bluuebunny/crossref_metadata_2025_split huggingface dataset:
CYP2D6 Genotyping and Antipsychotic-Associated Extrapyramidal Adverse Effects in a Randomized Trial of Aripiprazole Versus Quetiapine Extended Release in Children and Adolescents, Aged 12–17 Years, With First Episode Psychosis
Authors: Rudå Ditte , Jensen Karsten Gjessing , Decara Marie Stentebjerg , Klauber Dea Gowers , Fagerlund Birgitte , Møllegaard Jens Richardt , Linnet Kristian , Werge Thomas , Correll Christoph U. , Fink-Jensen Anders , Jürgens Gesche , Pagsberg Anne Katrine 
Published: November 2021

Abstract

Purpose/Background
The aim of this study was to examine the association between genetically predicted CYP2D6 phenotypes and extrapyramidal symptoms (EPSs).

Methods/Procedures
Data from the Tolerability and Efficacy of Antipsychotics trial of adolescents with first-episode psychosis randomized to aripiprazole versus quetiapine extended release were studied. Extrapyramidal symptom assessments included the Simpson-Angus Scale and the Barnes Akathisia Rating Scale. Patients were CYP2D6 genotyped. Plasma concentrations of antipsychotics and antidepressants were analyzed.

Findings/Results
One hundred thirteen youths (age, 12–17 years; males, 30%; antipsychotic naive, 51%) were enrolled. Poor metabolizers had a significantly higher dose-adjusted aripiprazole plasma concentration (±SD) compared with normal metabolizers at week 4 (24.30 ± 6.40 ng/mL per milligram vs 14.85 ± 6.15 ng/mL per milligram; P = 0.019), but not at week 12 (22.15 ± 11.04 ng/mL per milligram vs 14.32 ± 4.52 ng/mL per milligram; P = 0.067). This association was not found in the quetiapine extended release group. No association between CYP2D6 genotype groups and global Barnes Akathisia Rating Scale score or Simpson-Angus Scale score was found in any of the treatment arms.

Implications/Conclusions
Our results do not support routine use of CYP2D6 testing as a predictor of drug-induced parkinsonism or akathisia risk in clinical settings. Further studies with larger samples of CYP2D6 poor metabolizers are needed.
Lifetime Cannabis Use Disorder Is Not Associated With Lifetime Impulsive Behavior and Severe Violence in Patients With Schizophrenia Spectrum Disorders From a High-Security Hospital
Authors: Comai Stefano , Fuamba Yves , Rivolta Maria Chiara , Gobbi Gabriella 
Published: November 2021

Abstract

Purpose/Background
The link between substances of abuse, impulsivity, and violence in psychotic patients remains unclear. This study aims at unraveling whether cannabis use disorder is associated with violent and/or psychotic behavior in patients who are hospitalized in a high-security hospital.

Methods/Procedures
We conducted a cross-sectional retrospective study in 124 patients with schizophrenia spectrum disorders admitted to a high-security hospital. Lifetime violent behavior was assessed using the History of Aggressive Behavior Form-Subject of the MacArthur Violence Risk Assessment Study and impulsivity using the Psychopathy Checklist–Revised (considering items: “proneness to boredom,” “lack of self-control,” and “impulsive thoughtless gestures”). Substance use disorder was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Positive and Negative Syndrome Scale was also administered.

Findings/Results
Violent and nonviolent psychotic patients showed similar prevalence of cannabis use disorder. Alcohol and cocaine use disorders were more prevalent among violent psychotic patients. Cannabis use disorder was not associated with any dimension of impulsivity, whereas alcohol use disorder was positively correlated to impulsive thoughtless gestures (standardized β = 0.213, P = 0.027) and cocaine use disorder with proneness to boredom (standardized β = 0.290, P = 0.002). Finally, logistic regression analysis revealed that, unlike cannabis and cocaine use disorders, alcohol use disorder (odds ratio, 3.964; 95% confidence interval, 1.729–9.087; P = 0.001) was a factor associated with violence.

