bluuebunny/crossref_metadata_2025_split huggingface dataset:
A layered, hybrid machine learning analytic workflow for mouse risk assessment behavior
Authors: Wang Jinxin , Karbasi Paniz , Wang Liqiang , Meeks Julian P. 
Published: August 2022

AbstractAccurate and efficient quantification of animal behavior facilitates the understanding of the brain. An emerging approach within machine learning (ML) field is to combine multiple ML-based algorithms to quantify animal behavior. These so-called hybrid models have emerged because of limitations associated with supervised (e.g., random forest, RF) and unsupervised (e.g., hidden Markov model, HMM) ML classifiers. For example, RF models lack temporal information across video frames, and HMM latent states are often difficult to interpret. We sought to develop a hybrid model, and did so in the context of a study of mouse risk assessment behavior. We utilized DeepLabCut to estimate the positions of mouse body parts. Positional features were calculated using DeepLabCut outputs and were used to train RF and HMM models with equal number of states, separately. The per-frame predictions from RF and HMM models were then passed to a second HMM model layer (“reHMM”). The outputs of the reHMM layer showed improved interpretability over the initial HMM output. Finally, we combined predictions from RF and HMM models with selected positional features to train a third HMM model (“reHMM+”). This reHMM+ layered hybrid model unveiled distinctive temporal and human-interpretable behavioral patterns. We applied this workflow to investigate risk assessment to trimethylthiazoline and snake feces odor, finding unique behavioral patterns to each that were separable from attractive and neutral stimuli. We conclude that this layered, hybrid machine learning workflow represents a balanced approach for improving the depth and reliability of ML classifiers in chemosensory and other behavioral contexts.Significance StatementIn this study, we integrate two widely-adopted machine learning (ML) classifiers, random forest and hidden Markov model, to develop a layered, hybrid ML-based workflow. Our workflow not only overcomes the intrinsic limitations of each model alone, but also improves the depth and reliability of ML models. Implementing this analytic workflow unveils distinctive and dynamic mouse behavioral patterns to chemosensory cues in the context of mouse risk assessment behavioral experiments. This study provides an efficient and interpretable analytic strategy for the quantification of animal behavior in diverse experimental settings.
Mitochondrial iron transport via MFRN1 is required for erythroid cell cycle progression
Authors: Perfetto Mark , Danoff Aidan , Ishfaq Muhammad , Monroe Heidi , Mohideen Aiden , Chen Meilin , Stratman Amber , Okawa Satoshi , Yien Yvette 
Published: August 2022

AbstractIron metabolism drives key erythropoietic processes, including hemoglobinization, survival, and proliferation. Here, we developedin vivomethods to interrogate how iron regulates erythropoiesis and report that mitochondrial iron transport via MFRN1 is essential for erythroid cell cycle progression.mfrn1embryos had severely decreased erythroid cell number caused by cell cycle arrest at G2/M. They had enlarged nuclei, suggesting a mitotic defect. Iron supplementation rescued the cell cycle defect, implicating mitochondrial iron deficiency as its cause. In contrast,fpn1mutants, anemic from systemic iron deficiency, had less severe decreases in erythroid mitochondrial iron thanmfrn1mutants and no proliferative defects. scRNAseq and FACS analyses forcd41(thrombocytic) andgata1reporters indicated that developmental defects inmfrn1mutants were largely erythroid restricted.mfrn1mutantgata1+erythroid progenitors were severely decreased at 3 dpf, and a further decrease inglobin-expressing terminally differentiating erythroid cells. While wild-type erythroid cells mostly lost expression of thegata1progenitor marker by 3 dpf,mfrn1mutant erythroid cells retainedgata1expression. These data are consistent with a model where mitochondrial iron transport facilitates development ofgata1+erythroid progenitors and is required for the completion of erythropoiesis by facilitating mitosis in the terminal cell cycles.
When do we become more prone to distraction? Progressive evolution of the different components of distractibility from early to late adulthood
Authors: Hoyer R.S. , Abdoun O. , Riedinger M. , Bouet R. , Elshafei H. , Bidet-Caulet A. 
Published: August 2022

