bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ketogenic diet therapy for pediatric epilepsy is associated with alterations in the human gut microbiome that confer seizure resistance in mice
Authors: Lum Gregory R. , Ha Sung Min , Olson Christine A. , Blencowe Montgomery , Paramo Jorge , Reyes Beck , Matsumoto Joyce H. , Yang Xia , Hsiao Elaine Y. 
Published: March 2023

SUMMARYThe gut microbiome modulates seizure susceptibility and the anti-seizure effects of the ketogenic diet (KD) in animal models, but whether these relationships translate to KD therapies for human drug-resistant epilepsy is unclear. Herein, we find that the clinical KD shifts the function of the gut microbiome in children with refractory epilepsy. Colonizing mice with KD-associated human gut microbes confers increased resistance to 6-Hz psychomotor seizures, as compared to colonization with gut microbes from matched pre-treatment controls. Parallel analysis of human donor and mouse recipient metagenomic and metabolomic profiles identifies subsets of shared functional features that are seen in response to KD treatment in humans and preserved upon transfer to mice fed a standard diet. These include enriched representation of microbial genes and metabolites related to anaplerosis, fatty acid beta-oxidation, and amino acid metabolism. Mice colonized with KD-associated human gut microbes further exhibit altered hippocampal and frontal cortical transcriptomic profiles relative to colonized pre-treatment controls, including differential expression of genes related to ATP synthesis, glutathione metabolism, oxidative phosphorylation, and translation. Integrative co-occurrence network analysis of the metagenomic, metabolomic, and brain transcriptomic datasets identifies features that are shared between human and mouse networks, and select microbial functional pathways and metabolites that are candidate primary drivers of hippocampal expression signatures related to epilepsy. Together, these findings reveal key microbial functions and biological pathways that are altered by clinical KD therapies for pediatric refractory epilepsy and further linked to microbiome-induced alterations in brain gene expression and seizure protection in mice.
Age and diet modulate the insulin-sensitizing effects of exercise: a tracer-based oral glucose tolerance test
Authors: Vieira-Lara Marcel A. , Reijne Aaffien C. , Koshian Serj , Ciapaite Jolita , Abegaz Fentaw , Talarovicova Alzbeta , van Dijk Theo H. , Versloot Christian J. , Bandsma Robert H.J. , Wolters Justina C. , Groen Albert K. , Reijngoud Dirk-Jan , van Dijk Gertjan , Bakker Barbara M. 
Published: March 2023

AbstractDiet modulates the development of insulin resistance during aging. This includes tissue-specific alterations in insulin signaling and mitochondrial function, which ultimately affect glucose homeostasis. Exercise stimulates glucose clearance, mitochondrial lipid oxidation and enhances insulin sensitivity. It is not well known how exercise interacts with age and diet in the development of insulin resistance. To investigate this, oral glucose tolerance tests (OGTT) with a tracer were conducted in mice ranging from 4 to 21 months of age, fed a low- (LFD) or high-fat diet (HFD), with or without life-long voluntary access to a running wheel (RW). We developed a computational model to derive glucose fluxes, which were commensurate with independent values from steady-state tracer infusions. Both insulin sensitivity indices derived for peripheral tissues and liver (IS-P and IS-L, respectively) were steeply decreased by aging and a HFD. This preceded the age-dependent decline in the mitochondrial capacity to oxidize lipids. In LFD young animals, RW access enhanced the IS-P concomitantly with the muscle β-oxidation capacity. Surprisingly, RW access completely prevented the age-dependent IS-L decrease, but only in LFD animals. This study indicates, therefore, that endurance exercise can improve the age-dependent decline in organ-specific IS mostly in the context of a healthy diet.
IGF2BP1 induces high-risk neuroblastoma and forms a druggable feedforward loop with MYCN promoting 17q oncogene expression
Authors: Hagemann Sven , Misiak Danny , Bell Jessica L. , Fuchs Tommy , Lederer Marcell I. , Bley Nadine , Hämmerle Monika , Ghazy Ehab , Sippl Wolfgang , Schulte Johannes H. , Hüttelmaier Stefan 
Published: March 2023

