• Accommodating individual travel history and unsampled diversity in Bayesian phylogeographic inference of SARS-CoV-2

      Lemey, Philippe; Hong, Samuel L; Hill, Verity; Baele, Guy; Poletto, Chiara; Colizza, Vittoria; O'Toole, Áine; McCrone, John T; Andersen, Kristian G; Worobey, Michael; et al. (NATURE RESEARCH, 2020-10-09)
      Spatiotemporal bias in genome sampling can severely confound discrete trait phylogeographic inference. This has impeded our ability to accurately track the spread of SARS-CoV-2, the virus responsible for the COVID-19 pandemic, despite the availability of unprecedented numbers of SARS-CoV-2 genomes. Here, we present an approach to integrate individual travel history data in Bayesian phylogeographic inference and apply it to the early spread of SARS-CoV-2. We demonstrate that including travel history data yields i) more realistic hypotheses of virus spread and ii) higher posterior predictive accuracy compared to including only sampling location. We further explore methods to ameliorate the impact of sampling bias by augmenting the phylogeographic analysis with lineages from undersampled locations. Our reconstructions reinforce specific transmission hypotheses suggested by the inclusion of travel history data, but also suggest alternative routes of virus migration that are plausible within the epidemiological context but are not apparent with current sampling efforts. Spatiotemporal sampling gaps in existing pathogen genomic data limits their use in understanding epidemiological patterns. Here, the authors apply a phylogeographic approach with SARS-CoV-2 genomes to accurately reproduce pathogen spread by accounting for spatial biases and travel history of the individual.
    • Anatomical and histological analyses reveal that tail repair is coupled with regrowth in wild-caught, juvenile American alligators (Alligator mississippiensis)

      Xu, Cindy; Palade, Joanna; Fisher, Rebecca E; Smith, Cameron I; Clark, Andrew R; Sampson, Samuel; Bourgeois, Russell; Rawls, Alan; Elsey, Ruth M; Wilson-Rawls, Jeanne; et al. (NATURE RESEARCH, 2020-11-18)
      Reptiles are the only amniotes that maintain the capacity to regenerate appendages. This study presents the first anatomical and histological evidence of tail repair with regrowth in an archosaur, the American alligator. The regrown alligator tails constituted approximately 6-18% of the total body length and were morphologically distinct from original tail segments. Gross dissection, radiographs, and magnetic resonance imaging revealed that caudal vertebrae were replaced by a ventrally-positioned, unsegmented endoskeleton. This contrasts with lepidosaurs, where the regenerated tail is radially organized around a central endoskeleton. Furthermore, the regrown alligator tail lacked skeletal muscle and instead consisted of fibrous connective tissue composed of type I and type III collagen fibers. The overproduction of connective tissue shares features with mammalian wound healing or fibrosis. The lack of skeletal muscle contrasts with lizards, but shares similarities with regenerated tails in the tuatara and regenerated limbs in Xenopus adult frogs, which have a cartilaginous endoskeleton surrounded by connective tissue, but lack skeletal muscle. Overall, this study of wild-caught, juvenile American alligator tails identifies a distinct pattern of wound repair in mammals while exhibiting features in common with regeneration in lepidosaurs and amphibia.
    • Cadherin repeat 5 mutation associated with Bt resistance in a field-derived strain of pink bollworm

