Where Does All the Poison Go? Investigating Toxicokinetics of Newt (Taricha) Tetrodotoxin (TTX) in Garter Snakes (Thamnophis).

Animals that consume toxic diets provide models for understanding the molecular and physiological adaptations to ecological challenges. Garter snakes (Thamnophis) in western North America prey on Pacific newts (Taricha), which employ tetrodotoxin (TTX) as an antipredator defense. These snakes possess mutations in voltage-gated sodium channels (Nav), the molecular targets of TTX, that decrease the binding ability of TTX to sodium channels (target-site resistance). However, genetic variation at these loci that cannot explain all the phenotypic variation in TTX resistance in Thamnophis. We explored a separate means of resistance, toxin metabolism, to determine if TTX-resistant snakes either rapidly remove TTX or sequester TTX. We examined the metabolism and distribution of TTX in the body (toxicokinetics), to determine differences between TTX-resistant and TTX-sensitive snakes in the rates at which TTX is eliminated from organs and the whole body (using TTX half-life as our metric). We assayed TTX half-life in snakes from TTX-resistant and TTX-sensitive populations of three garter snake species with a coevolutionary history with newts (T. atratus, T. couchii, T. sirtalis), as well as two non-resistant "outgroup" species (T. elegans, Pituophis catenifer) that seldom (if ever) engage newts. We found TTX half-life varied across species, populations, and tissues. Interestingly, TTX half-life was shortest in T. elegans and P. catenifer compared to all other snakes. Furthermore, TTX-resistant populations of T. couchii and T. sirtalis eliminated TTX faster (shorter TTX half-life) than their TTX-sensitive counterparts, while populations of TTX-resistant and TTX-sensitive T. atratus showed no difference rates of TTX removal (same TTX half-life). The ability to rapidly eliminate TTX may have permitted increased prey consumption, which may have promoted the evolution of additional resistance mechanisms. Finally, snakes still retain substantial amounts of TTX, and we projected that snakes could be dangerous to their own predators days to weeks following the ingestion of a single newt. Thus, aspects of toxin metabolism may have been key in driving predator-prey relationships, and important in determining other ecological interactions.

Symptomatic Pericardial Effusion Associated With Graves' Disease in a Pediatric Patient.

Pericarditis is a well-known complication of hypothyroidism. Although pericarditis and pericardial effusions have been reported as rare complications of hyperthyroidism in adults, they are rarely reported in the pediatric population. In this case report, we describe a 12-year-old, previously healthy girl with nighttime chest pain, dyspnea, tachycardia, and abnormal thyroid function studies consistent with hyperthyroidism who was found to have pericarditis and pericardial effusion requiring pericardiocentesis.

The 2023 Impact of Inflammatory Bowel Disease in Canada: COVID-19 and IBD.

The COVID-19 pandemic had a monumental impact on the inflammatory bowel disease (IBD) community. At the beginning of the pandemic, knowledge on the effect of SARS-CoV-2 on IBD was lacking, especially in those with medication-suppressed immune systems. Throughout the pandemic, scientific literature exponentially expanded, resulting in clinical guidance and vaccine recommendations for individuals with IBD. Crohn's and Colitis Canada established the COVID-19 and IBD Taskforce to process and communicate rapidly transforming knowledge into guidance for individuals with IBD and their caregivers, healthcare providers, and policy makers. Recommendations at the onset of the pandemic were based on conjecture from experience of prior viruses, with a precautionary principle in mind. We now know that the risk of acquiring COVID-19 in those with IBD is the same as the general population. As with healthy populations, advanced age and comorbidities increase the risk for severe COVID-19. Individuals with IBD who are actively flaring and/or who require high doses of prednisone are susceptible to severe COVID-19 outcomes. Consequently, sustaining maintenance therapies (e.g., biologics) is recommended. A three-dose mRNA COVID-19 vaccine regimen in those with IBD produces a robust antibody response with a similar adverse event profile as the general population. Breakthrough infections following vaccine have been observed, particularly as the virus continues to evolve, which supports receiving a bivalent vaccine booster. Limited data exist on the impact of IBD and its therapies on long-term outcomes following COVID-19. Ongoing research is necessary to address new concerns manifesting in those with IBD throughout the evolving pandemic.