Implications/Conclusions
These findings show that cannabis and alcohol are largely abused and coabused by psychotic patients with a propsensity for violence, but only alcohol is associated with impulsive and violent behavior. Therefore, especially alcohol abuse should be seriously considered by practitioners when evaluating the dangerousness of patients with schizophrenia spectrum disorders.
Cognitive Patterns and Conversion in a Representative Sample of Individuals at Risk for Psychosis
Authors: Haddad Natalia Mansur , Hortêncio Lucas , Andrade Julio Cesar , Serpa Mauricio Henriques , Alves Tania Maria , van de Bilt Martinus Theodorus , Rössler Wulf , Gattaz Wagner Farid , Loch Alexandre Andrade 
Published: November 2021

Abstract
Clinical high-risk (CHR) individuals belong to a heterogeneous group, of which only a few will cross the threshold for a clinical diagnosis. Cognitive disturbances are present in CHR subjects and may be indicative of transition. Our study aims to identify such deficits in a representative CHR for psychosis sample. Our sample comprised 92 CHR individuals and 54 controls from a representative cohort of the general population. They were followed up for a mean of 2.5 years, with 15 individuals converting to schizophrenia or other Diagnostic and Statistical Manual of Mental Disorders, 5th Edition diagnoses. Neurocognitive assessment was performed with the University of Pennsylvania Computerized Neuropsychological Testing, and CHR status was assessed with the Structured Interview for Prodromal Syndromes (SIPS). Baseline scores were entered in a latent profile analysis model. Our study brought forward a four-class model on cognitive performance. One class displayed better performance, whereas the other three performed worse, all compared with controls. The class with lower executive function also had the highest score on disorganized communication (SIPS P5 = 1.36, p < 0.05), although unrelated to conversion. Among the low performers, the class significantly related to conversion (p = 0.023) had the highest score in decreased expression of emotion (SIPS N3 = 0.85, p < 0.05). Our study brings new and relevant data on non–help-seeking CHR individuals and the relationship between cognitive patterns and conversion. We have highlighted a specific cognitive signature, associated with negative symptoms, which represents a stable trait with presumed lower conversion to a psychiatric illness.
Recommendations for improving statistical inference in population genomics
Authors: Johri Parul , Aquadro Charles F. , Beaumont Mark , Charlesworth Brian , Excoffier Laurent , Eyre-Walker Adam , Keightley Peter D. , Lynch Michael , McVean Gil , Payseur Bret A. , Pfeifer Susanne P. , Stephan Wolfgang , Jensen Jeffrey D. 
Published: November 2021

ABSTRACTThe field of population genomics has grown rapidly in response to the recent advent of affordable, large-scale sequencing technologies. As opposed to the situation during the majority of the 20th century, in which the development of theoretical and statistical population-genetic insights out-paced the generation of data to which they could be applied, genomic data are now being produced at a far greater rate than they can be meaningfully analyzed and interpreted. With this wealth of data has come a tendency to focus on fitting specific (and often rather idiosyncratic) models to data, at the expense of a careful exploration of the range of possible underlying evolutionary processes. For example, the approach of directly investigating models of adaptive evolution in each newly sequenced population or species often neglects the fact that a thorough characterization of ubiquitous non-adaptive processes is a prerequisite for accurate inference. We here describe the perils of these tendencies, present our consensus views on current best practices in population genomic data analysis, and highlight areas of statistical inference and theory that are in need of further attention. Thereby, we argue for the importance of defining a biologically relevant baseline model tuned to the details of each new analysis, of skepticism and scrutiny in interpreting model-fitting results, and of carefully defining addressable hypotheses and underlying uncertainties.
Spatiotemporal patterns of urban mosquitoes are modulated by socioeconomic status and environmental traits in the United States
Authors: Yitbarek Senay , Chen Kelvin , Celestin Modeline , McCary Matthew 
Published: November 2021