      Wang, Ling; Ma, Yuemin; Wei, Wei; Wan, Peng; Liu, Kaiyu; Xu, Min; Cong, Shengbo; Wang, Jintao; Xu, Dong; Xiao, Yutao; et al. (NATURE RESEARCH, 2020-10-08)
      Evolution of resistance by pests reduces the benefits of transgenic crops that produce insecticidal proteins from Bacillus thuringiensis (Bt). Here we analyzed resistance to Bt toxin Cry1Ac in a field-derived strain of pink bollworm (Pectinophora gossypiella), a global pest of cotton. We discovered that the r14 allele of the pink bollworm cadherin gene (PgCad1) has a 234-bp insertion in exon 12 encoding a mutant PgCad1 protein that lacks 36 amino acids in cadherin repeat 5 (CR5). A strain homozygous for this allele had 237-fold resistance to Cry1Ac, 1.8-fold cross-resistance to Cry2Ab, and developed from neonate to adult on Bt cotton producing Cry1Ac. Inheritance of resistance to Cry1Ac was recessive and tightly linked with r14. PgCad1 transcript abundance in midgut tissues did not differ between resistant and susceptible larvae. Toxicity of Cry1Ac to transformed insect cells was lower for cells expressing r14 than for cells expressing wild-type PgCad1. Wild-type PgCad1 was transported to the cell membrane, whereas PgCad1 produced by r14 was not. In larval midgut tissue, PgCad1 protein occurred primarily on the brush border membrane only in susceptible larvae. The results imply r14 mediates pink bollworm resistance to Cry1Ac by reduced translation, increased degradation, and/or mislocalization of cadherin.
    • Co-regulation of the transcription controlling ATF2 phosphoswitch by JNK and p38

      Kirsch, Klára; Zeke, András; Tőke, Orsolya; Sok, Péter; Sethi, Ashish; Sebő, Anna; Kumar, Ganesan Senthil; Egri, Péter; Póti, Ádám L; Gooley, Paul; et al. (NATURE RESEARCH, 2020-11-13)
      Transcription factor phosphorylation at specific sites often activates gene expression, but how environmental cues quantitatively control transcription is not well-understood. Activating protein 1 transcription factors are phosphorylated by mitogen-activated protein kinases (MAPK) in their transactivation domains (TAD) at so-called phosphoswitches, which are a hallmark in response to growth factors, cytokines or stress. We show that the ATF2 TAD is controlled by functionally distinct signaling pathways (JNK and p38) through structurally different MAPK binding sites. Moreover, JNK mediated phosphorylation at an evolutionarily more recent site diminishes p38 binding and made the phosphoswitch differently sensitive to JNK and p38 in vertebrates. Structures of MAPK-TAD complexes and mechanistic modeling of ATF2 TAD phosphorylation in cells suggest that kinase binding motifs and phosphorylation sites line up to maximize MAPK based co-regulation. This study shows how the activity of an ancient transcription controlling phosphoswitch became dependent on the relative flux of upstream signals. The ATF2 transcription factor is phosphorylated by different mitogen-activated protein (MAP) kinases. Here, the authors show that the functionally distinct MAP kinases JNK and p38 control ATF2 through different binding sites and differential phosphorylation, thereby modulating ATF2's sensitivity to the JNK and p38 pathways.
    • Deep phenotyping of 34,128 adult patients hospitalised with COVID-19 in an international network study

      Burn, Edward; You, Seng Chan; Sena, Anthony G; Kostka, Kristin; Abedtash, Hamed; Abrahão, Maria Tereza F; Alberga, Amanda; Alghoul, Heba; Alser, Osaid; Alshammari, Thamir M; et al. (NATURE RESEARCH, 2020-10-06)
      Comorbid conditions appear to be common among individuals hospitalised with coronavirus disease 2019 (COVID-19) but estimates of prevalence vary and little is known about the prior medication use of patients. Here, we describe the characteristics of adults hospitalised with COVID-19 and compare them with influenza patients. We include 34,128 (US: 8362, South Korea: 7341, Spain: 18,425) COVID-19 patients, summarising between 4811 and 11,643 unique aggregate characteristics. COVID-19 patients have been majority male in the US and Spain, but predominantly female in South Korea. Age profiles vary across data sources. Compared to 84,585 individuals hospitalised with influenza in 2014-19, COVID-19 patients have more typically been male, younger, and with fewer comorbidities and lower medication use. While protecting groups vulnerable to influenza is likely a useful starting point in the response to COVID-19, strategies will likely need to be broadened to reflect the particular characteristics of individuals being hospitalised with COVID-19. Detailed knowledge of the characteristics of COVID-19 patients helps with public health planning. Here, the authors use routinely-collected data from seven databases in three countries to describe the characteristics of >30,000 patients admitted with COVID-19 and compare them with those admitted for influenza in previous years.
    • Design and development of innovative microparticulate/nanoparticulate inhalable dry powders of a novel synthetic trifluorinated chalcone derivative and Nrf2 agonist.

