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Background: Allergic rhinitis is a common inflammatory condition of the nasal mucosa that imposes a considerable health burden. Air pollution has been observed to increase the risk of developing allergic rhinitis. We addressed the hypotheses that early life exposure to air toxics is associated with developing allergic rhinitis, and that these effects are mediated by DNA methylation and gene expression in the nasal mucosa. Methods: In a case–control cohort of 505 participants, we geocoded participants' early life exposure to air toxics using data from the US Environmental Protection Agency, assessed physician diagnosis of allergic rhinitis by questionnaire, and collected nasal brushings for whole‐genome DNA methylation and transcriptome profiling. We then performed a series of analyses including differential expression, Mendelian randomization, and causal mediation analyses to characterize relationships between early life air toxics, nasal DNA methylation, nasal gene expression, and allergic rhinitis. Results: Among the 505 participants, 275 had allergic rhinitis. The mean age of the participants was 16.4 years (standard deviation = 9.5 years). Early life exposure to air toxics such as acrylic acid, phosphine, antimony compounds, and benzyl chloride was associated with developing allergic rhinitis. These air toxics exerted their effects by altering the nasal DNA methylation and nasal gene expression levels of genes involved in respiratory ciliary function, mast cell activation, pro‐inflammatory TGF‐β1 signaling, and the regulation of myeloid immune cell function. Conclusions: Our results expand the range of air pollutants implicated in allergic rhinitis and shed light on their underlying biological mechanisms in nasal mucosa. [ABSTRACT FROM AUTHOR]

Interactions between protein kinases and their substrates are critical for the modulation of complex signaling pathways. Currently, there is a large amount of information available about kinases and their substrates in disparate public databases. However, these data are difficult to interpret in the context of cellular systems, which can be facilitated by examining interactions among multiple proteins at once, such as the network of interactions that constitute a signaling pathway. We present KiNet, a user-friendly web portal that integrates and shares information about kinase-substrate interactions from multiple databases of post-translational modifications. KiNet enables the visual exploration of these interactions in systems contexts, such as pathways, domain families, and custom protein set inputs, in an interactive fashion. We expect KiNet to be useful as a knowledge discovery tool for kinase-substrate interactions, and the aggregated KiNet dataset to be useful for protein kinase studies and systems-level analyses. The portal is available at https://kinet.kinametrix.com/. [ABSTRACT FROM AUTHOR]

Protein kinase function and interactions with drugs are controlled in part by the movement of the DFG and ɑC-Helix motifs that are related to the catalytic activity of the kinase. Small molecule ligands elicit therapeutic effects with distinct selectivity profiles and residence times that often depend on the active or inactive kinase conformation(s) they bind. Modern AI-based structural modeling methods have the potential to expand upon the limited availability of experimentally determined kinase structures in inactive states. Here, we first explored the conformational space of kinases in the PDB and models generated by AlphaFold2 (AF2) and ESMFold, two prominent AI-based protein structure prediction methods. Our investigation of AF2's ability to explore the conformational diversity of the kinome at various multiple sequence alignment (MSA) depths showed a bias within the predicted structures of kinases in DFG-in conformations, particularly those controlled by the DFG motif, based on their overabundance in the PDB. We demonstrate that predicting kinase structures using AF2 at lower MSA depths explored these alternative conformations more extensively, including identifying previously unobserved conformations for 398 kinases. Ligand enrichment analyses for 23 kinases showed that, on average, docked models distinguished between active molecules and decoys better than random (average AUC (avgAUC) of 64.58), but select models perform well (e.g., avgAUCs for PTK2 and JAK2 were 79.28 and 80.16, respectively). Further analysis explained the ligand enrichment discrepancy between low- and high-performing kinase models as binding site occlusions that would preclude docking. The overall results of our analyses suggested that, although AF2 explored previously uncharted regions of the kinase conformational space and select models exhibited enrichment scores suitable for rational drug discovery, rigorous refinement of AF2 models is likely still necessary for drug discovery campaigns. Author summary: Greater abundance of kinase structural data in inactive conformations, currently lacking in structural databases, would improve our understanding of how protein kinases function, and expand drug discovery and development for this important family of therapeutic targets. Modern approaches utilizing artificial intelligence and machine learning, like AlphaFold2 and ESMFold, have potential for efficiently capturing novel protein conformations. We provide evidence for a bias within AlphaFold2 and ESMFold to predict structures of kinases in their active states, similar to their overrepresentation in the PDB. We show that lowering the multiple sequence alignment depth used in the AlphaFold2 algorithm can help explore the kinase conformational space more broadly. Through a series of quantitative and visual analyses of the models, we also offer a critique of AlphaFold2-generated models, highlighting their potential utility in drug discovery, but also underscoring the need for further refinement to enhance their suitability for rational drug design. Furthermore, many of the high-quality and high-enriching models we make available may represent starting points for novel drug discovery campaigns. [ABSTRACT FROM AUTHOR]

Air pollution is a well-known contributor to asthma. Air toxics are hazardous air pollutants that cause or may cause serious health effects. Although individual air toxics have been associated with asthma, only a limited number of studies have specifically examined combinations of air toxics associated with the disease. We geocoded air toxic levels from the US National Air Toxics Assessment (NATA) to residential locations for participants of our AiRway in Asthma (ARIA) study. We then applied Data-driven ExposurE Profile extraction (DEEP), a machine learning- based method, to discover combinations of early-life air toxics associated with current use of daily asthma controller medication, lifetime emergency department visit for asthma, and lifetime overnight hospitalization for asthma. We discovered 20 multi-air toxic combinations and 18 single air toxics associated with at least 1 outcome. The multi-air toxic combinations included those containing acrylic acid, ethylidene dichloride, and hydroquinone, and they were significantly associated with asthma outcomes. Several air toxic members of the combinations would not have been identified by single air toxic analyses, supporting the use of machine learning-based methods designed to detect combinatorial effects. Our findings provide knowledge about air toxic combinations associated with childhood asthma., Introduction Air toxics are hazardous air pollutants that cause or may cause serious health effects (1). They are well-established detriments to human respiratory health, especially for children (2-8). In particular, [...]