ABSTRACTThe distribution of mosquitoes and associated vector diseases (e.g., West Nile, dengue, and Zika viruses) is likely a function of environmental conditions in the landscape. Urban environments are highly heterogeneous in the amount of vegetation, standing water, and concrete structures covering the land at a given time, each having the capacity to influence mosquito abundance and disease transmission. Previous research suggests that socioeconomic status is correlated with the ecology of the landscape, with lower-income neighborhoods generally having more concrete structures and standing water via residential abandonment, garbage dumps, and inadequate sewage. Whether these socio-ecological factors affect mosquito distributions across urban environments in the United States (US) remains unclear. Here, we present a meta-analysis of 22 paired observations from 15 articles testing how socioeconomic status relates to overall mosquito burden in urban landscapes in the United States. We then analyzed a comprehensive dataset from a socioeconomic gradient in Baltimore, Maryland to model spatiotemporal patterns of Aedes albopictus using a spatial regression model with socio-ecological covariates. The meta-analysis revealed that lower-income neighborhoods (regions making less than $50,000 per year on average) are exposed to 151% greater mosquito densities and mosquito-borne illnesses compared to higher-income neighborhoods (≥$50,000 per year). Two species of mosquito (Ae. albopictus and Aedes aegypti) showed the strongest relationship with socioeconomic status, with Ae. albopictus and Ae. aegypti being 62% and 22% higher in low-income neighborhoods, respectively. In the spatial regression analysis in Baltimore, we found that Ae. albopictus spatial spread of 1.2 km per year was significantly associated with median household income, vegetation cover, tree density, and abandoned buildings. Specifically, Ae. albopictus abundance was negatively correlated with median household income, vegetation cover, and tree density. Ae. albopictus abundance and the cover of abandoned buildings were positively correlated. Together, these results indicate that socio-ecological interactions can lead to disproportionate impacts of mosquitoes on humans in urban landscapes. Thus, concerted efforts to manage mosquito populations in low-income urban neighborhoods are required to reduce mosquito burden for the communities most vulnerable to human disease.
DeepMAPS: Single-cell biological network inference using heterogeneous graph transformer
Authors: Ma Anjun , Wang Xiaoying , Wang Cankun , Li Jingxian , Xiao Tong , Wang Juexing , Li Yang , Liu Yuntao , Chang Yuzhou , Wang Duolin , Jiang Yuexu , Li Jinpu , Su Li , Gu Shaopeng , Xin Gang , Li Zihai , Liu Bingqiang , Xu Dong , Ma Qin 
Published: November 2021

AbstractWe present DeepMAPS (Deep learning-based Multi-omics Analysis Platform for Single-cell data) for biological network inference from single-cell multi-omics (scMulti-omics). DeepMAPS includes both cells and genes in a heterogeneous graph to simultaneously infer cell-cell, cell-gene, and gene-gene relations. The multi-head attention mechanism in a graph transformer considers the heterogeneous relation among cells and genes within both local and global context, making DeepMAPS robust to data noise and scale. We benchmarked DeepMAPS on 18 scMulti-omics datasets for cell clustering and biological network inference, and the results showed that our method outperformed various existing tools. We further applied DeepMAPS on lung tumor leukocyte CITE-seq data and matched diffuse small lymphocytic lymphoma scRNA-seq and scATAC-seq data. In both cases, DeepMAPS showed competitive performance in cell clustering and predicted biologically meaningful cell-cell communication pathways based on the inferred gene networks. Note that we deployed a webserver using DeepMAPS implementation equipped with multiple functions and visualizations to improve the feasibility and reproducibility of scMulti-omics data analysis. Overall, DeepMAPS represents a heterogeneous graph transformer for single-cell study and may benefit the use of scMulti-omics data in various biological systems.
Generation and Culture of Cardiac Microtissues in a Microfluidic Chip with a Reversible Open Top Enables Electrical Pacing, Dynamic Drug Dosing and Endothelial Cell Co-Culture
Authors: Vivas Aisen , IJspeert Camilo , Pan Jesper Yue , Vermeul Kim , Berg Albert van den , Passier Robert , Keller Stephan Sylvest , Meer Andries D. van der 
Published: November 2021