      Muralidharan, Priya; Jones, Brielle; Allaway, Graham; Biswal, Shyam S; Mansour, Heidi M; Univ Arizona, Coll Pharm; Univ Arizona, Coll Med; Univ Arizona, Coll Med, Dept Med, Div Translat & Regenerat Med; Univ Arizona, BIO5 Res Inst; Univ Arizona, Inst Environm; et al. (NATURE RESEARCH, 2020-11-13)
      Chalcone derivatives are shown to possess excellent anti-inflammatory and anti-oxidant properties which are of great interest in treating respiratory diseases such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF). This study successfully designed and developed dry powder inhaler (DPI) formulations of TMC (2-trifluoromethyl-2 ' -methoxychalone), a new synthetic trifluorinated chalcone and Nrf2 agonist, for targeted pulmonary inhalation aerosol drug delivery. An advanced co-spray drying particle engineering technique was used to design and produce microparticulate/nanoparticulate formulations of TMC with a suitable excipient (mannitol) as inhalable particles with tailored particle properties for inhalation. Raw TMC and co-spray dried TMC formulations were comprehensively characterized for the first time using scanning electron microscopy (SEM) with energy dispersive X-ray (EDX) spectroscopy, thermal analysis, X-ray powder diffraction (XRPD), and molecular fingerprinting as dry powders by ATR-FTIR spectroscopy and Raman spectroscopy. Further, biocompatibility and suitability of formulations were tested with in vitro cellular transepithelial electrical resistance (TEER) in air-interface culture (AIC) using a human pulmonary airway cell line. The ability of these TMC formulations to perform as aerosolized dry powders was systematically evaluated by design of experiments (DOEs) using three different FDA-approved human inhaler devices followed by interaction parameter analyses. Multiple spray drying pump rates (25%, 75%, and 100%) successfully produced co-spray dried TMC:mannitol powders. Raw TMC exhibited a first-order phase transition temperature at 58.15 +/- 0.38 degrees C. Furthermore, the results demonstrate that these innovative TMC dry powder particles are suitable for targeted delivery to the airways by inhalation.
    • Empirical evidence for resilience of tropical forest photosynthesis in a warmer world

      Smith, Marielle N; Taylor, Tyeen C; van Haren, Joost; Rosolem, Rafael; Restrepo-Coupe, Natalia; Adams, John; Wu, Jin; de Oliveira, Raimundo C; da Silva, Rodrigo; de Araujo, Alessandro C; et al. (NATURE RESEARCH, 2020-10-12)
      Tropical forests may be vulnerable to climate change1-3 if photosynthetic carbon uptake currently operates near a high temperature limit4-6. Predicting tropical forest function requires understanding the relative contributions of two mechanisms of high-temperature photosynthetic declines: stomatal limitation (H1), an indirect response due to temperature-associated changes in atmospheric vapour pressure deficit (VPD)7, and biochemical restrictions (H2), a direct temperature response8,9. Their relative control predicts different outcomes-H1 is expected to diminish with stomatal responses to future co-occurring elevated atmospheric [CO2], whereas H2 portends declining photosynthesis with increasing temperatures. Distinguishing the two mechanisms at high temperatures is therefore critical, but difficult because VPD is highly correlated with temperature in natural settings. We used a forest mesocosm to quantify the sensitivity of tropical gross ecosystem productivity (GEP) to future temperature regimes while constraining VPD by controlling humidity. We then analytically decoupled temperature and VPD effects under current climate with flux-tower-derived GEP trends in situ from four tropical forest sites. Both approaches showed consistent, negative sensitivity of GEP to VPD but little direct response to temperature. Importantly, in the mesocosm at low VPD, GEP persisted up to 38 °C, a temperature exceeding projections for tropical forests in 2100 (ref. 10). If elevated [CO2] mitigates VPD-induced stomatal limitation through enhanced water-use efficiency as hypothesized9,11, tropical forest photosynthesis may have a margin of resilience to future warming.
    • Ensemble dimensionality reduction and feature gene extraction for single-cell RNA-seq data