AbstractBackgroundNeuroblastoma is the most common solid tumor in infants accounting for approximately 15% of all cancer-related deaths. Over 50% of high-risk neuroblastoma relapse, emphasizing the need of novel drug targets and therapeutic strategies. In neuroblastoma, chromosomal gains at chromosome 17q, includingIGF2BP1, andMYCNamplification at chromosome 2p are associated with adverse outcome. Recent, pre-clinical evidence indicates the feasibility of direct and indirect targeting of IGF2BP1 and MYCN in cancer treatment.MethodsCandidate oncogenes on 17q were identified by profiling the transcriptomic/genomic landscape of 100 human neuroblastoma samples and public gene essentiality data. Molecular mechanisms and gene expression profiles underlying the oncogenic and therapeutic target potential of the 17q oncogeneIGF2BP1and its cross-talk withMYCNwere characterized and validated in human neuroblastoma cells, xenografts and PDX as well as novel IGF2BP1/MYCN transgene mouse models.ResultsWe reveal a novel, druggable feedforward loop of IGF2BP1 (17q) and MYCN (2p) in high-risk neuroblastoma. This promotes 2p/17q chromosomal gains and unleashes an oncogene storm resulting in fostered expression of 17q oncogenes like BIRC5 (survivin). Conditional, sympatho- adrenal transgene expression of IGF2BP1 induces neuroblastoma at a 100% incidence. IGF2BP1- driven malignancies are reminiscent to human high-risk neuroblastoma, including 2p/17q-syntenic chromosomal gains and upregulation of Mycn, Birc5, as well as key neuroblastoma circuit factors like Phox2b. Co-expression of IGF2BP1/MYCN reduces disease latency and survival probability by fostering oncogene expression. Combined inhibition of IGF2BP1 by BTYNB, MYCN by BRD inhibitors or BIRC5 by YM-155 is beneficialin vitroand, for BTYNB, alsoin vivo.ConclusionWe reveal a novel, druggable neuroblastoma oncogene circuit settling on strong, transcriptional/post-transcriptional synergy of MYCN and IGF2BP1. MYCN/IGF2BP1 feed-forward regulation promotes an oncogene storm harboring high therapeutic potential for combined, targeted inhibition of IGF2BP1, MYCN expression and MYCN/IGF2BP1-effectors like BIRC5.
Identification of annotation artifacts concerning theCHALCONE SYNTHASE(CHS)
Authors: Bartas Martin , Volna Adriana , Cerven Jiri , Pucker Boas 
Published: March 2023

AbstractObjectiveChalcone synthase (CHS) catalyzes the initial step of the flavonoid biosynthesis. The CHS encoding gene is well studied in numerous plant species. Rapidly growing sequence databases contain hundreds of CHS entries that are the result of automatic annotation. In this study, we evaluated apparent multiplication of CHS domains inCHSgene models of four plant species.Main findingsCHSgenes with an apparent triplication of the CHS domain encoding part were discovered through database searches. Such genes were found inMacadamia integrifolia, Musa balbisiana, Musa troglodytarum, andNymphaea colorata. A manual inspection of theCHSgene models in these four species with massive RNA-seq data suggests that these gene models are the result of artificial fusions in the annotation process. While there are hundreds of apparently correct CHS records in the databases, it is not clear why these annotation artifacts appeared.
Application of the ANDROMEDA Software for Prediction of the Human Pharmacokinetics of Modern Anticancer Drugs
Authors: Fagerholm Urban , Hellberg Sven , Alvarsson Jonathan , Spjuth Ola 
Published: March 2023

ABSTRACTThe ANDROMEDA toolkit for prediction of human clinical pharmacokinetics, based on machine learning, conformal prediction and a new physiologically-based pharmacokinetic model, was used to predict and characterize the human clinical pharmacokinetics of 12 small anticancer drugs marketed in 2021 and 2022 (molecular weight 355 to 1326 g/mol). The study is part of a series of software validations. A majority of clinical pharmacokinetic data was missing. ANDROMEDA successfully filled this gap. Most drugs were predicted/measured to have relatively complex pharmacokinetics, with limited passive permeability+efflux, high degree of plasma protein binding, significant gut-wall elimination and food interaction, biliary excretion and/or limited dissolution potential. Median, mean and maximum prediction errors for steady state volume of distribution, unbound fraction in plasma, blood-to-plasma concentration ratio, hepatic, renal and total clearance, fraction absorbed, oral bioavailability, half-life and degree of food interaction were 1.6-, 2.4- and 17-fold, respectively. Less than 3-fold errors were found for 78 % of predictions. Results are consistent with those obtained in previous validation studies and are better than with the best laboratory-based prediction methods, which validates ANDROMEDA for predictions of human clinical pharmacokinetics of modern small anticancer drugs with multi-mechanistical and challenging pharmacokinetics.
Bacterial genome engineering using CRISPR RNA-guided transposases
Authors: Gelsinger Diego R. , Vo Phuc Leo H. , Klompe Sanne E. , Ronda Carlotta , Wang Harris , Sternberg Samuel H. 
Published: March 2023

