Displaying publications 1 - 20 of 80 in total

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  1. Twining JP, Sutherland C, Zalewski A, Cove MV, Birks J, Wearn OR, et al.
    Proc Natl Acad Sci U S A, 2024 Mar 19;121(12):e2312252121.
    PMID: 38466845 DOI: 10.1073/pnas.2312252121
    The social system of animals involves a complex interplay between physiology, natural history, and the environment. Long relied upon discrete categorizations of "social" and "solitary" inhibit our capacity to understand species and their interactions with the world around them. Here, we use a globally distributed camera trapping dataset to test the drivers of aggregating into groups in a species complex (martens and relatives, family Mustelidae, Order Carnivora) assumed to be obligately solitary. We use a simple quantification, the probability of being detected in a group, that was applied across our globally derived camera trap dataset. Using a series of binomial generalized mixed-effects models applied to a dataset of 16,483 independent detections across 17 countries on four continents we test explicit hypotheses about potential drivers of group formation. We observe a wide range of probabilities of being detected in groups within the solitary model system, with the probability of aggregating in groups varying by more than an order of magnitude. We demonstrate that a species' context-dependent proclivity toward aggregating in groups is underpinned by a range of resource-related factors, primarily the distribution of resources, with increasing patchiness of resources facilitating group formation, as well as interactions between environmental conditions (resource constancy/winter severity) and physiology (energy storage capabilities). The wide variation in propensities to aggregate with conspecifics observed here highlights how continued failure to recognize complexities in the social behaviors of apparently solitary species limits our understanding not only of the individual species but also the causes and consequences of group formation.
  2. Chisholm RA, Kristensen NP, Rheindt FE, Chong KY, Ascher JS, Lim KKP, et al.
    Proc Natl Acad Sci U S A, 2023 Dec 19;120(51):e2309034120.
    PMID: 38079550 DOI: 10.1073/pnas.2309034120
    There is an urgent need for reliable data on the impacts of deforestation on tropical biodiversity. The city-state of Singapore has one of the most detailed biodiversity records in the tropics, dating back to the turn of the 19th century. In 1819, Singapore was almost entirely covered in primary forest, but this has since been largely cleared. We compiled more than 200 y of records for 10 major taxonomic groups in Singapore (>50,000 individual records; >3,000 species), and we estimated extinction rates using recently developed and novel statistical models that account for "dark extinctions," i.e., extinctions of undiscovered species. The estimated overall extinction rate was 37% (95% CI [31 to 42%]). Extrapolating our Singapore observations to a future business-as-usual deforestation scenario for Southeast Asia suggests that 18% (95% CI [16 to 22%]) of species will be lost regionally by 2100. Our extinction estimates for Singapore and Southeast Asia are a factor of two lower than previous estimates that also attempted to account for dark extinctions. However, we caution that particular groups such as large mammals, forest-dependent birds, orchids, and butterflies are disproportionately vulnerable.
  3. Clark CJ, Jussim L, Frey K, Stevens ST, Al-Gharbi M, Aquino K, et al.
    Proc Natl Acad Sci U S A, 2023 Nov 28;120(48):e2301642120.
    PMID: 37983511 DOI: 10.1073/pnas.2301642120
    Science is among humanity's greatest achievements, yet scientific censorship is rarely studied empirically. We explore the social, psychological, and institutional causes and consequences of scientific censorship (defined as actions aimed at obstructing particular scientific ideas from reaching an audience for reasons other than low scientific quality). Popular narratives suggest that scientific censorship is driven by authoritarian officials with dark motives, such as dogmatism and intolerance. Our analysis suggests that scientific censorship is often driven by scientists, who are primarily motivated by self-protection, benevolence toward peer scholars, and prosocial concerns for the well-being of human social groups. This perspective helps explain both recent findings on scientific censorship and recent changes to scientific institutions, such as the use of harm-based criteria to evaluate research. We discuss unknowns surrounding the consequences of censorship and provide recommendations for improving transparency and accountability in scientific decision-making to enable the exploration of these unknowns. The benefits of censorship may sometimes outweigh costs. However, until costs and benefits are examined empirically, scholars on opposing sides of ongoing debates are left to quarrel based on competing values, assumptions, and intuitions.