Multiple Clonostachys rosea UDP-Glycosyltransferases Contribute to the Production of 15-Acetyl-Deoxynivalenol-3-O-Glycoside When Confronted with Fusarium graminearum.

Mycotoxins, derived from toxigenic fungi such as Fusarium, Aspergillus, and Penicillium species have impacted the human food chain for thousands of years. Deoxynivalenol (DON), is a tetracyclic sesquiterpenoid type B trichothecene mycotoxin predominantly produced by F. culmorum and F. graminearum during the infection of corn, wheat, oats, barley, and rice. Glycosylation of DON is a protective detoxification mechanism employed by plants. More recently, DON glycosylating activity has also been detected in fungal microparasitic (biocontrol) fungal organisms. Here we follow up on the reported conversion of 15-acetyl-DON (15-ADON) into 15-ADON-3-O-glycoside (15-ADON-3G) in Clonostachys rosea. Based on the hypothesis that the reaction is likely being carried out by a uridine diphosphate glycosyl transferase (UDP-GTase), we applied a protein structural comparison strategy, leveraging the availability of the crystal structure of rice Os70 to identify a subset of potential C. rosea UDP-GTases that might have activity against 15-ADON. Using CRISPR/Cas9 technology, we knocked out several of the selected UDP-GTases in the C. rosea strain ACM941. Evaluation of the impact of knockouts on the production of 15-ADON-3G in confrontation assays with F. graminearum revealed multiple UDP-GTase enzymes, each contributing partial activities. The relationship between these positive hits and other UDP-GTases in fungal and plant species is discussed.

Clonostachys rosea 'omics profiling: identification of putative metabolite-gene associations mediating its in vitro antagonism against Fusarium graminearum.

BACKGROUND: Clonostachys rosea is an established biocontrol agent. Selected strains have either mycoparasitic activity against known pathogens (e.g. Fusarium species) and/or plant growth promoting activity on various crops. Here we report outcomes from a comparative 'omics analysis leveraging a temporal variation in the in vitro antagonistic activities of C. rosea strains ACM941 and 88-710, toward understanding the molecular mechanisms underpinning mycoparasitism. RESULTS: Transcriptomic data highlighted specialized metabolism and membrane transport related genes as being significantly upregulated in ACM941 compared to 88-710 at a time point when the ACM941 strain had higher in vitro antagonistic activity than 88-710. In addition, high molecular weight specialized metabolites were differentially secreted by ACM941, with accumulation patterns of some metabolites matching the growth inhibition differences displayed by the exometabolites of the two strains. In an attempt to identify statistically relevant relationships between upregulated genes and differentially secreted metabolites, transcript and metabolomic abundance data were associated using IntLIM (Integration through Linear Modeling). Of several testable candidate associations, a putative C. rosea epidithiodiketopiperazine (ETP) gene cluster was identified as a prime candidate based on both co-regulation analysis and transcriptomic-metabolomic data association. CONCLUSIONS: Although remaining to be validated functionally, these results suggest that a data integration approach may be useful for identification of potential biomarkers underlying functional divergence in C. rosea strains.

Major proliferation of transposable elements shaped the genome of the soybean rust pathogen Phakopsora pachyrhizi.

With >7000 species the order of rust fungi has a disproportionately large impact on agriculture, horticulture, forestry and foreign ecosystems. The infectious spores are typically dikaryotic, a feature unique to fungi in which two haploid nuclei reside in the same cell. A key example is Phakopsora pachyrhizi, the causal agent of Asian soybean rust disease, one of the world's most economically damaging agricultural diseases. Despite P. pachyrhizi's impact, the exceptional size and complexity of its genome prevented generation of an accurate genome assembly. Here, we sequence three independent P. pachyrhizi genomes and uncover a genome up to 1.25 Gb comprising two haplotypes with a transposable element (TE) content of ~93%. We study the incursion and dominant impact of these TEs on the genome and show how they have a key impact on various processes such as host range adaptation, stress responses and genetic plasticity.