      Sun, Xiaoxiao; Liu, Yiwen; An, Lingling; Univ Arizona, Dept Epidemiol & Biostat; Univ Arizona, Dept Biosyst Engn (NATURE RESEARCH, 2020-11-17)
      Single-cell RNA sequencing (scRNA-seq) technologies allow researchers to uncover the biological states of a single cell at high resolution. For computational efficiency and easy visualization, dimensionality reduction is necessary to capture gene expression patterns in low-dimensional space. Here we propose an ensemble method for simultaneous dimensionality reduction and feature gene extraction (EDGE) of scRNA-seq data. Different from existing dimensionality reduction techniques, the proposed method implements an ensemble learning scheme that utilizes massive weak learners for an accurate similarity search. Based on the similarity matrix constructed by those weak learners, the low-dimensional embedding of the data is estimated and optimized through spectral embedding and stochastic gradient descent. Comprehensive simulation and empirical studies show that EDGE is well suited for searching for meaningful organization of cells, detecting rare cell types, and identifying essential feature genes associated with certain cell types. Dimensionality reduction is used to make the analysis of single-cell RNA sequencing data more efficient. Here the authors propose a method, EDGE, which simultaneously carries out dimensionality reduction and feature gene extraction.
    • FADS genetic and metabolomic analyses identify the ∆5 desaturase (FADS1) step as a critical control point in the formation of biologically important lipids

      Reynolds, Lindsay M; Dutta, Rahul; Seeds, Michael C; Lake, Kirsten N; Hallmark, Brian; Mathias, Rasika A; Howard, Timothy D; Chilton, Floyd H; Univ Arizona, Dept Nutr Sci; Univ Arizona, BIO5 Inst (NATURE RESEARCH, 2020-09-28)
      Humans have undergone intense evolutionary selection to optimize their capacity to generate necessary quantities of long chain (LC-) polyunsaturated fatty acid (PUFA)-containing lipids. To better understand the impact of genetic variation within a locus of three FADS genes (FADS1, FADS2, and FADS3) on a diverse family of lipids, we examined the associations of 247 lipid metabolites (including four major classes of LC-PUFA-containing molecules and signaling molecules) with common and low-frequency genetic variants located within the FADS locus. Genetic variation in the FADS locus was strongly associated (p < 1.2 × 10-8) with 52 LC-PUFA-containing lipids and signaling molecules, including free fatty acids, phospholipids, lyso-phospholipids, and an endocannabinoid. Notably, the majority (80%) of FADS-associated lipids were not significantly associated with genetic variants outside of this FADS locus. These findings highlight the central role genetic variation at the FADS locus plays in regulating levels of physiologically critical LC-PUFA-containing lipids that participate in innate immunity, energy homeostasis, and brain development/function.
    • Global distribution and conservation status of ecologically rare mammal and bird species

      Loiseau, Nicolas; Mouquet, Nicolas; Casajus, Nicolas; Grenié, Matthias; Guéguen, Maya; Maitner, Brian; Mouillot, David; Ostling, Annette; Renaud, Julien; Tucker, Caroline; et al. (NATURE RESEARCH, 2020-10-08)
      Identifying species that are both geographically restricted and functionally distinct, i.e. supporting rare traits and functions, is of prime importance given their risk of extinction and their potential contribution to ecosystem functioning. We use global species distributions and functional traits for birds and mammals to identify the ecologically rare species, understand their characteristics, and identify hotspots. We find that ecologically rare species are disproportionately represented in IUCN threatened categories, insufficiently covered by protected areas, and for some of them sensitive to current and future threats. While they are more abundant overall in countries with a low human development index, some countries with high human development index are also hotspots of ecological rarity, suggesting transboundary responsibility for their conservation. Altogether, these results state that more conservation emphasis should be given to ecological rarity given future environmental conditions and the need to sustain multiple ecosystem processes in the long-term. There are many available ways to rank species for conservation prioritization. Here the authors identify species of mammals and birds that are both spatially restricted and functionally distinct, finding that such species are currently insufficiently protected and disproportionately sensitive to current and future threats.
    • Highly accurate long-read HiFi sequencing data for five complex genomes