ABSTRACTLife expectancy has steadily increased for over a century; we thus live longer and are more likely to experience cognitive difficulties such as increased distractibility which can hamper autonomy. This cross-sectional behavioral study aimed to characterize the decline of the cognitive components of distractibility during typical aging, and the onset of this decline. 191 participants from 21 to 86 years old, distributed within seven age groups, were tested using the Competitive Attention Test. Results indicate that cognitive components contributing to distractibility follow different trajectories with aging: voluntary orienting remains stable from 21 to 86 years old, sustained attention decreases while distraction increases between 26 and 86 years old, finally, impulsivity is lower in older compared to younger adults. Increased distractibility in older adults thus seems to result from a dominance of involuntary over voluntary attention processes, whose detrimental effect on performance is partly compensated by enhanced recruitment of motor control.
SPEX: A modular end-to-end platform for high-plex tissue spatial omics analysis
Authors: Li Xiao , Pechuan-Jorge Ximo , Risom Tyler , Foo Conrad , Prilipko Alexander , Zubkov Artem , Chan Caleb , Chang Patrick , Peale Frank , Ziai James , Rost Sandra , Hibar Derrek , McGinnis Lisa , Tabatsky Evgeniy , Ye Xin , Bravo Hector Corrada , Shi Zhen , Nowicka Malgorzata , Scherdin Jon , Cowan James , Giltnane Jennifer , Orlova Darya , Jesudason Rajiv 
Published: August 2022

ABSTRACTRecent advancements in transcriptomics and proteomics have opened the possibility for spatially resolved molecular characterization of tissue architecture with the promise of enabling a deeper understanding of tissue biology in either homeostasis or disease. The wealth of data generated by these technologies has recently driven the development of a wide range of computational methods. These methods have the requirement of advanced coding fluency to be applied and integrated across the full spatial omics analysis process thus presenting a hurdle for widespread adoption by the biology research community. To address this, we introduce SPEX (Spatial Expression Explorer), a web-based analysis platform that employs modular analysis pipeline design, accessible through a user-friendly interface. SPEX’s infrastructure allows for streamlined access to open source image data management systems,analysis modules, and fully integrated data visualization solutions. Analysis modules include essential steps covering image processing, single-cell and spatial analysis. We demonstrate SPEX’s ability to facilitate the discovery of biological insights in spatially resolved omics datasets from healthy tissue to tumor samples.
SREBP1 activation contributes to fatty acid accumulations in necroptosis
Authors: Lu Daniel , Parisi Laura R. , Gokcumen Omer , Atilla-Gokcumen G. Ekin 
Published: August 2022

ABSTRACTNecroptosis is a type of programmed cell death. It is characterized by membrane permeabilization and is associated with a strong inflammatory response due to the release of intracellular components due to compromised membrane integrity. We recently showed that the accumulation of very long chain fatty acids (VLCFAs) contributes to membrane permeabilization during necroptosis. However, the mechanisms that result in the accumulation of these cytotoxic lipids remain unknown. Using comparative transcriptomics, we found that sterol regulatory element-binding protein 1 (SREBP1) is activated and that its downstream gene targets result in the accumulation of VLCFAs during necroptosis. We demonstrated that activation of SREBP1 during necroptosis exacerbates cell death. On the contrary, inactivation of SREBP1 reversed the accumulation of VLCFAs, and restored cell death and membrane permeabilization during necroptosis. Collectively, our results highlight a role for SREBP1 in regulating lipid changes during necroptosis and suggest SREBP1 as a potential target for therapeutics to reduce membrane permeabilization during necroptosis.
Miltefosine attenuates inflammation, reduces atherosclerosis, and alters gut microbiota in hyperlipidemic mice
Authors: Traughber C. Alicia , Iacano Amanda J , Khan Mariam R , Neupane Kalash , Opoku Emmanuel , Nunn Tina , Sangwan Naseer , Hazen Stanley L , Smith Jonathan D , Gulshan Kailash 
Published: August 2022

