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Abstract Background Environmental reservoirs of antibiotic resistance pose a threat to human and animal health. Aquatic biofilms impacted by wastewater effluent (WW) are known environmental reservoirs for antibiotic resistance; however, the relative importance of biotic factors and abiotic factors from WW on the abundance of antibiotic resistance genes (ARGs) within aquatic biofilms remains unclear. Additionally, experimental evidence is limited within complex aquatic microbial communities as to whether genes bearing low sequence similarity to validated reference ARGs are functional as ARGs. Results To disentangle the effects of abiotic and biotic factors on ARG abundances, natural biofilms were previously grown in flume systems with different proportions of stream water and either ultrafiltered or non-ultrafiltered WW. In this study, we conducted deep shotgun metagenomic sequencing of 75 biofilm, stream, and WW samples from these flume systems and compared the taxonomic and functional microbiome and resistome composition. Statistical analysis revealed an alignment of the resistome and microbiome composition and a significant association with experimental treatment. Several ARG classes exhibited an increase in normalized metagenomic abundances in biofilms grown with increasing percentages of non-ultrafiltered WW. In contrast, sulfonamide and extended-spectrum beta-lactamase ARGs showed greater abundances in biofilms grown in ultrafiltered WW compared to non-ultrafiltered WW. Overall, our results pointed toward the dominance of biotic factors over abiotic factors in determining ARG abundances in WW-impacted stream biofilms and suggested gene family-specific mechanisms for ARGs that exhibited divergent abundance patterns. To investigate one of these specific ARG families experimentally, we biochemically characterized a new beta-lactamase from the Planctomycetota (Phycisphaeraceae). This beta-lactamase displayed activity in the cleavage of cephalosporin analog despite sharing a low sequence identity with known ARGs. Conclusions This discovery of a functional planctomycete beta-lactamase ARG is noteworthy, not only because it was the first beta-lactamase to be biochemically characterized from this phylum, but also because it was not detected by standard homology-based ARG tools. In summary, this study conducted a metagenomic analysis of the relative importance of biotic and abiotic factors in the context of WW discharge and their impact on both known and new ARGs in aquatic biofilms. Video Abstract

Enzymatic biotransformation of xenobiotics by the human microbiota mediates diet-drug-microbe-host interactions and affects human health. Most research on xenobiotics has focused on the gut microbiota while neglecting other body sites, yet over two-thirds of pharmaceuticals are primarily excreted in urine. As a result, the urinary microbiota is exposed to many xenobiotics in much higher concentrations than in the gut. Microbial xenobiotic biocatalysis in the bladder has implications for urinary tract infections and the emergence of antibiotic resistance. However, we have limited knowledge of biotransformations catalyzed by the urinary microbiota. In this perspective, we investigated differences in physicochemical conditions and microbial community composition between the gut and urinary tract. We used a comparative enzyme class mining approach to profile the distribution of xenobiotic-transforming enzyme homologs in genomes of urinary bacteria. Our analysis revealed a discontinuous distribution of enzyme classes even among closely related organisms. We detected diverse amidase homologs involved in pharmaceutical and dietary additive biotransformation pathways, pinpointing microbial candidates to validate for their involvement in xenobiotic transformations in urine. Overall, we highlight the biocatalytic potential of urinary tract bacteria as a lens to study how the human microbiota may respond and adapt to xenobiotic inputs.

Isolation during critical periods of development prevents development of normal social behaviours in mice, and this is thought to involve the prefrontal cortex. Here, the authors identify an activation pattern in parvalbumin-positive interneurons in the dorsal medial prefrontal cortex that when activated promotes sociability behaviours in mice.

The tens of thousands of industrial and synthetic chemicals released into the environment have an unknown but potentially significant capacity to interfere with neurodevelopment. Consequently, there is an urgent need for systematic approaches that can identify disruptive chemicals. Little is known about the impact of environmental chemicals on critical periods of developmental neuroplasticity, in large part, due to the challenge of screening thousands of chemicals. Using an integrative bioinformatics approach, we systematically scanned 2001 environmental chemicals and identified 50 chemicals that consistently dysregulate two transcriptional signatures of critical period plasticity. These chemicals included pesticides (e.g., pyridaben), antimicrobials (e.g., bacitracin), metals (e.g., mercury), anesthetics (e.g., halothane), and other chemicals and mixtures (e.g., vehicle emissions). Application of a chemogenomic enrichment analysis and hierarchical clustering across these diverse chemicals identified two clusters of chemicals with one that mimicked an immune response to pathogen, implicating inflammatory pathways and microglia as a common chemically induced neuropathological process. Thus, we established an integrative bioinformatics approach to systematically scan thousands of environmental chemicals for their ability to dysregulate molecular signatures relevant to critical periods of development.