Pea and lentil 7S globulin crystal structures with comparative immunoglobulin epitope mapping.

Legumes represent an affordable high protein, nutrient dense food source. However, the vast majority of legume crops contain proteins that are known allergens for susceptible individuals. These include proteins from the 7S globulin family, which comprise a vast majority of seed storage proteins. Here, the crystal structures of 7S globulins from Pisum sativum L. (pea) and Lens culinaris Medicus (lentil) are presented for the first time, including pea vicillin and convicilin, and lentil vicilin. All three structures maintain the expected 7S globulin fold, with trimeric quaternary structure and monomers comprised of ß-barrel N- and C-modules. The potential impact of sequence differences on structure and packing in the different crystal space groups is noted, with potential relevance to packing upon seed deposition. Mapping on the obtained crystal structures highlights significant Ig epitope overlap between pea, lentil, peanut and soya bean and significant coverage of the entire seed storage protein, emphasizing the challenge in addressing food allergies. How recently developed biologicals might be refined to be more effective, or how these seed storage proteins might be modified in planta to be less immuno-reactive remain challenges for the future. With legumes representing an affordable, high protein, nutrient dense food source, this work will enable important research in the context of global food security and human health on an ongoing basis.

A Community-Based Participatory Intervention in the United States Using Data to Shift the Community Narrative From Deficits to Strengths.

With Minneapolis, Minnesota, partners, we developed a community-based participatory intervention using a mobile health application to provide actionable data to communities. More than 550 participants completed the survey. Key messages included strengths in our homes, neighborhoods, and faith communities. Key challenges were related to substance use and sleeping. We jointly conducted virtual community meetings such as webinars, Facebook Live shows, and online newsletters to begin to shift the community narrative from deficits to whole-person health, including strengths. (Am J Public Health. 2022;112(S3):S275-S278. https://doi.org/10.2105/AJPH.2022.306852).

A general pattern of trade-offs between ecosystem resistance and resilience to tropical cyclones.

Tropical cyclones drive coastal ecosystem dynamics, and their frequency, intensity, and spatial distribution are predicted to shift with climate change. Patterns of resistance and resilience were synthesized for 4138 ecosystem time series from n = 26 storms occurring between 1985 and 2018 in the Northern Hemisphere to predict how coastal ecosystems will respond to future disturbance regimes. Data were grouped by ecosystems (fresh water, salt water, terrestrial, and wetland) and response categories (biogeochemistry, hydrography, mobile biota, sedentary fauna, and vascular plants). We observed a repeated pattern of trade-offs between resistance and resilience across analyses. These patterns are likely the outcomes of evolutionary adaptation, they conform to disturbance theories, and they indicate that consistent rules may govern ecosystem susceptibility to tropical cyclones.

Big or small, patchy all: Resolution of marine plankton patch structure at micro- to submesoscales for 36 taxa.

Despite the ecological importance of microscale (0.01­1 meter) and fine-scale (1 to hundreds of meters) plankton patchiness, the dimensions and taxonomic identity of patches in the ocean are nearly unknown. We used underwater imaging to identify the position, horizontal length scale, and density of taxa-specific patches of 32 million organisms representing 36 taxa (200 micrometers to 20 centimeters) in the continental and oceanic environments of a subtropical, western boundary current. Patches were the most frequent in shallow, continental waters. For multiple taxa, patch count varied parabolically with background density. Taxa-specific patch length and organism size exhibited negative size scaling relationships. Organism size explained 21 to 30% of the variance in patch length. The dominant length scale was phylogenetically random and <100 meters for 64% of taxa. The predominance of micro- and fine-scale patches among a diverse suite of plankton suggests social and coactive processes may contribute to patch formation.

Phenotypic and functional variation in venom and venom resistance of two sympatric rattlesnakes and their prey.