  4. Hung TH, So T, Thammavong B, Chamchumroon V, Theilade I, Phourin C, et al.
    Proc Natl Acad Sci U S A, 2023 Aug 15;120(33):e2301603120.
    PMID: 37549265 DOI: 10.1073/pnas.2301603120
    In the billion-dollar global illegal wildlife trade, rosewoods have been the world's most trafficked wild product since 2005. Dalbergia cochinchinensis and Dalbergia oliveri are the most sought-after rosewoods in the Greater Mekong Subregion. They are exposed to significant genetic risks and the lack of knowledge on their adaptability limits the effectiveness of conservation efforts. Here, we present genome assemblies and range-wide genomic scans of adaptive variation, together with predictions of genomic offset to climate change. Adaptive genomic variation was differentially associated with temperature and precipitation-related variables between the species, although their natural ranges overlap. The findings are consistent with differences in pioneering ability and in drought tolerance. We predict their genomic offsets will increase over time and with increasing carbon emission pathway but at a faster pace in D. cochinchinensis than in D. oliveri. These results and the distinct gene-environment association in the eastern coastal edge of Vietnam suggest species-specific conservation actions: germplasm representation across the range in D. cochinchinensis and focused on hotspots of genomic offset in D. oliveri. We translated our genomic models into a seed source matching application, seedeR, to rapidly inform restoration efforts. Our ecological genomic research uncovering contrasting selection forces acting in sympatric rosewoods is of relevance to conserving tropical trees globally and combating risks from climate change.
  5. Gardner EM, Bruun-Lund S, Niissalo M, Chantarasuwan B, Clement WL, Geri C, et al.
    Proc Natl Acad Sci U S A, 2023 Jul 11;120(28):e2222035120.
    PMID: 37399402 DOI: 10.1073/pnas.2222035120
    Studies investigating the evolution of flowering plants have long focused on isolating mechanisms such as pollinator specificity. Some recent studies have proposed a role for introgressive hybridization between species, recognizing that isolating processes such as pollinator specialization may not be complete barriers to hybridization. Occasional hybridization may therefore lead to distinct yet reproductively connected lineages. We investigate the balance between introgression and reproductive isolation in a diverse clade using a densely sampled phylogenomic study of fig trees (Ficus, Moraceae). Codiversification with specialized pollinating wasps (Agaonidae) is recognized as a major engine of fig diversity, leading to about 850 species. Nevertheless, some studies have focused on the importance of hybridization in Ficus, highlighting the consequences of pollinator sharing. Here, we employ dense taxon sampling (520 species) throughout Moraceae and 1,751 loci to investigate phylogenetic relationships and the prevalence of introgression among species throughout the history of Ficus. We present a well-resolved phylogenomic backbone for Ficus, providing a solid foundation for an updated classification. Our results paint a picture of phylogenetically stable evolution within lineages punctuated by occasional local introgression events likely mediated by local pollinator sharing, illustrated by clear cases of cytoplasmic introgression that have been nearly drowned out of the nuclear genome through subsequent lineage fidelity. The phylogenetic history of figs thus highlights that while hybridization is an important process in plant evolution, the mere ability of species to hybridize locally does not necessarily translate into ongoing introgression between distant lineages, particularly in the presence of obligate plant-pollinator relationships.
  6. Kobayashi Y, Komatsuya K, Imamura S, Nozaki T, Watanabe YI, Sato S, et al.
    Proc Natl Acad Sci U S A, 2023 Jul 11;120(28):e2214765120.
    PMID: 37406097 DOI: 10.1073/pnas.2214765120
    The malaria parasite Plasmodium falciparum has a nonphotosynthetic plastid called the apicoplast, which contains its own genome. Regulatory mechanisms for apicoplast gene expression remain poorly understood, despite this organelle being crucial for the parasite life cycle. Here, we identify a nuclear-encoded apicoplast RNA polymerase σ subunit (sigma factor) which, along with the α subunit, appears to mediate apicoplast transcript accumulation. This has a periodicity reminiscent of parasite circadian or developmental control. Expression of the apicoplast subunit gene, apSig, together with apicoplast transcripts, increased in the presence of the blood circadian signaling hormone melatonin. Our data suggest that the host circadian rhythm is integrated with intrinsic parasite cues to coordinate apicoplast genome transcription. This evolutionarily conserved regulatory system might be a future target for malaria treatment.
