bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polygenic scores clarify the relationship between mental health and gender diversity
Authors: Thomas Taylor R. , Tener Ashton J. , Pearlman Amy M. , Imborek Katherine L. , Yang Ji Seung , Strang John F. , Michaelson Jacob J. 
Published: November 2021

ABSTRACTBACKGROUNDGender diverse individuals are at increased risk for mental health problems, but it is unclear whether this is due to shared environmental or genetic factors.METHODSIn two SPARK samples, we tested for 16 polygenic scores (PGS) effects on quantitative measures of gender diversity and mental health. In Study 1,N= 639 independent adults (59% autistic) reported their mental health with the Adult Self Report and their gender diversity with the Gender Self Report (GSR). The GSR has two dimensions: Binary (degree of identification with the gender opposite that implied by sex designated at birth) and Nonbinary (degree of identification with a gender that is neither male nor female). In Study 2 (N= 5, 165), we used categorical gender identity.RESULTSIn Study 1, neuropsychiatric PGS were positively associated with mental health problems. Externalizing was positively associated with ADHD PGS (ρ= 0.12,p <0.001, FDR = 0.10), and Internalizing was positively associated with PGS for depression (ρ= 0.08,p= 0.04, FDR = 1) and neuroticism (ρ= 0.11,p= 0.01, FDR = 0.41). Interestingly, we found no associations between gender diversity and neuropsychiatric PGS (80% powered to detectρ > ±0.11). However, the GSR was positively associated with cognitive performance PGS (Binaryρ= 0.11,p <0.001, FDR = 0.23 and Nonbinaryρ= 0.12,p <0.001, FDR = 0.13). Binary was also positively associated with PGS for non-heterosexual sexual behavior (ρ= 0.09,p= 0.03, FDR = 0.69). In Study 2, the cognitive performance PGS effect replicated; transgender and non-binary individuals had higher PGS:t= 4.16,p <0.001, FDR<0.001. They also had higher risky behavior and anorexia PGS.CONCLUSIONSWe show that while gender diversity as a trait is positively associated with mental health problems, the strongest PGS associations with gender diversity were with cognitive performance, not neuropsychiatric conditions.
In VitroNasal Tissue Model for the Validation of Nasopharyngeal and Mid-turbinate Swabs for SARS-CoV-2 Testing
Authors: Hartigan Devon R. , Adelfio Miryam , Shutt Molly E. , Jones Stephanie M. , Patel Shreya , Marchand Joshua T. , McGuinness Pamela D. , Buchholz Bryan O. , Ghezzi Chiara E. 
Published: November 2021

AbstractLarge-scale population testing is a key tool to mitigate the spread of respiratory pathogens, as in the current COVID-19 pandemic, where swabs are used to collect samples in the upper airways (e.g. nasopharyngeal and mid-turbinate nasal cavities) for diagnostics. However, the high volume of supplies required to achieve large-scale population testing has posed unprecedented challenges for swab manufacturing and distribution, resulting in a global shortage that has heavily impacted testing capacity world-wide and prompted the development of new swabs suitable for large-scale production. Newly designed swabs require rigorous pre-clinical and clinical validation studies that are costly and time consuming (i.e. months to years long); reducing the risks associated with swab validation is therefore paramount for their rapid deployment. To address these shortages, we developed a 3D-printed tissue model that mimics the nasopharyngeal and mid-turbinate nasal cavities, and we validated its use as a new tool to rapidly test swab performance. In addition to the nasal architecture, the tissue model mimics the soft nasal tissue with a silk-based sponge lining, and the physiological nasal fluid with asymptomatic and symptomatic viscosities of synthetic mucus. We performed several assays comparing standard flocked and injection-molded swabs. We quantified the swab pick-up and release, and determined the effect of viral load and mucus viscosity on swab efficacy by spiking the synthetic mucus with heat-inactivated SARS-CoV-2 virus. By molecular assays, we found that injected molded swabs performed similarly or superiorly in comparison to standard flocked swabs and we underscored a viscosity-dependent difference in cycle threshold values between the asymptomatic and symptomatic mucus for both swabs. To conclude, we developed anin vitronasal tissue model, that corroborated previous swab performance data from clinical studies, with the potential of providing researchers with a clinically relevant, reproducible, safe, and cost-effective validation tool for the rapid development of newly designed swabs.
A multi-class gene classifier for SARS-CoV-2 variants based on convolutional neural network
Authors: Fan Junyu , Chen Chutao , Song Chen , Pan Jiajie , Wu Guifu 
Published: November 2021