      Hon, Ting; Mars, Kristin; Young, Greg; Tsai, Yu-Chih; Karalius, Joseph W; Landolin, Jane M; Maurer, Nicholas; Kudrna, David; Hardigan, Michael A; Steiner, Cynthia C; et al. (NATURE RESEARCH, 2020-11-17)
      The PacBio® HiFi sequencing method yields highly accurate long-read sequencing datasets with read lengths averaging 10-25 kb and accuracies greater than 99.5%. These accurate long reads can be used to improve results for complex applications such as single nucleotide and structural variant detection, genome assembly, assembly of difficult polyploid or highly repetitive genomes, and assembly of metagenomes. Currently, there is a need for sample data sets to both evaluate the benefits of these long accurate reads as well as for development of bioinformatic tools including genome assemblers, variant callers, and haplotyping algorithms. We present deep coverage HiFi datasets for five complex samples including the two inbred model genomes Mus musculus and Zea mays, as well as two complex genomes, octoploid Fragaria × ananassa and the diploid anuran Rana muscosa. Additionally, we release sequence data from a mock metagenome community. The datasets reported here can be used without restriction to develop new algorithms and explore complex genome structure and evolution. Data were generated on the PacBio Sequel II System.
    • Highly sampled measurements in a controlled atmosphere at the Biosphere 2 Landscape Evolution Observatory

      Arevalo, Jorge; Zeng, Xubin; Durcik, Matej; Sibayan, Michael; Pangle, Luke; Abramson, Nate; Bugaj, Aaron; Ng, Wei-Ren; Kim, Minseok; Barron-Gafford, Greg; et al. (NATURE RESEARCH, 2020-09)
      Land-atmosphere interactions at different temporal and spatial scales are important for our understanding of the Earth system and its modeling. The Landscape Evolution Observatory (LEO) at Biosphere 2, managed by the University of Arizona, hosts three nearly identical artificial bare-soil hillslopes with dimensions of 11x30 m(2) (1m depth) in a controlled and highly monitored environment within three large greenhouses. These facilities provide a unique opportunity to explore these interactions. The dataset presented here is a subset of the measurements in each LEO's hillslopes, from 1 July 2015 to 30 June 2019 every 15minutes, consisting of temperature, water content and heat flux of the soil (at 5cm depth) for 12 co-located points; temperature, relative humidity and wind speed above ground at 5 locations and 5 different heights ranging from 0.25m to 9-10m; 3D wind at 1 location; the four components of radiation at 2 locations; spatially aggregated precipitation rates, total subsurface discharge, and relative water storage; and the measurements from a weather station outside the greenhouses.
    • A multi-scale eco-evolutionary model of cooperation reveals how microbial adaptation influences soil decomposition

      Abs, Elsa; Leman, Hélène; Ferrière, Régis; Univ Arizona; Univ Arizona, Dept Ecol & Evolutionary Biol (NATURE RESEARCH, 2020-09-21)
      The decomposition of soil organic matter (SOM) is a critical process in global terrestrial ecosystems. SOM decomposition is driven by micro-organisms that cooperate by secreting costly extracellular (exo-)enzymes. This raises a fundamental puzzle: the stability of microbial decomposition in spite of its evolutionary vulnerability to "cheaters"-mutant strains that reap the benefits of cooperation while paying a lower cost. Resolving this puzzle requires a multi-scale eco-evolutionary model that captures the spatio-temporal dynamics of molecule-molecule, molecule-cell, and cell-cell interactions. The analysis of such a model reveals local extinctions, microbial dispersal, and limited soil diffusivity as key factors of the evolutionary stability of microbial decomposition. At the scale of whole-ecosystem function, soil diffusivity influences the evolution of exo-enzyme production, which feeds back to the average SOM decomposition rate and stock. Microbial adaptive evolution may thus be an important factor in the response of soil carbon fluxes to global environmental change. Abs et al. develop a multi-scale model to explain the evolution of microbial cooperation driving the decomposition of soil organic matter. Their model shows that the evolutionary stability of decomposition depends on a combination of local extinctions, microbial dispersal, and limited soil diffusivity.
    • Mutations disrupting neuritogenesis genes confer risk for cerebral palsy