  7. Liu L, Li S, Pan D, Hui D, Zhang X, Li B, et al.
    Proc Natl Acad Sci U S A, 2023 Jul 11;120(28):e2302234120.
    PMID: 37399391 DOI: 10.1073/pnas.2302234120
    The deformation-coordination ability between ductile metal and brittle dispersive ceramic particles is poor, which means that an improvement in strength will inevitably sacrifice ductility in dispersion-strengthened metallic materials. Here, we present an inspired strategy for developing dual-structure-based titanium matrix composites (TMCs) that achieve 12.0% elongation comparable to the matrix Ti6Al4V alloys and enhanced strength compared to homostructure composites. The proposed dual-structure comprises a primary structure, namely, a TiB whisker-rich region engendered fine grain Ti6Al4V matrix with a three-dimensional micropellet architecture (3D-MPA), and an overall structure consisting of evenly distributed 3D-MPA "reinforcements" and a TiBw-lean titanium matrix. The dual structure presents a spatially heterogeneous grain distribution with 5.8 μm fine grains and 42.3 μm coarse grains, which exhibits excellent hetero-deformation-induced (HDI) hardening and achieves a 5.8% ductility. Interestingly, the 3D-MPA "reinforcements" show 11.1% isotropic deformability and 66% dislocation storage, which endows the TMCs with good strength and loss-free ductility. Our enlightening method uses an interdiffusion and self-organization strategy based on powder metallurgy to enable metal matrix composites with the heterostructure of the matrix and the configuration of reinforcement to address the strength-ductility trade-off dilemma.
  8. Chen M, Carrasco G, Zhao N, Wang X, Lee JN, Tanzil JTI, et al.
    Proc Natl Acad Sci U S A, 2023 Feb 07;120(6):e2213163120.
    PMID: 36716377 DOI: 10.1073/pnas.2213163120
    Material fluxes at the land-ocean interface impact seawater composition and global cycling of elements. However, most attention has been focused on the fluvial dissolved fluxes. For elements like lead (Pb), whose fluvial particulate flux into the ocean is two orders of magnitude higher than the dissolved counterpart, the role of particulates in elemental cycling is potentially important but currently less appreciated. Using both chemical analyses on samples collected from around equatorial Southeast Asia and model simulations, we show that particulate-dissolved exchange is an important mechanism controlling the concentration and isotopic composition of dissolved Pb in the ocean. Our model indicates that Pb contributed from particulate-dissolved exchange at ocean boundaries is larger than, or at least comparable to, other major Pb sources to the seawater before the Anthropocene, when the anthropogenic Pb was absent. Our work highlights the importance of boundary exchange in understanding marine element cycling and weathering-climate feedback.
  9. Mills MB, Malhi Y, Ewers RM, Kho LK, Teh YA, Both S, et al.
    Proc Natl Acad Sci U S A, 2023 Jan 17;120(3):e2214462120.
    PMID: 36623189 DOI: 10.1073/pnas.2214462120
    Logged and structurally degraded tropical forests are fast becoming one of the most prevalent land-use types throughout the tropics and are routinely assumed to be a net carbon sink because they experience rapid rates of tree regrowth. Yet this assumption is based on forest biomass inventories that record carbon stock recovery but fail to account for the simultaneous losses of carbon from soil and necromass. Here, we used forest plots and an eddy covariance tower to quantify and partition net ecosystem CO2 exchange in Malaysian Borneo, a region that is a hot spot for deforestation and forest degradation. Our data represent the complete carbon budget for tropical forests measured throughout a logging event and subsequent recovery and found that they constitute a substantial and persistent net carbon source. Consistent with existing literature, our study showed a significantly greater woody biomass gain across moderately and heavily logged forests compared with unlogged forests, but this was counteracted by much larger carbon losses from soil organic matter and deadwood in logged forests. We estimate an average carbon source of 1.75 ± 0.94 Mg C ha-1 yr-1 within moderately logged plots and 5.23 ± 1.23 Mg C ha-1 yr-1 in unsustainably logged and severely degraded plots, with emissions continuing at these rates for at least one-decade post-logging. Our data directly contradict the default assumption that recovering logged and degraded tropical forests are net carbon sinks, implying the amount of carbon being sequestered across the world's tropical forests may be considerably lower than currently estimated.