Air pollution is a well-known contributor to asthma. Air toxics are hazardous air pollutants that cause or may cause serious health effects. Although individual air toxics have been associated with asthma, only a limited number of studies have specifically examined combinations of air toxics associated with the disease. We geocoded air toxic levels from the US National Air Toxics Assessment (NATA) to residential locations for participants of our AiRway in Asthma (ARIA) study. We then applied Data-driven ExposurE Profile extraction (DEEP), a machine learning-based method, to discover combinations of early-life air toxics associated with current use of daily asthma controller medication, lifetime emergency department visit for asthma, and lifetime overnight hospitalization for asthma. We discovered 20 multi-air toxic combinations and 18 single air toxics associated with at least 1 outcome. The multi-air toxic combinations included those containing acrylic acid, ethylidene dichloride, and hydroquinone, and they were significantly associated with asthma outcomes. Several air toxic members of the combinations would not have been identified by single air toxic analyses, supporting the use of machine learning-based methods designed to detect combinatorial effects. Our findings provide knowledge about air toxic combinations associated with childhood asthma. [ABSTRACT FROM AUTHOR]

Background: The prevalence of type 2 diabetes mellitus (DM) and pre-diabetes mellitus (pre-DM) has been increasing among youth in recent decades in the United States, prompting an urgent need for understanding and identifying their associated risk factors. Such efforts, however, have been hindered by the lack of easily accessible youth pre-DM/DM data., Objective: We aimed to first build a high-quality, comprehensive epidemiological data set focused on youth pre-DM/DM. Subsequently, we aimed to make these data accessible by creating a user-friendly web portal to share them and the corresponding codes. Through this, we hope to address this significant gap and facilitate youth pre-DM/DM research., Methods: Building on data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018, we cleaned and harmonized hundreds of variables relevant to pre-DM/DM (fasting plasma glucose level ≥100 mg/dL or glycated hemoglobin  ≥5.7%) for youth aged 12-19 years (N=15,149). We identified individual factors associated with pre-DM/DM risk using bivariate statistical analyses and predicted pre-DM/DM status using our Ensemble Integration (EI) framework for multidomain machine learning. We then developed a user-friendly web portal named Prediabetes/diabetes in youth Online Dashboard (POND) to share the data and codes., Results: We extracted 95 variables potentially relevant to pre-DM/DM risk organized into 4 domains (sociodemographic, health status, diet, and other lifestyle behaviors). The bivariate analyses identified 27 significant correlates of pre-DM/DM (P<.001, Bonferroni adjusted), including race or ethnicity, health insurance, BMI, added sugar intake, and screen time. Among these factors, 16 factors were also identified based on the EI methodology (Fisher P of overlap=7.06×10 6 ). In addition to those, the EI approach identified 11 additional predictive variables, including some known (eg, meat and fruit intake and family income) and less recognized factors (eg, number of rooms in homes). The factors identified in both analyses spanned across all 4 of the domains mentioned. These data and results, as well as other exploratory tools, can be accessed on POND., Conclusions: Using NHANES data, we built one of the largest public epidemiological data sets for studying youth pre-DM/DM and identified potential risk factors using complementary analytical approaches. Our results align with the multifactorial nature of pre-DM/DM with correlates across several domains. Also, our data-sharing platform, POND, facilitates a wide range of applications to inform future youth pre-DM/DM studies., (©Catherine McDonough, Yan Chak Li, Nita Vangeepuram, Bian Liu, Gaurav Pandey. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 02.07.2024.)

One of the promising opportunities of digital health is its potential to lead to more holistic understandings of diseases by interacting with the daily life of patients and through the collection of large amounts of real-world data. Validating and benchmarking indicators of disease severity in the home setting is difficult, however, given the large number of confounders present in the real world and the challenges in collecting ground truth data in the home. Here we leverage two datasets collected from patients with Parkinson's disease, which couples continuous wrist-worn accelerometer data with frequent symptom reports in the home setting, to develop digital biomarkers of symptom severity. Using these data, we performed a public benchmarking challenge in which participants were asked to build measures of severity across 3 symptoms (on/off medication, dyskinesia, and tremor). 42 teams participated and performance was improved over baseline models for each subchallenge. Additional ensemble modeling across submissions further improved performance, and the top models validated in a subset of patients whose symptoms were observed and rated by trained clinicians., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: YG serves as scientific advisor for Eli Lilly and Company and Merck & Co.; serves as scientific advisor and receives grants from Merck KGaA. YH has grant funding through BBJ from Sanofi S.A. and UCB for unrelated projects. BBJ has grant funding from Sanofi S.A. and UCB for unrelated projects. AJ is funded by MJ Fox Foundation for data curation. All other authors report no competing interests., (Copyright: © 2023 Sieberts et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)