Predator-prey interactions often lead to the coevolution of adaptations associated with avoiding predation and, for predators, overcoming those defences. Antagonistic coevolutionary relationships are often not simple interactions between a single predator and prey but rather a complex web of interactions between multiple coexisting species. Coevolution between venomous rattlesnakes and small mammals has led to physiological venom resistance in several mammalian taxa. In general, viperid venoms contain large quantities of snake venom metalloproteinase toxins (SVMPs), which are inactivated by SVMP inhibitors expressed in resistant mammals. We explored variation in venom chemistry, SVMP expression, and SVMP resistance across four co-distributed species (California Ground Squirrels, Bryant's Woodrats, Southern Pacific Rattlesnakes, and Red Diamond Rattlesnakes) collected from four different populations in Southern California. Our aim was to understand phenotypic and functional variation in venom and venom resistance in order to compare coevolutionary dynamics of a system involving two sympatric predator-prey pairs to past studies that have focused on single pairs. Proteomic analysis of venoms indicated that these rattlesnakes express different phenotypes when in sympatry, with Red Diamonds expressing more typical viperid venom (with a diversity of SVMPs) and Southern Pacifics expressing a more atypical venom with a broader range of non-enzymatic toxins. We also found that although blood sera from both mammals were generally able to inhibit SVMPs from both rattlesnake species, inhibition depended strongly on the snake population, with snakes from one geographic site expressing SVMPs to which few mammals were resistant. Additionally, we found that Red Diamond venom, rather than woodrat resistance, was locally adapted. Our findings highlight the complexity of coevolutionary relationships between multiple predators and prey that exhibit similar offensive and defensive strategies in sympatry.

The low FODMAP diet for IBS; A multicentre UK study assessing long term follow up.

BACKGROUND: The low FODMAP diet (LFD) is effective in managing irritable bowel syndrome (IBS) in the short term. This study assessed the long-term effect of the LFD on symptoms, nutritional composition and socialising. METHODS: Patients with IBS who received dietetic-led LFD advice were approached at long term follow up (>6 months post LFD advice) from six centres across the United Kingdom. Participants completed questionnaires assessing gastrointestinal symptoms, adherence, nutritional intake, dietary acceptability and food related quality of life (QOL). RESULTS: 205 participants completed the study, with a mean follow up of 44 months (3.7 years). Adequate symptom relief was noted in 60% of individuals at long term follow up, with 76% being on the personalisation phase of the LFD (pLFD). Mean nutritional intake did not differ between individuals on the pLFD versus habitual diet, with no difference in fructan intake (2.9 g/d vs 2.9 g/d, p = 0.96). The majority (80%) of individuals on the pLFD consumed specific 'free-from' products at the long term, with the purchase of gluten or wheat free products being the commonest (68%). CONCLUSION: The majority of patients follow the pLFD in the long term, with a large proportion purchasing gluten or wheat free products to manage their symptoms.

Predicting consequences of POP-induced disruption of blubber glucose uptake, mass gain rate and thyroid hormone levels for weaning mass in grey seal pups.

Persistent organic pollutants (POPs) are endocrine disruptors that alter adipose tissue development, regulation and function. Top marine predators are particularly vulnerable because they possess large fat stores that accumulate POPs. However, links between endocrine or adipose tissue function disruption and whole animal energetics have rarely been investigated. We predicted the impact of alterations to blubber metabolic characteristics and circulating thyroid hormone (TH) levels associated with polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides (OCPs) on suckling mass gain and weaning mass in wild grey seal pups. Glucose uptake by inner blubber was a strong predictor of whole animal mass gain rate, which in turn, resulted in heavier weaning mass. Weaning mass was predicted to increase by 3.7 ± 1.59 (sem) %, through increased mass gain rate, in the absence of the previously reported suppressive effect of dioxin-like PCB (DL-PCBs) on blubber glucose uptake. PBDEs were, conversely, associated with faster mass gain. Alleviation of this effect was predicted to reduce weaning mass by 6.02 ± 1.86% (sem). To better predict POPs effects on energy balance, it is crucial to determine if and how PBDEs promote mass gain in grey seal pups. Weaning mass was negatively related to total T3 (TT3) levels. A 20% (range = 9.3-31.7%) reduction in TT3 by DL-PCBs partially overcame the effect of DL-PCB -mediated reduction in blubber glucose uptake. Overall, DL-PCBs were thus predicted to reduce weaning mass by 1.86 ± 1.60%. Organohalogen impacts on whole-animal energy balance in grey seal pups appear to partially offset each other through opposing effects on different mechanisms. POP effects were generally minor, but the largest POP-induced reductions in weaning mass were predicted to occur in pups that were already small. Since weaning mass is positively related to first-year survival, POPs may disproportionately affect smaller individuals, and could continue to have population-level impacts even when levels are relatively low compared to historical values. Our findings show how in vitro experiments combined with measurements in vivo can help elucidate mechanisms that underpin energy balance regulation and help to quantify the magnitude of disruptive effects by contaminants and other stressors in wildlife.