AbstractExcess cholesterol induces foam cell formation, NLRP3 inflammasome activation, and IL-1β release in atherosclerotic plaques. We have shown previously that Miltefosine increased cholesterol release and dampened NLRP3 inflammasome assembly in macrophages. Here, we show that Miltefosine reduced LPS-induced choline uptake by macrophages and attenuated NLRP3 inflammasome assembly in mice. Miltefosine-fed mice showed reduced plasma IL-1β in a polymicrobial cecal slurry injection model of systemic inflammation. Miltefosine-fed mice showed increased reverse cholesterol transport from macrophages to plasma, liver, and feces. Hyperlipidemic apoE−/−mice fed with Miltefosine showed significantly reduced weight gain and markedly reduced atherosclerotic lesions vs. control mice. 16S rDNA sequencing and analysis showed alterations in the gut microbiota profile of Miltefosine-fed hyperlipidemic apoE−/−vs. control mice, with the most notable changes inRomboutsiaandBacteroidetes species. Taken together, these data indicate that Miltefosine causes pleiotropic effects on lipid metabolism, inflammasome activity, atherosclerosis, and the gut microbiota.
Myeloid-cell-specific role of Gasdermin D in promoting lung cancer progression in mice
Authors: Traughber C. Alicia , Deshpande Gauravi M , Neupane Kalash , Khan Mariam R , McMullen Megan R , Swaidani Shadi , Opoku Emmanuel , Muppala Santoshi , Smith Jonathan D , Nagy Laura E , Gulshan Kailash 
Published: August 2022

AbstractThe activities of the NLRP3 and AIM2 inflammasomes and Gasdermin D (GsdmD), the final executor of inflammasome activity, are implicated in lung cancer pathophysiology but it’s not clear if their contributions promote or retard lung cancer progression. GsdmD plays a role in release of interleukin-1beta (IL-1 β), and the CANTOS trial and recent studies have highlighted a crucial role of IL-1β in promoting lung cancer. Expression of GsdmD was shown to be upregulated in human non-small cell lung cancer (NSCLC) tissue, but its contribution to in vivo lung cancer metastasis is not known. Using a metastatic Lewis Lung Carcinoma (LLC) cell model, we show that GsdmD knockout (GsdmD-/-) mice form significantly fewer cancer foci in lung, and exhibit markedly decreased lung cancer metastasis. Furthermore, GsdmD-/- mice show a significant ~ 50% increase in median survival rate vs. isogenic WT C57BL6J mice. The cleaved forms of GsdmD and IL-1 β were detected in lung tumor tissue, indicating inflammasome activity in lung tumor microenvironment (TME). Increased migration and growth of LLC cells was observed upon exposure to the conditioned media derived from inflammasome-induced wild type, but not the GsdmD-/-, macrophages. Exposure of human A549 lung cancer cells to the conditioned media derived from inflammasome-induced THP-1 macrophages also resulted in increased cell migration. Using bone marrow transplantation, we show the myeloid-specific contribution of GsdmD in lung cancer metastasis. Taken together, our data show that inflammasome activation in macrophages promotes lung cancer growth and migration, and GsdmD plays a myeloid-specific role in lung cancer progression in mice.
Cytoplasmic nucleoporin foci are stress-sensitive, non-essential condensates in C. elegans
Authors: Thomas Laura , Ismail Basma Taleb , Askjaer Peter , Seydoux Geraldine 
Published: August 2022

AbstractNucleoporins (Nups) assemble nuclear pores that form the permeability barrier that separates nucleoplasm from cytoplasm. Nups have also been observed in cytoplasmic foci proposed to function as pore pre-assembly intermediates. Here we characterize the composition and incidence of cytoplasmic Nup foci in an intact animal,C. elegans. We find that, in young non-stressed animals, Nup foci only appear in developing sperm, oocytes, and embryos, tissues that express high Nup levels. The foci are condensates of highly cohesive FG-Nups that are maintained near their solubility limit in the cytoplasm by posttranslational modifications and chaperone activity. Only a minor fraction of FG-Nup molecules concentrate in Nup foci, which dissolve during M phase and are dispensable for nuclear pore assembly. Nup condensation is enhanced by stress and advancing age, and overexpression of a single FG-Nup in post-mitotic neurons is sufficient to induce ectopic condensation and organismal paralysis. Our results suggest that Nup foci are non-essential, “accidental”, and potentially toxic condensates whose assembly is actively suppressed in healthy cells.
A Mesp1-dependent developmental breakpoint in transcriptional and epigenomic specification of early cardiac precursors
Authors: Krup Alexis Leigh , Winchester Sarah A.B. , Ranade Sanjeev S. , Agrawal Ayushi , Devine W. Patrick , Sinha Tanvi , Choudhary Krishna , Dominguez Martin H. , Thomas Reuben , Black Brian L. , Srivastava Deepak , Bruneau Benoit G. 
Published: August 2022