Abstract Given that thousands of chemicals released into the environment have the potential capacity to harm neurodevelopment, there is an urgent need to systematically evaluate their toxicity. Neurodevelopment is marked by critical periods of plasticity wherein neural circuits are refined by the environment to optimize behavior and function. If chemicals perturb these critical periods, neurodevelopment can be permanently altered. Focusing on 214 human neurotoxicants, we applied an integrative bioinformatics approach using publically available data to identify dozens of neurotoxicant signatures that disrupt a transcriptional signature of a critical period for brain plasticity. This identified lead (Pb) as a critical period neurotoxicant and we confirmed in vivo that Pb partially suppresses critical period plasticity at a time point analogous to exposure associated with autism. This work demonstrates the utility of a novel informatics approach to systematically identify neurotoxicants that disrupt childhood neurodevelopment and can be extended to assess other environmental chemicals.

Abstract Background Worldwide, over 14% of individuals hospitalized for psychiatric reasons have readmissions to hospitals within 30 days after discharge. Predicting patients at risk and leveraging accelerated interventions can reduce the rates of early readmission, a negative clinical outcome (i.e., a treatment failure) that affects the quality of life of patient. To implement individualized interventions, it is necessary to predict those individuals at highest risk for 30-day readmission. In this study, our aim was to conduct a data-driven investigation to find the pharmacological factors influencing 30-day all-cause, intra- and interdepartmental readmissions after an index psychiatric admission, using the compendium of prescription data (prescriptome) from electronic medical records (EMR). Methods The data scientists in the project received a deidentified database from the Mount Sinai Data Warehouse, which was used to perform all analyses. Data was stored in a secured MySQL database, normalized and indexed using a unique hexadecimal identifier associated with the data for psychiatric illness visits. We used Bayesian logistic regression models to evaluate the association of prescription data with 30-day readmission risk. We constructed individual models and compiled results after adjusting for covariates, including drug exposure, age, and gender. We also performed digital comorbidity survey using EMR data combined with the estimation of shared genetic architecture using genomic annotations to disease phenotypes. Results Using an automated, data-driven approach, we identified prescription medications, side effects (primary side effects), and drug-drug interaction-induced side effects (secondary side effects) associated with readmission risk in a cohort of 1275 patients using prescriptome analytics. In our study, we identified 28 drugs associated with risk for readmission among psychiatric patients. Based on prescription data, Pravastatin had the highest risk of readmission (OR = 13.10; 95% CI (2.82, 60.8)). We also identified enrichment of primary side effects (n = 4006) and secondary side effects (n = 36) induced by prescription drugs in the subset of readmitted patients (n = 89) compared to the non-readmitted subgroup (n = 1186). Digital comorbidity analyses and shared genetic analyses further reveals that cardiovascular disease and psychiatric conditions are comorbid and share functional gene modules (cardiomyopathy and anxiety disorder: shared genes (n = 37; P = 1.06815E-06)). Conclusions Large scale prescriptome data is now available from EMRs and accessible for analytics that could improve healthcare outcomes. Such analyses could also drive hypothesis and data-driven research. In this study, we explored the utility of prescriptome data to identify factors driving readmission in a psychiatric cohort. Converging digital health data from EMRs and systems biology investigations reveal a subset of patient populations that have significant comorbidities with cardiovascular diseases are more likely to be readmitted. Further, the genetic architecture of psychiatric illness also suggests overlap with cardiovascular diseases. In summary, assessment of medications, side effects, and drug-drug interactions in a clinical setting as well as genomic information using a data mining approach could help to find factors that could help to lower readmission rates in patients with mental illness.

We describe a new spatial discretization of a continuum gyrokinetic Vlasov model in axisymmetric tokamak edge plasma geometries. The geometries are represented using a multiblock decomposition in which logically distinct blocks are smoothly mapped from rectangular computational domains and are aligned with magnetic flux surfaces to accommodate strong anisotropy induced by the magnetic field. We employ a fourth-order, finite-volume discretization in mapped coordinates to mitigate the computational expense associated with discretization on 4D phase space grids. Applied to a conservative formulation of the gyrokinetic system, a finite-volume approach expresses local conservation discretely in a natural manner involving the calculation of normal fluxes at cell faces. In the approach presented here, the normal fluxes are computed in terms of face-averaged velocity normals in such a way that (i) the divergence-free property of the gyrokinetic velocity is preserved discretely to machine precision, (ii) the configuration space normal velocities are independent of mapping metrics, and (iii) the configuration space normal velocities are computed from exact pointwise evaluation of magnetic field data except for one term. The algorithms described in this paper form the foundation of a continuum gyrokinetic edge code named COGENT, which is used here to perform a convergence study verifying the accuracy of the spatial discretization.