AbstractSurveillance of circulating variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of great importance in controlling the coronavirus disease 2019 (COVID-19) pandemic. We propose an alignment-free in silico approach for classifying SARS-CoV-2 variants based on their genomic sequences. A deep learning model was constructed utilizing a stacked 1-D convolutional neural network and multilayer perceptron (MLP). The pre-processed genomic sequencing data of the four SARS-CoV-2 variants were first fed to three stacked convolution-pooling nets to extract local linkage patterns in the sequences. Then a 2-layer MLP was used to compute the correlations between the input and output. Finally, a logistic regression model transformed the output and returned the probability values. Learning curves and stratified 10-fold cross-validation showed that the proposed classifier enables robust variant classification. External validation of the classifier showed an accuracy of 0.9962, precision of 0.9963, recall of 0.9963 and F1 score of 0.9962, outperforming other machine learning methods, including logistic regression, K-nearest neighbor, support vector machine, and random forest. By comparing our model with an MLP model without the convolution-pooling network, we demonstrate the essential role of convolution in extracting viral variant features. Thus, our results indicate that the proposed convolution-based multi-class gene classifier is efficient for the variant classification of SARS-CoV-2.
Identification of occupations susceptible to high exposure and risk associated with multiple toxicants in an observational study: National Health and Nutrition Examination Survey 1999-2014
Authors: Nguyen Vy Kim , Colacino Justin , Patel Chirag J , Sartor Maureen , Jolliet Olivier 
Published: November 2021

AbstractBackgroundAccording to the World Health Organization, occupational exposures to hazardous chemicals are estimated to cause over 370,000 premature annual deaths. The risks due to multiple workplace chemical exposures, and those occupations most susceptible to the resulting health effects, remain poorly characterized.ObjectivesThe aim of this study is to identify occupations with elevated toxicant biomarker concentrations and increased health risk associated with toxicant exposures in a working US population from diverse categories of occupation. More specifically, we aim to 1) define differences in chemical exposures based on occupation description, 2) identify occupational groups with similar chemical exposure profiles, and 3) identify occupational groups with chemical biomarker levels exceeding acceptable health-based biomarker levels.MethodsFor this observational study of 51,008 participants, we used data from the 1999-2014 National Health and Nutrition Examination Survey. We characterized differences in chemical exposures by occupational group for 129 chemicals by applying a series of generalized linear models with the outcome as biomarker concentrations and the main predictor as the occupational groups, adjusting for age, sex, race/ethnicity, poverty income ratio, study period, and biomarker of tobacco use. We identified groups of occupations with similar chemical exposure profiles via hierarchical clustering. For each occupational group, we calculated percentages of participants with chemical biomarker levels exceeding acceptable health-based guidelines.ResultsBlue collar workers from “Construction”, “Professional, Scientific, Technical Services”, “Real Estate, Rental, Leasing”, “Manufacturing”, and “Wholesale Trade” have higher biomarker levels of toxic chemicals such as several heavy metals, acrylamide, glycideamide, and several volatile organic compounds compared to their white-collar counterparts. For these toxicants, 1-58% of blue-collar workers from these industries have toxicant concentrations exceeding acceptable levels.DiscussionBlue collar workers have toxicant levels higher relative to their white-collar counterparts, often exceeding acceptable levels associated with noncancer effects. Our findings identify multiple occupations to prioritize for targeted interventions and health policies to monitor and reduce high toxicant exposures.
Plasticity of extrachromosomal and intrachromosomal BRAF amplifications in mediating targeted therapy dosage challenges
Authors: Song Kai , Minami Jenna K. , Crosson William P. , Salazar Jesus , Pazol Eli , Senaratne Niroshi T. , Rao Nagesh , Paraiso Kim , Graeber Thomas G. 
Published: November 2021