  10. Lim CH, Soga T, Parhar IS
    Proc Natl Acad Sci U S A, 2023 Jan 17;120(3):e2117547120.
    PMID: 36623187 DOI: 10.1073/pnas.2117547120
    Social disturbance in interpersonal relationships is the primary source of stress in humans. Spexin (SPX, SPX1a in cichlid), an evolutionarily conserved neuropeptide with diverse physiological functions, is up-regulated in the brain during chronic social defeat stress in teleost. On the other hand, repeated exposure to social stress can lead to dysregulation of the monoaminergic system and increase the vulnerability of developing depression. Since dysfunction of the serotonin (5-hydroxytryptamine, 5-HT) system is associated with social stress and the pathophysiology of depression, the present study investigated the regulatory relationship between the central 5-HT system and SPX1a in the male teleost, Nile tilapia (Oreochromis niloticus). To identify stress factors that regulate SPX1a gene expression, cortisol, dexamethasone (DEX), and 5-HT were used to treat tilapia brain primary cultures. Our study shows cortisol and DEX treatment had no effect on SPX1a gene expression, but SPX1a gene expression was down-regulated following 5-HT treatment. Anatomical localization showed a close association between 5-HT immunoreactive projections and SPX1a neurons in the semicircular torus. In addition, 5-HT receptors (5-HT2B) were expressed in SPX1a neurons. SPX1a immunoreactive neurons and SPX1a gene expression were significantly increased in socially defeated tilapia. On the other hand, citalopram (antidepressant, 5-HT antagonist) treatment to socially defeated tilapia normalized SPX1a gene expression to control levels. Taken together, the present study shows that 5-HT is an upstream regulator of SPX1a and that the inhibited 5-HT activates SPX1a during social defeat.
  11. Yebra G, Harling-Lee JD, Lycett S, Aarestrup FM, Larsen G, Cavaco LM, et al.
    Proc Natl Acad Sci U S A, 2022 Dec 13;119(50):e2211217119.
    PMID: 36469788 DOI: 10.1073/pnas.2211217119
    Most new pathogens of humans and animals arise via switching events from distinct host species. However, our understanding of the evolutionary and ecological drivers of successful host adaptation, expansion, and dissemination are limited. Staphylococcus aureus is a major bacterial pathogen of humans and a leading cause of mastitis in dairy cows worldwide. Here we trace the evolutionary history of bovine S. aureus using a global dataset of 10,254 S. aureus genomes including 1,896 bovine isolates from 32 countries in 6 continents. We identified 7 major contemporary endemic clones of S. aureus causing bovine mastitis around the world and traced them back to 4 independent host-jump events from humans that occurred up to 2,500 y ago. Individual clones emerged and underwent clonal expansion from the mid-19th to late 20th century coinciding with the commercialization and industrialization of dairy farming, and older lineages have become globally distributed via established cattle trade links. Importantly, we identified lineage-dependent differences in the frequency of host transmission events between humans and cows in both directions revealing high risk clones threatening veterinary and human health. Finally, pangenome network analysis revealed that some bovine S. aureus lineages contained distinct sets of bovine-associated genes, consistent with multiple trajectories to host adaptation via gene acquisition. Taken together, we have dissected the evolutionary history of a major endemic pathogen of livestock providing a comprehensive temporal, geographic, and gene-level perspective of its remarkable success.
  12. Demarchi B, Stiller J, Grealy A, Mackie M, Deng Y, Gilbert T, et al.
    Proc Natl Acad Sci U S A, 2022 Oct 25;119(43):e2109326119.