AbstractCRISPR-associated transposons (CASTs) have the potential to transform the technology landscape for kilobase-scale genome engineering, by virtue of their ability to integrate large genetic payloads with high accuracy, easy programmability, and no requirement for homologous recombination machinery. These transposons encode efficient, CRISPR RNA-guided transposases that execute genomic insertions inE. coliat efficiencies approaching ∼100%, generate multiplexed edits when programmed with multiple guides, and function robustly in diverse Gram-negative bacterial species. Here we present a detailed protocol for engineering bacterial genomes using CAST systems, including guidelines on the available homologs and vectors, customization of guide RNAs and DNA payloads, selection of common delivery methods, and genotypic analysis of integration events. We further describe a computational crRNA design algorithm to avoid potential off-targets and CRISPR array cloning pipeline for DNA insertion multiplexing. Starting from available plasmid constructs, the isolation of clonal strains containing a novel genomic integration event-of-interest can be achieved in 1 week using standard molecular biology techniques.
GD2 and its biosynthetic enzyme GD3 synthase promote tumorigenesis in prostate cancer by regulating cancer stem cell behavior
Authors: Bhat Aaqib M. , Mohapatra Bhopal C. , Luan Haitao , Mushtaq Insha , Chakraborty Sukanya , Kumar Siddhartha , Wu Wangbin , Nolan Ben , Dutta Samikshan , Storck Matthew D. , Schott Micah , Meza Jane L. , Lele Subodh M. , Lin Ming-Fong , Cook Leah M. , Corey Eva , Morrissey Colm , Coulter Donald W. , Rowley M. Jordan , Natarajan Amarnath , Datta Kaustubh , Band Vimla , Band Hamid 
Published: March 2023

ABSTRACTWhile better management of loco-regional prostate cancer (PC) has greatly improved survival, advanced PC remains a major cause of cancer deaths. Identification of novel targetable pathways that contribute to tumor progression in PC could open new therapeutic options. The di-ganglioside GD2 is a target of FDA-approved antibody therapies in neuroblastoma, but the role of GD2 in PC is unexplored. Here, we show that GD2 is expressed in a small subpopulation of PC cells in a subset of patients and a higher proportion of metastatic tumors. Variable levels of cell surface GD2 expression were seen on many PC cell lines, and the expression was highly upregulated by experimental induction of lineage progression or enzalutamide resistance in CRPC cell models. GD2highcell fraction was enriched upon growth of PC cells as tumorspheres and GD2highfraction was enriched in tumorsphere-forming ability. CRISPR-Cas9 knockout (KO) of the rate-limiting GD2 biosynthetic enzyme GD3 Synthase (GD3S) in GD2highCRPC cell models markedly impaired thein vitrooncogenic traits and growth as bone-implanted xenograft tumors and reduced the cancer stem cell (CSC) and epithelial-mesenchymal transition (EMT) marker expression. Our results support the potential role of GD3S and its product GD2 in promoting PC tumorigenesis by maintaining cancer stem cells and suggest the potential for GD2 targeting in advanced PC.
Reward prediction-errors weighted by cue salience produces addictive behaviors in simulations, with asymmetrical learning and steeper delay discounting
Authors: Kalhan Shivam , Garrido Marta I. , Hester Robert , David Redish A. 
Published: March 2023