AbstractCancer cells display two modes of focal amplifications (FAs), extrachromosomal DNA/double-minutes (ecDNA/DMs) and intrachromosomal homogenously staining regions (HSRs). Understanding the plasticity of these two modes is critical for preventing targeted therapy resistance. We developed a combined BRAF plus MEK inhibitor resistance melanoma model that bears high BRAF amplifications through both DM and HSR modes, and investigated FA dynamics in the context of drug resistance plasticity. Cells harboring FAs displayed mode switching between DMs and HSRs, from both de novo genetic changes and selection of preexisting subpopulations. We found that copy number plasticity is not exclusive to DMs. Single cell-derived clones with HSRs also exhibit BRAF copy number and corresponding HSR length plasticity that allows them to respond to dose reduction and recover from drug addiction. Upon kinase inhibitor escalation, we observed reproducible selection for cells with BRAF kinase domain duplications residing on DMs. In sum, the plasticity of FAs allows cancer cells to respond to drug dose changes through a myriad of mechanisms. These mechanisms include increases or decreases in DMs, shortening of HSRs, acquisition of secondary resistance mechanisms, and expression of alternative slicing oncogene variants. These results highlight the challenges in targeting the cellular vulnerabilities tied to focal amplifications.Statement of SignificanceUnderstanding the dynamics of oncogene amplifications is critical for appreciating tumorigenesis and preventing anticancer drug resistance. We found melanoma cells harboring BRAF amplifications in either DM or HSR formats to have high plasticity under different kinase inhibitor dosage challenges with evidence supporting de novo alterations, clonal selection, and coupling to additional resistance mechanisms. In in the absence of DMs, HSRs can offer comparable levels of plasticity as DMs.
Lymphatic Thrombosis and Impaired Lymph Drainage in Cigarette Smoke-Associated Emphysema
Authors: Summers Barbara D. , Kim Kihwan , Khan Zohaib , Thangaswamy Sangeetha , Clement Cristina C. , McCright Jacob , Maisel Katharina , Zamora Sofia , Quintero Stephanie , Racanelli Alexandra C. , Yang Jisheng , D’Armiento Jeanine , Monticelli Laurel , Kahn Mark L. , Choi Augustine M. K. , Santambrogio Laura , Reed Hasina Outtz 
Published: November 2021

AbstractThe lymphatic vasculature is critical for lung function, but defects in lymphatic function in the pathogenesis of lung disease is understudied. In mice, lymphatic dysfunction alone is sufficient to cause lung injury that resembles human emphysema. Whether lymphatic function is disrupted in cigarette smoke (CS)-induced emphysema is unknown. In this study, we investigated lung lymphatic function in the pathogenesis of CS-induced emphysema. Analysis of human lung tissue revealed significant lung lymphatic thrombosis in patients with emphysema compared to control smokers that increased with disease severity. In vitro assays demonstrated a direct effect of CS on lymphatic endothelial cell integrity. In a mouse model, CS exposure led to lung lymphatic thrombosis, decreased lymphatic drainage, and impaired leukocyte trafficking that preceded emphysema. Proteomic analysis of lymph confirmed upregulation of coagulation and inflammatory pathways in the lymphatics of CS-exposed mice compared to control mice. These data suggest that CS exposure results in lung lymphatic dysfunction with thrombosis, impaired leukocyte trafficking, and changes in the composition of lymph. In patients with emphysema, lung lymphatic thrombosis is seen with increasing disease severity. These studies for the first time demonstrate lung lymphatic dysfunction after cigarette smoke exposure and suggest a novel component in the pathogenesis of emphysema.
Activation of neuronal FLT3 promotes exaggerated sensorial and emotional pain-related behaviors facilitating the transition from acute to chronic pain
Authors: Tassou Adrien , Thouaye Maxime , Gilabert Damien , Jouvenel Antoine , Leyris Jean-Philippe , Sonrier Corinne , Diouloufet Lucie , Mechaly Ilana , Mallié Sylvie , Chentouf Myriam , Neiveyans Madeline , Pugnière Martine , Martineau Pierre , Robert Bruno , Capdevila Xavier , Valmier Jean , Rivat Cyril 
Published: November 2021