AbstractCardiovascular disease morbidity has increased worldwide in recent years while drug development has been affected by failures in clinical trials and lack of physiologically relevant models. Organs-on-chips and human pluripotent stem cell technologies aid to overcome some of the limitations in cardiac in vitro models. Here, a bi-compartmental, monolithic heart-on-chip device that facilitates porous membrane integration in a single fabrication step is presented. Moreover, the device includes open-top compartments that allow facile co-culture of human pluripotent stem cell-derived cardiomyocytes and human adult cardiac fibroblast into geometrically defined cardiac microtissues. The device can be reversibly closed with a glass seal or a lid with fully customized 3D-printed pyrolytic carbon electrodes allowing electrical stimulation of cardiac microtissues. A subjacent microfluidic channel allowed localized and dynamic drug administration to the cardiac microtissues, as demonstrated by a chronotropic response to isoprenaline. Moreover, the microfluidic channel could also be populated with human induced pluripotent stem-derived endothelial cells allowing co-culture of heterotypic cardiac cells in one device. Overall, this study demonstrates a unique heart-on-chip model that systematically integrates the structure and electromechanical microenvironment of cardiac tissues in a device that enables active perfusion and dynamic drug dosing. Advances in the engineering of human heart-on-chip models represent an important step towards making organ-on-a-chip technology a routine aspect of preclinical cardiac drug development.
Multilineage plasticity in prostate cancer through expansion of stem–like luminal epithelial cells with elevated inflammatory signaling
Authors: Zaidi Samir , Zhao Jimmy L. , Chan Joseph M. , Roudier Martine P. , Wadosky Kristine M. , Gopalan Anuradha , Karthaus Wouter R. , Choi Jungmin , Lawrence Kayla , Chaudhary Ojasvi , Xu Tianhao , Masilionis Ignas , Mazutis Linas , Chaligné Ronan , Linkov Irina , Barlas Afsar , Jungbluth Achim , Rekhtman Natasha , Silber Joachim , Manova–Todorova Katia , Watson Philip A. , True Lawrence D. , Nelson Peter S. , Scher Howard I. , Rathkopf Dana E. , Morris Michael J. , Haffner Michael C. , Goodrich David W. , Pe’er Dana , Sawyers Charles L. 
Published: November 2021

AbstractLineage plasticity is a well–established mechanism of resistance to targeted therapies in lung and prostate cancer, where tumors transition from adenocarcinoma to small–cell or neuroendocrine carcinoma. Through single–cell analysis of a cohort of heavily–treated castration–resistant human prostate cancers (CRPC), we report a greater degree of plasticity than previously appreciated, with multiple distinct neuroendocrine (NEPC), mesenchymal (EMT–like), and other subpopulations detected within single biopsies. To explore the steps leading to this plasticity, we turned to two genetically engineered mouse models of prostate cancer that recapitulate progression from adenocarcinoma to neuroendocrine disease. Time course studies reveal expansion of stem–like luminal epithelial cells (Sca1+,Psca+, called L2) that, based on trajectories, gave rise to at least 4 distinct subpopulations, NEPC (Ascl1+), POU2F3 (Pou2f3+), TFF3 (Tff3+) and EMT–like (Vim+,Ncam1+)––these populations are also seen in human prostate and small cell lung cancers. Transformed L2–like cells express stem–like and gastrointestinal endoderm–like transcriptional programs, indicative of reemerging developmental plasticity programs, as well as elevated Jak/Stat and interferon pathway signaling. In sum, while the magnitude of multilineage heterogeneity, both within and across patients, raises considerable treatment challenges, the identification of highly plastic luminal cells as the likely source of this heterogeneity provides a target for more focused therapeutic intervention.One Sentence SummaryMultilineage plasticity results from expansion of stem–like luminal cells with JAK/STAT activation, serving as a therapeutic target.
Optimality of extracellular enzyme production and activity in dynamic flux balance modeling
Authors: Quintin Michael , Dukovski Ilija , Bhatnagar Jennifer , Segrè Daniel 
Published: November 2021