AbstractDysfunction in learning and motivational systems are thought to contribute to addictive behaviours. Previous models have suggested that dopaminergic roles in learning and motivation could produce addictive behaviours through pharmacological manipulations that provide excess dopaminergic signalling towards these learning and motivational systems. Redish 2004 suggested a role based on dopaminergic signals of value prediction error, while Zhang et al. 2009 suggested a role based on dopaminergic signals of motivation. Both these models present significant limitations. They do not explain the reduced sensitivity to drug-related costs/negative consequences, the increased impulsivity generally found in people with a substance use disorder, craving behaviours, and non-pharmacological dependence, all of which are key hallmarks of addictive behaviours. Here, we propose a novel mathematical definition of salience, that combines aspects of dopamine’s role in both, learning and motivation, within the reinforcement learning framework. Using a single parameter regime, we simulated addictive behaviours that the Zhang et al. 2009 and Redish 2004 models also produce but we went further in simulating the downweighting of drug-related negative prediction-errors, steeper delay discounting of drug rewards, craving behaviours and aspects of behavioural/non-pharmacological addictions. The current salience model builds on our recently proposed conceptual theory that salience modulates internal representation updating and may contribute to addictive behaviours by producing misaligned internal representations (Kalhan et al., 2021). Critically, our current mathematical model of salience argues that the seemingly disparate learning and motivational aspects of dopaminergic functioning may interact through a salience mechanism that modulates internal representation updating.
Nasopharyngeal Angiotensin Converting Enzyme 2 (ACE2) Expression as a Risk-Factor for SARS-CoV-2 Transmission in Concurrent Hospital Associated Outbreaks
Authors: Nikiforuk Aidan M. , Kuchinski Kevin S. , Short Katy , Roman Susan , Irvine Mike A. , Prystajecky Natalie , Jassem Agatha N. , Patrick David M. , Sekirov Inna 
Published: March 2023

AbstractBackgroundWidespread human-to-human transmission of the severe acute respiratory syndrome coronavirus two (SARS-CoV-2) stems from a strong affinity for the cellular receptor angiotensin converting enzyme two (ACE2). We investigate the relationship between a patient’s nasopharyngealACE2transcription and secondary transmission within a series of concurrent hospital associated SARS-CoV-2 outbreaks in British Columbia, Canada.MethodsEpidemiological case data from the outbreak investigations was merged with public health laboratory records and viral lineage calls, from whole genome sequencing, to reconstruct the concurrent outbreaks using infection tracing transmission network analysis.ACE2transcription and RNA viral load were measured by quantitative real-time polymerase chain reaction. The transmission network was resolved to calculate the number of potential secondary cases. Bivariate and multivariable analyses using Poisson and Negative Binomial regression models was performed to estimate the association betweenACE2transcription the number of SARS-CoV-2 secondary cases.ResultsThe infection tracing transmission network provided n = 76 potential transmission events across n = 103 cases. Bivariate comparisons found that on averageACE2transcription did not differ between patients and healthcare workers (P = 0.86). HighACE2transcription was observed in 98.6% of transmission events, either the primary or secondary case had above averageACE2. Multivariable analysis found that the association betweenACE2transcription and the number of secondary transmission events differs between patients and healthcare workers. In health care workers Negative Binomial regression estimated that a one unit change inACE2transcription decreases the number of secondary cases (B = −0.132 (95%CI: −0.255 to −0.0181) adjusting for RNA viral load. Conversely, in patients a one unit change inACE2transcription increases the number of secondary cases (B = 0.187 (95% CI: 0.0101 to 0.370) adjusting for RNA viral load. Sensitivity analysis found no significant relationship betweenACE2and secondary transmission in health care workers and confirmed the positive association among patients.ConclusionOur study suggests thatACE2transcription has a positive association with SARS-CoV-2 secondary transmission in admitted inpatients, but not health care workers in concurrent hospital associated outbreaks, and it should be further investigated as a risk-factor for viral transmission.
MIMOSA: A resource consisting of improved methylome imputation models increases power to identify DNA methylation-phenotype associations
Authors: Melton Hunter J. , Zhang Zichen , Deng Hong-Wen , Wu Lang , Wu Chong 
Published: March 2023

AbstractAlthough DNA methylation has been implicated in the pathogenesis of numerous complex diseases, the exact methylation sites that play key roles in these processes remain elusive. One strategy to identify putative causal CpG sites and enhance disease etiology understanding is to conduct methylome-wide association studies (MWASs), in which predicted DNA methylation that is associated with complex diseases can be identified.However, current MWAS models are primarily trained by using the data from single studies, thereby limiting the methylation prediction accuracy and the power of subsequent association studies. Here, we introduce a new resource, MWAS Imputing Methylome Obliging Summary-level mQTLs and Associated LD matrices (MIMOSA), a set of models that substantially improve the prediction accuracy of DNA methylation and subsequent MWAS power through the use of a large, summary-level mQTL dataset provided by the Genetics of DNA Methylation Consortium (GoDMC). With the analyses of GWAS (genome-wide association study) summary statistics for 28 complex traits and diseases, we demonstrate that MIMOSA considerably increases the accuracy of DNA methylation prediction in whole blood, crafts fruitful prediction models for low heritability CpG sites, and determines markedly more CpG site-phenotype associations than preceding methods. Finally, we use MIMOSA to conduct a case study in high cholesterol, pinpointing 146 putatively causal CpG sites.
The Change of Screen Time and Screen Addiction, and their Association with Psychological Well-being During the COVID-19 Pandemic: An Analysis of US Country-Wide School-Age Children and Adolescents Between 2018 and 2020
Authors: Wu Helena T. , Li Jiandong , Tsurumi Amy 
Published: March 2023