Draft Genome Resources for Plant-Beneficial Fungi Clonostachys rosea Strains ACM941 and 88-710.

Clonostachys rosea strains ACM941 and 88-710 are beneficial microbes recognized for their plant disease control and growth promotion properties, respectively, when applied to economically important crops. In addition to their geographical and functional overlap, the two strains also share a high degree of genetic similarity. In an effort to identify the subtleties that underlie their strain-specific applications, their genomic sequence is reported here. The genome size of ACM941 was estimated to be 56.9 Mb, encoding 17,585 putative genes, while strain 88-710 was estimated to have a 55.5 Mb genome size, containing 17,188 predicted genes. Overall, ACM941 and 88-710 share >96% of their encoded genomes, such that their strain-specific characteristics are likely encoded in either the remaining variable 4% or differentially regulated shared genes or both. These genomic sequences form a foundation for future studies aimed at identifying the genomic and metabolic machinery driving their respective beneficial properties.

Project Orbis: Global Collaborative Review Program.

In 2019, the FDA Oncology Center of Excellence launched Project Orbis, a global collaborative review program to facilitate faster patient access to innovative cancer therapies across multiple countries. Project Orbis aims for concurrent submission, review, and regulatory action for high-impact clinically significant marketing applications among the participating partner countries. Current Project Orbis partners (POP) include the regulatory health authorities (RHA) of Australia, Brazil, Canada, Singapore, and Switzerland. Project Orbis leverages the existing scientific and regulatory partnerships between the various RHA under mutual confidentiality agreements. While FDA serves as the primary coordinator for application selection and review, each country remains fully independent on their final regulatory decision. In the first year of Project Orbis (June 2019 to June 2020), a total of 60 oncology marketing applications were received, representing 16 unique projects, and resulting in 38 approvals. New molecular entities, also known as new active substances, comprised 28% of the received marketing applications. The median time gap between FDA and Orbis submission dates was 0.6 months with a range of -0.8 to 9.0 months. Across the program, the median time-to-approval was similar between FDA (4.2 months, range 0.9-6.9, N = 18) and the POP (4.4 months, range 1.7-6.8, N = 20). Participating countries have signified a strong commitment for continuation and growth of the program. Project Orbis expansion considerations include the addition of more countries and management of more complex applications.

Global variability in seawater Mg:Ca and Sr:Ca ratios in the modern ocean.