    PMID: 35609205 DOI: 10.1073/pnas.2109326119
    The realization that ancient biomolecules are preserved in "fossil" samples has revolutionized archaeological science. Protein sequences survive longer than DNA, but their phylogenetic resolution is inferior; therefore, careful assessment of the research questions is required. Here, we show the potential of ancient proteins preserved in Pleistocene eggshell in addressing a longstanding controversy in human and animal evolution: the identity of the extinct bird that laid large eggs which were exploited by Australia's indigenous people. The eggs had been originally attributed to the iconic extinct flightless bird Genyornis newtoni (†Dromornithidae, Galloanseres) and were subsequently dated to before 50 ± 5 ka by Miller et al. [Nat. Commun. 7, 10496 (2016)]. This was taken to represent the likely extinction date for this endemic megafaunal species and thus implied a role of humans in its demise. A contrasting hypothesis, according to which the eggs were laid by a large mound-builder megapode (Megapodiidae, Galliformes), would therefore acquit humans of their responsibility in the extinction of Genyornis. Ancient protein sequences were reconstructed and used to assess the evolutionary proximity of the undetermined eggshell to extant birds, rejecting the megapode hypothesis. Authentic ancient DNA could not be confirmed from these highly degraded samples, but morphometric data also support the attribution of the eggshell to Genyornis. When used in triangulation to address well-defined hypotheses, paleoproteomics is a powerful tool for reconstructing the evolutionary history in ancient samples. In addition to the clarification of phylogenetic placement, these data provide a more nuanced understanding of the modes of interactions between humans and their environment.
  13. Wilkinson JL, Boxall ABA, Kolpin DW, Leung KMY, Lai RWS, Galbán-Malagón C, et al.
    Proc Natl Acad Sci U S A, 2022 Feb 22;119(8).
    PMID: 35165193 DOI: 10.1073/pnas.2113947119
    Environmental exposure to active pharmaceutical ingredients (APIs) can have negative effects on the health of ecosystems and humans. While numerous studies have monitored APIs in rivers, these employ different analytical methods, measure different APIs, and have ignored many of the countries of the world. This makes it difficult to quantify the scale of the problem from a global perspective. Furthermore, comparison of the existing data, generated for different studies/regions/continents, is challenging due to the vast differences between the analytical methodologies employed. Here, we present a global-scale study of API pollution in 258 of the world's rivers, representing the environmental influence of 471.4 million people across 137 geographic regions. Samples were obtained from 1,052 locations in 104 countries (representing all continents and 36 countries not previously studied for API contamination) and analyzed for 61 APIs. Highest cumulative API concentrations were observed in sub-Saharan Africa, south Asia, and South America. The most contaminated sites were in low- to middle-income countries and were associated with areas with poor wastewater and waste management infrastructure and pharmaceutical manufacturing. The most frequently detected APIs were carbamazepine, metformin, and caffeine (a compound also arising from lifestyle use), which were detected at over half of the sites monitored. Concentrations of at least one API at 25.7% of the sampling sites were greater than concentrations considered safe for aquatic organisms, or which are of concern in terms of selection for antimicrobial resistance. Therefore, pharmaceutical pollution poses a global threat to environmental and human health, as well as to delivery of the United Nations Sustainable Development Goals.
  14. Liu PP, Caricchi L, Chung SL, Li XH, Li QL, Zhou MF, et al.
    Proc Natl Acad Sci U S A, 2021 11 09;118(45).
