of known and potential uses of Malagasy species reported here, in conjunction with the inherent value of this unique and biodiverse region, reinforce the importance of conserving this unique biota in the face of major threats such as habitat loss and overexploitation. The gathering and analysis of data on Madagascar’s remarkable biota must continue and accelerate if we are to safeguard this unique and highly threatened subset of Earth’s biodiversity. Emergence and composition of Madagascar’s extraordinary biodiversity. Madagascar’s biota is the result of over 160 million years of evolution, mostly in geographic isolation, combined with sporadic long distance immigration events and local extinctions. (Left) We show the age of the oldest endemic Malagasy clade for major groups (from bottom to top): arthropods, bony fishes, reptiles, flatworms, birds, amphibians, flowering plants, mammals, non-flowering vascular plants, and mollusks). Humans arrived recently, some 10,000 to 2000 years (top right) and have directly or indirectly caused multiple extinctions (including hippopotamus, elephant birds, giant tortoises, and giant lemurs) and introduced many new species (such as dogs, zebu, rats, African bushpigs, goats, sheep, rice). Endemism is extremely high and unevenly distributed across the island (the heat map depicts Malagasy palm diversity, a group characteristic of the diverse humid forest). Human use of biodiversity is widespread, including 1916 plant species with reported uses. The scientific description of Malagasy biodiversity has accelerated greatly in recent years (bottom right), yet the diversity and evolution of many groups remain practically unknown, and many discoveries await.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2022
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  • 6
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 365, No. 6452 ( 2019-08-02), p. 505-509
    Abstract: Technologies that define the atomic-level structure of neutralization-sensitive epitopes on viral surface proteins are transforming vaccinology and guiding new vaccine development approaches. Previously, iterative rounds of protein engineering were performed to preserve the prefusion conformation of the respiratory syncytial virus (RSV) fusion (F) glycoprotein, resulting in a stabilized subunit vaccine candidate (DS-Cav1), which showed promising results in mice and macaques. Here, phase I human immunogenicity data reveal a more than 10-fold boost in neutralizing activity in serum from antibodies targeting prefusion-specific surfaces of RSV F. These findings represent a clinical proof of concept for structure-based vaccine design, suggest that development of a successful RSV vaccine will be feasible, and portend an era of precision vaccinology.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2019
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  • 7
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 11 ( 2023-03-14)
    Abstract: A common challenge in drug design pertains to finding chemical modifications to a ligand that increases its affinity to the target protein. An underutilized advance is the increase in structural biology throughput, which has progressed from an artisanal endeavor to a monthly throughput of hundreds of different ligands against a protein in modern synchrotrons. However, the missing piece is a framework that turns high-throughput crystallography data into predictive models for ligand design. Here, we designed a simple machine learning approach that predicts protein–ligand affinity from experimental structures of diverse ligands against a single protein paired with biochemical measurements. Our key insight is using physics-based energy descriptors to represent protein–ligand complexes and a learning-to-rank approach that infers the relevant differences between binding modes. We ran a high-throughput crystallography campaign against the SARS-CoV-2 main protease (M Pro ), obtaining parallel measurements of over 200 protein–ligand complexes and their binding activities. This allows us to design one-step library syntheses which improved the potency of two distinct micromolar hits by over 10-fold, arriving at a noncovalent and nonpeptidomimetic inhibitor with 120 nM antiviral efficacy. Crucially, our approach successfully extends ligands to unexplored regions of the binding pocket, executing large and fruitful moves in chemical space with simple chemistry.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
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  • 8
    In: Behavior Genetics, Springer Science and Business Media LLC, Vol. 53, No. 3 ( 2023-05), p. 249-264
    Type of Medium: Online Resource
    ISSN: 0001-8244 , 1573-3297
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 9
    In: Journal of Communication Disorders, Elsevier BV, Vol. 46, No. 1 ( 2013-01), p. 30-52
    Type of Medium: Online Resource
    ISSN: 0021-9924
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2013
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