Seawater Mg:Ca and Sr:Ca ratios are biogeochemical parameters reflecting the Earth-ocean-atmosphere dynamic exchange of elements. The ratios' dependence on the environment and organisms' biology facilitates their application in marine sciences. Here, we present a measured single-laboratory dataset, combined with previous data, to test the assumption of limited seawater Mg:Ca and Sr:Ca variability across marine environments globally. High variability was found in open-ocean upwelling and polar regions, shelves/neritic and river-influenced areas, where seawater Mg:Ca and Sr:Ca ratios range from ∼4.40 to 6.40 mmol:mol and ∼6.95 to 9.80 mmol:mol, respectively. Open-ocean seawater Mg:Ca is semiconservative (∼4.90 to 5.30 mol:mol), while Sr:Ca is more variable and nonconservative (∼7.70 to 8.80 mmol:mol); both ratios are nonconservative in coastal seas. Further, the Ca, Mg, and Sr elemental fluxes are connected to large total alkalinity deviations from International Association for the Physical Sciences of the Oceans (IAPSO) standard values. Because there is significant modern seawater Mg:Ca and Sr:Ca ratios variability across marine environments we cannot absolutely assume that fossil archives using taxa-specific proxies reflect true global seawater chemistry but rather taxa- and process-specific ecosystem variations, reflecting regional conditions. This variability could reconcile secular seawater Mg:Ca and Sr:Ca ratio reconstructions using different taxa and techniques by assuming an error of 1 to 1.50 mol:mol, and 1 to 1.90 mmol:mol, respectively. The modern ratios' variability is similar to the reconstructed rise over 20 Ma (Neogene Period), nurturing the question of seminonconservative behavior of Ca, Mg, and Sr over modern Earth geological history with an overlooked environmental effect.

Transcriptomic and Exometabolomic Profiling Reveals Antagonistic and Defensive Modes of Clonostachys rosea Action Against Fusarium graminearum.

The mycoparasite Clonostachys rosea ACM941 is under development as a biocontrol organism against Fusarium graminearum, the causative agent of Fusarium head blight in cereals. To identify molecular factors associated with this interaction, the transcriptomic and exometabolomic profiles of C. rosea and F. graminearum GZ3639 were compared during coculture. Prior to physical contact, the antagonistic activity of C. rosea correlated with a response heavily dominated by upregulation of polyketide synthase gene clusters, consistent with the detected accumulation of corresponding secondary metabolite products. Similarly, prior to contact, trichothecene gene clusters were upregulated in F. graminearum, while those responsible for fusarielin and fusarin biosynthesis were downregulated, correlating with an accumulation of trichothecene products in the interaction zone over time. A concomitant increase in 15-acetyl deoxynivalenol-3-glucoside in the interaction zone was also detected, with C. rosea established as the source of this detoxified mycotoxin. After hyphal contact, C. rosea was found to predominantly transcribe genes encoding cell wall-degradation enzymes, major facilitator superfamily sugar transporters, anion:cation symporters, as well as alternative carbon source utilization pathways, together indicative of a transition to necrotropism at this stage. F. graminearum notably activated the transcription of phosphate starvation pathway signature genes at this time. Overall, a number of signature molecular mechanisms likely contributing to antagonistic activity by C. rosea against F. graminearum, as well as its mycotoxin tolerance, are identified in this report, yielding several new testable hypotheses toward understanding the basis of C. rosea as a biocontrol agent for continued agronomic development and application.

Prey and predator overlap at the edge of a mesoscale eddy: fine-scale, in-situ distributions to inform our understanding of oceanographic processes.

Eddies can enhance primary as well as secondary production, creating a diverse meso- and sub-mesoscale seascape at the eddy front which can affect the aggregation of plankton and particles. Due to the coarse resolution provided by sampling with plankton nets, our knowledge of plankton distributions at these edges is limited. We used a towed, undulating underwater imaging system to investigate the physical and biological drivers of zoo- and ichthyoplankton aggregations at the edge of a decaying mesoscale eddy (ME) in the Straits of Florida. Using a sparse Convolutional Neural Network we identified 132 million images of plankton. Larval fish and Oithona spp. copepod concentrations were significantly higher in the eddy water mass, compared to the Florida Current water mass, only four days before the ME's dissipation. Larval fish and Oithona distributions were tightly coupled, indicating potential predator-prey interactions. Larval fishes are known predators of Oithona, however, Random Forests models showed that Oithona spp. and larval fish concentrations were primarily driven by variables signifying the physical footprint of the ME, such as current speed and direction. These results suggest that eddy-related advection leads to largely passive overlap between predator and prey, a positive, energy-efficient outcome for predators at the expense of prey.