AbstractPrevious studies on screen use and children’s mental health during the Coronavirus Disease 2019 (COVID-19) pandemic either focused only on the timeframe during the pandemic, or only on children previously reporting COVID-related severe family economic hardship or worries. Instead, we used a large sample (n=63,211) of the National Survey of Children’s Health (NSCH) years 2018-20 to analyze changes in the trends of recreational screen device use before, versus during the COVID-19 pandemic, and associations with psychological well-being, widely among school-age children (6-17 year-olds) across the US. We assessed recreational screen use, instead of overall use including both instructional and recreational use, and developed psychological well-being issue scores to evaluate the associations among the pandemic, recreational screen use, and psychological well-being states. We found an increase in the prevalence of screen overuse/addiction and psychological well-being issues during the pandemic compared to the years prior, detected an association between the pandemic and psychological well-being issue scores (p <0.01 across all models), and observed increased magnitude of association between recreational screen overuse/addiction and mental health during the pandemic year (p <0.01 across all models). Further studies on elucidating and addressing the specific aspects of the pandemic that contribute to these associations are critical.
Structural basis for functional properties of cytochromecoxidase
Authors: Ishigami Izumi , Sierra Raymond G. , Su Zhen , Peck Ariana , Wang Cong , Poitevin Frederic , Lisova Stella , Hayes Brandon , Moss Frank R. , Boutet Sébastien , Sublett Robert E. , Yoon Chun Hong , Yeh Syun-Ru , Rousseau Denis L. 
Published: March 2023

AbstractCytochromecoxidase (CcO) is an essential enzyme in mitochondrial and bacterial respiration. It catalyzes the four-electron reduction of molecular oxygen to water and harnesses the chemical energy to translocate four protons across biological membranes, thereby establishing the proton gradient required for ATP synthesis1. The full turnover of the CcO reaction involves an oxidative phase, in which the reduced enzyme (R) is oxidized by molecular oxygen to the metastable oxidizedOHstate, and a reductive phase, in whichOHis reduced back to theRstate. During each of the two phases, two protons are translocated across the membranes2. However, ifOHis allowed to relax to the resting oxidized state (O), a redox equivalent toOH, its subsequent reduction toRis incapable of driving proton translocation2,3. How theOstate structurally differs fromOHremains an enigma in modern bioenergetics. Here, with resonance Raman spectroscopy and serial femtosecond X-ray crystallography (SFX)4, we show that the hemea3iron and CuBin the active site of theOstate, like those in theOHstate5,6, are coordinated by a hydroxide ion and a water molecule, respectively. However, Y244, a residue covalently linked to one of the three CuBligands and critical for the oxygen reduction chemistry, is in the neutral protonated form, which distinguishesOfromOH, where Y244 is in the deprotonated tyrosinate form. These structural characteristics ofOprovide new insights into the proton translocation mechanism of CcO.
Mammals achieve common neural coverage of visual scenes using distinct sampling behaviors
Authors: Samonds Jason M. , Szinte Martin , Barr Carrie , Montagnini Anna , Masson Guillaume S , Priebe Nicholas J. 
Published: March 2023

AbstractMost vertebrates use head and eye movements to quickly change gaze orientation and sample different portions of the environment with periods of stable fixation. Visual information must be integrated across several fixations to construct a more complete perspective of the visual environment. In concert with this sampling strategy, neurons adapt to unchanging input to conserve energy and ensure that only novel information from each fixation is processed. We demonstrate how adaptation recovery times and saccade properties interact, and thus shape spatiotemporal tradeoffs observed in the motor and visual systems of different species. These tradeoffs predict that in order to achieve similar visual coverage over time, animals with smaller receptive field sizes require faster saccade rates. Indeed, we find comparable sampling of the visual environment by neuronal populations across mammals when integrating measurements of saccadic behavior with receptive field sizes and V1 neuronal density. We propose that these mammals share a common statistically driven strategy of maintaining coverage of their visual environment over time calibrated to their respective visual system characteristics.