      Jin, Sheng Chih; Lewis, Sara A; Bakhtiari, Somayeh; Zeng, Xue; Sierant, Michael C; Shetty, Sheetal; Nordlie, Sandra M; Elie, Aureliane; Corbett, Mark A; Norton, Bethany Y; et al. (NATURE RESEARCH, 2020-09-28)
      Whole-exome sequencing of 250 parent-offspring trios identifies an enrichment of rare damaging de novo mutations in individuals with cerebral palsy and implicates genetically mediated dysregulation of early neuronal connectivity in the etiology of this disorder. In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.
    • Neutral sphingomyelinase 2 regulates inflammatory responses in monocytes/macrophages induced by TNF-α

      Al-Rashed, Fatema; Ahmad, Zunair; Thomas, Reeby; Melhem, Motasem; Snider, Ashley J; Obeid, Lina M; Al-Mulla, Fahd; Hannun, Yusuf A; Ahmad, Rasheed; Univ Arizona, Coll Agr & Life Sci, Dept Nutr Sci (NATURE RESEARCH, 2020-10-08)
      Obesity is associated with elevated levels of TNF-alpha and proinflammatory CD11c monocytes/macrophages. TNF-alpha mediated dysregulation in the plasticity of monocytes/macrophages is concomitant with pathogenesis of several inflammatory diseases, including metabolic syndrome, but the underlying mechanisms are incompletely understood. Since neutral sphingomyelinase-2 (nSMase2: SMPD3) is a key enzyme for ceramide production involved in inflammation, we investigated whether nSMase2 contributed to the inflammatory changes in the monocytes/macrophages induced by TNF-alpha. In this study, we demonstrate that the disruption of nSMase activity in monocytes/macrophages either by chemical inhibitor GW4869 or small interfering RNA (siRNA) against SMPD3 results in defects in the TNF-alpha mediated expression of CD11c. Furthermore, blockage of nSMase in monocytes/macrophages inhibited the secretion of inflammatory mediators IL-1 beta and MCP-1. In contrast, inhibition of acid SMase (aSMase) activity did not attenuate CD11c expression or secretion of IL-1 beta and MCP-1. TNF-alpha-induced phosphorylation of JNK, p38 and NF-kappa B was also attenuated by the inhibition of nSMase2. Moreover, NF-kB/AP-1 activity was blocked by the inhibition of nSMase2. SMPD3 was elevated in PBMCs from obese individuals and positively corelated with TNF-alpha gene expression. These findings indicate that nSMase2 acts, at least in part, as a master switch in the TNF-alpha mediated inflammatory responses in monocytes/macrophages.
    • Seasonal flow dynamics exacerbate overlap between artisanal fisheries and imperiled Ganges River dolphins

      Paudel, Shambhu; Koprowski, John L; Cove, Michael V; Univ Arizona, Sch Nat Resources & Environm (NATURE RESEARCH, 2020-11-02)
      Here we quantify the effects of artisanal fisheries on the ecology of a small cetacean, the Ganges River dolphin (Platanista gangetica gangetica, GRD), in a large river system of Nepal. We examine the size-classes of fisheries' catches, behavioural changes in GRD in response to fishing activities, and diel overlap between GRD and fishing activity. We observed high human exploitation rates (>60% of the total catch per effort) of GRD-preferred prey sizes, indicating risks of high resource competition and dietary overlap, especially during the low water season when resource availability is reduced. Competitive interactions in the feeding niches during the low water season, plus temporal overlap between the peak exploitation and critical life-history events (e.g., reproduction), likely have ecological consequences. Furthermore, we detected 48% (95% CI 43-52%) increase in the chance of behavioural changes among dolphins exposed to anthropopressure (fishing activity), risking social behaviour impairment in exposed dolphins. The higher diel overlap and increased diel coefficient as the surveys progressed towards the monsoon season suggest temporal shifts in GRD socio-behavioural states and seasonal effects on resource partitioning, respectively. This work identifies drivers of small cetaceans-fisheries interactions and their consequences, and can be used to help reduce biologically significant fishing impacts on small cetaceans. Mitigation strategies, together with river sanctuary and distanced-based approaches, should be urgently included in a framework of ecosystem-based management.