AbstractIn microbial communities, many vital metabolic functions, including the degradation of cellulose, proteins and other complex macromolecules, are carried out by costly, extracellularly secreted enzymes. While significant effort has been dedicated to analyzing genome-scale metabolic networks for individual microbes and communities, little is known about the interplay between global allocation of metabolic resources in the cell and extracellular enzyme secretion and activity. Here we introduce a method for modeling the secretion and catalytic functions of extracellular enzymes using dynamic flux balance analysis. This new addition, implemented within COMETS (Computation Of Microbial Ecosystems in Time and Space), simulates the costly production and secretion of enzymes and their diffusion and activity throughout the environment, independent of the producing organism. After tuning our model based on data for a Saccharomyces cerevisiae strain engineered to produce exogenous cellulases, we explored the dynamics of the system at different cellulose concentrations and enzyme production rates. We found that there are distinct rates of constitutive enzyme secretion which maximize either growth rate or biomass yield. These optimal rates are strongly dependent on enzyme kinetic properties and environmental conditions, including the amount of cellulose substrate available. Our framework will facilitate the development of more realistic simulations of microbial community dynamics within environments rich in complex macromolecules, with applications in the study of soil and plant-associated ecosystems, and other natural and engineered microbiomes.ImportanceMany organisms - including soil, marine and human-associated bacteria and fungi - perform part of their metabolic functions outside of the boundary of the cell, through the secretion of extracellular enzymes that can diffuse and facilitate reactions independently of the organism that produced them. In order to better understand and predict microbial ecosystems, it would be helpful to create mathematical models incorporating these extracellular reactions within simulations of metabolism at the whole-cell level. In this paper we demonstrate the implementation of such a methodology and apply it to study a cellulase-secreting yeast. This work will be useful for a number of microbial ecology applications, including modeling of microbiome dynamics, engineering of bioproducts (e.g. biofuels) from plant biomass through synthetic communities or modified organisms, and testing of basic ecological hypotheses about the balance between cost and benefits of the production of common goods in microbial communities.
Natural variation in the maternal and zygotic mRNA complements of the early embryo in Drosophila melanogaster
Authors: Feitzinger Anna A. , Le Anthony , Thompson Ammon , Haseeb Mehnoor , Murugesan Mohan K. , Tang Austin M. , Lott Susan E. 
Published: November 2021

AbstractMaternal gene products supplied to the egg during oogenesis drive the earliest events of development in all metazoans. After the initial stages of embryogenesis, maternal transcripts are degraded as zygotic transcription is activated, this is known as the maternal to zygotic transition (MZT). Altering the abundances of maternally deposited factors in the laboratory can have a dramatic effect on development, adult phenotypes and ultimately fitness. Zygotic transcription activation is a tightly regulated process, where the zygotic genome takes over control of development from the maternal genome, and is required for the viability of the organism. Recently, it has been shown that the expression of maternal and zygotic transcripts have evolved in the Drosophila genus over the course of 50 million years of evolution. However, the extent of natural variation of maternal and zygotic transcripts within a species has yet to be determined. We asked how the maternal and zygotic pools of mRNA vary within and between populations of D. melanogaster. In order to maximize sampling of genetic diversity, African lines of D. melanogaster originating from Zambia as well as DGRP lines originating from North America were chosen for transcriptomic analysis. Single embryo RNA-seq was performed at a stage before and a stage after zygotic genome activation in order to determine which transcripts are maternally deposited and which are zygotically expressed within and between these populations. Differential gene expression analysis has been used to quantify quantitative changes in RNA levels within populations as well as fixed expression differences between populations at both stages. Generally, we find that maternal transcripts are more highly conserved, and zygotic transcripts evolve at a higher rate. We find that there is more within population variation in transcript abundance than between populations and that expression variation is highest post-MZT between African lines. Determining the natural variation of gene expression surrounding the MZT in natural populations of D. melanogaster gives insight into the extent of how a tightly regulated process may vary within a species, the extent of developmental constraint at both stages and on both the maternal and zygotic genomes, and reveals expression changes allowing this species to adapt as it spread across the world.