AbstractAcute pain events have been associated with persistent pain sensitization of nociceptive pathways increasing the risk of transition from acute to chronic pain. However, it is unclear whether injuryinduced persistent pain sensitization can promote long-term mood disorders. The receptor tyrosine kinase FLT3 is causally required for pain chronification after peripheral nerve injury, questioning its role in the development of pain-induced mood alterations. Here, we evaluated the emotional and sensorial components of pain after a single (SI) or double paw incision (DI). We then investigated the role of FLT3 either by inhibition using transgenic knock-out mice and functional antibodies or by activation with FLT3 ligand (FL) administrations.DI mice showed significant anxiodepressive-like and spontaneous pain behaviors as opposed to SI mice. DI also promoted and extended mechanical pain hypersensitivity compared to SI. This emotional and sensorial pain exaggeration correlated with spinal changes especially by increased microglia activation after DI versus SI. Intrathecal minocycline, a microglial inhibitor, specifically reversed DI inducedmechanical hypersensitivity in males. Repeated treatment with the microglia proliferation inhibitor GW2580 not only eliminated the exaggerated pain hypersensitivity produced by DI but also prevented anxiodepressive-related behaviors in DI animals. Finally, FL injections in naive animals provoked mechanical allodynia and anxiodepressive-like disorders concomitant with a strong microglial activation while Flt3 silencing in a genetic mouse line or FLT3 blocking via functional antibodies, blunted the development of persistent pain and depression after DI. Altogether our results show that the repetition of peripheral lesions facilitate not only exaggerated nociceptive behaviors but also induced anxiodepressive disorders supported by spinal central changes. The inhibition of FLT3 could thus become a promising therapy in the management of pain sensitization and related mood alterations.
In vitro and in vivo CRISPR-Cas9 screens reveal drivers of aging in neural stem cells of the brain
Authors: Ruetz Tyson J. , Kashiwagi Chloe M. , Morton Bhek , Yeo Robin W. , Leeman Dena S. , Morgens David W. , Tsui C. Kimberly , Li Amy , Bassik Michael C. , Brunet Anne 
Published: November 2021

AbstractAging impairs the ability of neural stem cells to transition from quiescence to activation (proliferation) in the adult mammalian brain. Neural stem cell (NSC) functional decline results in decreased production of new neurons and defective regeneration upon injury during aging1–9, and this is exacerbated in Alzheimer’s disease10. Many genes are upregulated with age in NSCs3, 11–13, and the knockout of some of these boosts old NSC activation and rejuvenates aspects of old brain function14–18. But systematic functional testing of genes in old NSCs – and more generally in old cells – has not been done. This has been a major limiting factor in identifying the most promising rejuvenation interventions. Here we develop in vitro and in vivo high-throughput CRISPR-Cas9 screening platforms to systematically uncover gene knockouts that boost NSC activation in old mice. Our genome-wide screening pipeline in primary cultures of young and old NSCs identifies over 300 gene knockouts that specifically restore old NSC activation. Interestingly, the top gene knockouts are involved in glucose import, cilium organization and ribonucleoprotein structures. To determine which gene knockouts have a rejuvenating effect for the aging brain, we establish a scalable CRISPR-Cas9 screening platform in vivo in old mice. Of the 50 gene knockouts we tested in vivo, 23 boost old NSC activation and production of new neurons in old brains. Notably, the knockout of Slc2a4, which encodes for the GLUT4 glucose transporter, is a top rejuvenating intervention for old NSCs. GLUT4 protein expression increases in the stem cell niche during aging, and we show that old NSCs indeed uptake ∼2-fold more glucose than their young counterparts. Transient glucose starvation increases the ability of old NSCs to activate, which is not further improved by knockout of Slc2a4/GLUT4. Together, these results indicate that a shift in glucose uptake contributes to the decline in NSC activation with age, but that it can be reversed by genetic or external interventions. Importantly, our work provides scalable platforms to systematically identify genetic interventions that boost old NSC function, including in vivo in old brains, with important implications for regenerative and cognitive decline during aging.
A chemical method to sequence 5-formylcytosine on RNA
Authors: Li Ang , Sun Xuemeng , Arguello A. Emilia , Kleiner Ralph E. 
Published: November 2021