    PMID: 34725149 DOI: 10.1073/pnas.2101695118
    The Toba volcanic system in Indonesia has produced two of the largest eruptions (>2,000 km3 dense-rock equivalent [DRE] each) on Earth since the Quaternary. U-Pb crystallization ages of zircon span a period of ∼600 ky before each eruptive event, and in the run-up to each eruption, the mean and variance of the zircons' U content decrease. To quantify the process of accumulation of eruptible magma underneath the Toba caldera, we integrated these observations with thermal and geochemical modeling. We show that caldera-forming eruptions at Toba are the result of progressive thermal maturation of the upper crustal magma reservoir, which grows and chemically homogenizes, by sustained magma influx at average volumetric rates between 0.008 and 0.01 km3/y over the past 2.2 My. Protracted thermal pulses related to magma-recharge events prime the system for eruption without necessarily requiring an increased magma-recharge rate before the two supereruptions. If the rate of magma input was maintained since the last supereruption of Toba at 75 ka, eruptible magma is currently accumulating at a minimum rate of ∼4.2 km3 per millennium, and the current estimate of the total volume of potentially eruptible magma available today is a minimum of ∼315 km3 Our approach to evaluate magma flux and the rate of eruptible magma accumulation is applicable to other volcanic systems capable of producing supereruptions and thereby could help in assessing the potential of active volcanic systems to feed supereruptions.
  15. Poli A, Abdul-Hamid S, Zaurito AE, Campagnoli F, Bevilacqua V, Sheth B, et al.
    Proc Natl Acad Sci U S A, 2021 08 03;118(31).
    PMID: 34312224 DOI: 10.1073/pnas.2010053118
    Regulatory T cells (Tregs) play fundamental roles in maintaining peripheral tolerance to prevent autoimmunity and limit legitimate immune responses, a feature hijacked in tumor microenvironments in which the recruitment of Tregs often extinguishes immune surveillance through suppression of T-effector cell signaling and tumor cell killing. The pharmacological tuning of Treg activity without impacting on T conventional (Tconv) cell activity would likely be beneficial in the treatment of various human pathologies. PIP4K2A, 2B, and 2C constitute a family of lipid kinases that phosphorylate PtdIns5P to PtdIns(4,5)P 2 They are involved in stress signaling, act as synthetic lethal targets in p53-null tumors, and in mice, the loss of PIP4K2C leads to late onset hyperinflammation. Accordingly, a human single nucleotide polymorphism (SNP) near the PIP4K2C gene is linked with susceptibility to autoimmune diseases. How PIP4Ks impact on human T cell signaling is not known. Using ex vivo human primary T cells, we found that PIP4K activity is required for Treg cell signaling and immunosuppressive activity. Genetic and pharmacological inhibition of PIP4K in Tregs reduces signaling through the PI3K, mTORC1/S6, and MAPK pathways, impairs cell proliferation, and increases activation-induced cell death while sparing Tconv. PIP4K and PI3K signaling regulate the expression of the Treg master transcriptional activator FOXP3 and the epigenetic signaling protein Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). Our studies suggest that the pharmacological inhibition of PIP4K can reprogram human Treg identity while leaving Tconv cell signaling and T-helper differentiation to largely intact potentially enhancing overall immunological activity.
  16. Wei GZ, Martin KA, Xing PY, Agrawal R, Whiley L, Wood TK, et al.
    Proc Natl Acad Sci U S A, 2021 Jul 06;118(27).
    PMID: 34210797 DOI: 10.1073/pnas.2021091118
    While modulatory effects of gut microbes on neurological phenotypes have been reported, the mechanisms remain largely unknown. Here, we demonstrate that indole, a tryptophan metabolite produced by tryptophanase-expressing gut microbes, elicits neurogenic effects in the adult mouse hippocampus. Neurogenesis is reduced in germ-free (GF) mice and in GF mice monocolonized with a single-gene tnaA knockout (KO) mutant Escherichia coli unable to produce indole. External administration of systemic indole increases adult neurogenesis in the dentate gyrus in these mouse models and in specific pathogen-free (SPF) control mice. Indole-treated mice display elevated synaptic markers postsynaptic density protein 95 and synaptophysin, suggesting synaptic maturation effects in vivo. By contrast, neurogenesis is not induced by indole in aryl hydrocarbon receptor KO (AhR-/-) mice or in ex vivo neurospheres derived from them. Neural progenitor cells exposed to indole exit the cell cycle, terminally differentiate, and mature into neurons that display longer and more branched neurites. These effects are not observed with kynurenine, another AhR ligand. The indole-AhR-mediated signaling pathway elevated the expression of β-catenin, Neurog2, and VEGF-α genes, thus identifying a molecular pathway connecting gut microbiota composition and their metabolic function to neurogenesis in the adult hippocampus. Our data have implications for the understanding of mechanisms of brain aging and for potential next-generation therapeutic opportunities.