AbstractEpitranscriptomic RNA modifications can regulate biological processes, but there remains a major gap in our ability to identify and measure individual modifications at nucleotide resolution. Here we present Mal-Seq, a chemical method to sequence 5-formylcytosine (f5C) modifications on RNA based upon selective and efficient malononitrile-mediated labeling of f5C residues to generate adducts that are read as C-to-T mutations upon reverse transcription and PCR amplification. We apply Mal-Seq to characterize the prevalence of f5C at the wobble position of mt-tRNA(Met) in different organisms and tissue types and find that high-level f5C modification is present in mammals but lacking in lower eukaryotes. Our work sheds light on mitochondrial tRNA modifications throughout eukaryotic evolution and provides a general platform for characterizing the f5C epitranscriptome.
SELENOT deficiency alters projection neuron migration during corticogenesis in mice
Authors: Carpentier Emmanuelle , Falluel-Morel Anthony , Brunet Lisa , Bénard Magalie , Godefroy David , Boukhzar Loubna , Arabo Arnaud , Anouar Youssef 
Published: November 2021

AbstractDuring corticogenesis, projection neurons migrate along the radial glial axis to form cortical layers, the alteration of which is associated with functional deficits in adulthood. As byproducts of cell metabolism, reactive oxygen species act as second messengers to contribute to neurodevelopment; however, free radical excess may impede this process. SELENOT is a thioredoxin-like enzyme of the endoplasmic reticulum abundantly expressed during embryogenesis whose gene disruption in the brain leads to neuroblast cell demise due to increased free radical levels. To determine the potential contribution of SELENOT to the establishment of cortical networks, we analyzed first its expression profile in the neocortex at different stages of development. These studies revealed the widespread expression of SELENOT in all cortical layers, and its continous increase throughout mouse lifespan. In addition, we disrupted the SELENOT gene in the cortex using in utero electroporation and Nes-Cre/lox knockout. SELENOT deficiency altered neuroblast migration polarity, at the level of radial scaffolding, and projection neuron positionning. These results indicate that SELENOT plays a crucial role during neurodevelopment by sustaining projection neuron migration.
New thermal-hydraulic correlations for printed circuit heat exchangers (PCHEs) with zigzag channels under high Reynolds numbers
Authors: Naveira-Cotta Carolina P. , Su Jian , Lucena Kreppel Paes Paulo , Egmont Philippe R. , Moreira Rodrigo P.M. , Silva Gabriel Caetano G.R. da , Monteiro André Sampaio 
Published: November 2021

Purpose
The purpose of this paper is to investigate the impact of semi-circular zigzag-channel printed circuit heat exchanger (PCHE) design parameters on heat transfer and pressure drop of flows under high Reynolds numbers and provide new thermal-hydraulic correlations relevant to conditions encountered in natural gas processing plants.

Design/methodology/approach
The correlations were developed using three-dimensional steady-state computational fluid dynamics simulations with varying semicircular channel diameter (from 1 to 5 mm), zigzag angle (from 15° to 45°) and Reynolds number (from 40,000 to 100,000). The simulation results were validated by comparison with experimental results and existing correlations.

Findings
The results revealed that the thermal-hydraulic performance was mostly affected by the zigzag angle, followed by the ratio of the zigzag channel length to the hydraulic diameter. Overall, smaller zigzag angles favored heat transfer intensification while keeping reasonably low pressure drops.

Originality/value
This study is, to date, the only one providing thermal-hydraulic correlations for PCHEs with zigzag channels under high Reynolds numbers. Besides, the broad range of parameters considered makes the proposed correlations valuable PCHE design tools.