  17. Nett RS, Dho Y, Low YY, Sattely ES
    Proc Natl Acad Sci U S A, 2021 06 15;118(24).
    PMID: 34112718 DOI: 10.1073/pnas.2102949118
    Plants synthesize many diverse small molecules that affect function of the mammalian central nervous system, making them crucial sources of therapeutics for neurological disorders. A notable portion of neuroactive phytochemicals are lysine-derived alkaloids, but the mechanisms by which plants produce these compounds have remained largely unexplored. To better understand how plants synthesize these metabolites, we focused on biosynthesis of the Lycopodium alkaloids that are produced by club mosses, a clade of plants used traditionally as herbal medicines. Hundreds of Lycopodium alkaloids have been described, including huperzine A (HupA), an acetylcholine esterase inhibitor that has generated interest as a treatment for the symptoms of Alzheimer's disease. Through combined metabolomic profiling and transcriptomics, we have identified a developmentally controlled set of biosynthetic genes, or potential regulon, for the Lycopodium alkaloids. The discovery of this putative regulon facilitated the biosynthetic reconstitution and functional characterization of six enzymes that act in the initiation and conclusion of HupA biosynthesis. This includes a type III polyketide synthase that catalyzes a crucial imine-polyketide condensation, as well as three Fe(II)/2-oxoglutarate-dependent dioxygenase (2OGD) enzymes that catalyze transformations (pyridone ring-forming desaturation, piperidine ring cleavage, and redox-neutral isomerization) within downstream HupA biosynthesis. Our results expand the diversity of known chemical transformations catalyzed by 2OGDs and provide mechanistic insight into the function of noncanonical type III PKS enzymes that generate plant alkaloid scaffolds. These data offer insight into the chemical logic of Lys-derived alkaloid biosynthesis and demonstrate the tightly coordinated coexpression of secondary metabolic genes for the biosynthesis of medicinal alkaloids.
  18. Singh GG, Harden-Davies H, Allison EH, Cisneros-Montemayor AM, Swartz W, Crosman KM, et al.
    Proc Natl Acad Sci U S A, 2021 02 02;118(5).
    PMID: 33504570 DOI: 10.1073/pnas.2100205118
  19. Epstein JH, Anthony SJ, Islam A, Kilpatrick AM, Ali Khan S, Balkey MD, et al.
    Proc Natl Acad Sci U S A, 2020 11 17;117(46):29190-29201.
    PMID: 33139552 DOI: 10.1073/pnas.2000429117
    Nipah virus (NiV) is an emerging bat-borne zoonotic virus that causes near-annual outbreaks of fatal encephalitis in South Asia-one of the most populous regions on Earth. In Bangladesh, infection occurs when people drink date-palm sap contaminated with bat excreta. Outbreaks are sporadic, and the influence of viral dynamics in bats on their temporal and spatial distribution is poorly understood. We analyzed data on host ecology, molecular epidemiology, serological dynamics, and viral genetics to characterize spatiotemporal patterns of NiV dynamics in its wildlife reservoir, Pteropus medius bats, in Bangladesh. We found that NiV transmission occurred throughout the country and throughout the year. Model results indicated that local transmission dynamics were modulated by density-dependent transmission, acquired immunity that is lost over time, and recrudescence. Increased transmission followed multiyear periods of declining seroprevalence due to bat-population turnover and individual loss of humoral immunity. Individual bats had smaller host ranges than other Pteropus species (spp.), although movement data and the discovery of a Malaysia-clade NiV strain in eastern Bangladesh suggest connectivity with bats east of Bangladesh. These data suggest that discrete multiannual local epizootics in bat populations contribute to the sporadic nature of NiV outbreaks in South Asia. At the same time, the broad spatial and temporal extent of NiV transmission, including the recent outbreak in Kerala, India, highlights the continued risk of spillover to humans wherever they may interact with pteropid bats and the importance of limiting opportunities for spillover throughout Pteropus's range.
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