AbstractTranscriptional networks governing cardiac precursor cell (CPC) specification are incompletely understood due in part to limitations in distinguishing CPCs from non-cardiac mesoderm in early gastrulation. We leveraged detection of early cardiac lineage transgenes within a granular single cell transcriptomic time course of mouse embryos to identify emerging CPCs and describe their transcriptional profiles. Mesp1, a transiently-expressed mesodermal transcription factor (TF), is canonically described as an early regulator of cardiac specification. However, we observed perdurance of CPC transgene-expressing cells in Mesp1 mutants, albeit mis-localized, prompting us to investigate the scope of Mesp1’s role in CPC emergence and differentiation. Mesp1 mutant CPCs failed to robustly activate markers of cardiomyocyte maturity and critical cardiac TFs, yet they exhibited transcriptional profiles resembling cardiac mesoderm progressing towards cardiomyocyte fates. Single cell chromatin accessibility analysis defined a Mesp1-dependent developmental breakpoint in cardiac lineage progression at a shift from mesendoderm transcriptional networks to those necessary for cardiac patterning and morphogenesis. These results reveal Mesp1-independent aspects of early CPC specification and underscore a Mesp1-dependent regulatory landscape required for progression through cardiogenesis.
Text mining of CHO bioprocess bibliome: Topic modeling and document classification
Authors: Wang Qinghua , Olshin Jonathan , Vijay-Shanker K. , Wu Cathy 
Published: August 2022

AbstractChinese hamster ovary (CHO) cells are widely used for mass production of therapeutic proteins in the pharmaceutical industry. With the growing need in optimizing the performance of producer CHO cell lines, research on CHO cell line development and bioprocess continues to increase in recent decades. Bibliographic mapping and classification of relevant research studies will be essential for identifying research gaps and trends in literature. To qualitatively and quantitatively understand the CHO literature, we have conducted topic modeling using a CHO bioprocess bibliome manually compiled in 2016, and compared the topics uncovered by the Latent Dirichlet Allocation (LDA) models with the human labels of the CHO bibliome. The results show a significant overlap between the manually selected categories and computationally generated topics, and reveal the machine-generated topic-specific characteristics. To identify relevant CHO bioprocessing papers from new scientific literature, we have developed a supervised learning model, Logistic Regression, to identify specific article topics and evaluated the results using three CHO bibliome datasets, Bioprocessing set, Glycosylation set, and Phenotype set. The use of top terms as features supports the explainability of document classification results to yield insights on new CHO bioprocessing papers.
Phenotypic and transcriptional features of the Araliaceae species under distinct light environments
Authors: Niu Yu-Qian , Zhang Yu-Xin , Wang Xin-Feng , Wang Zhen-Hui , Yang Ji , Wang Yu-Guo , Zhang Wen-Ju , Song Zhi-Ping , Li Lin-Feng 
Published: August 2022

AbstractElucidating how the plant species respond to variable light conditions is essential to understand the ecological adaptation to heterogeneous environments. Plant performance and gene regulatory network underpinning the adaptation have been well-documented in sun-grown species. In this study, we surveyed phenotypic and transcriptomic features of four shade-grown and one sun-grown woody species of the family Araliaceae under distinct light conditions. Our phenotypic comparisons demonstrate that the four shade-grown species possess lower light saturation point and higher assimilation ability of the net photosynthetic rate compared to the sun-grown species. In particular, the four shade-grown species maintain similar photosynthesis efficiency in both highlight and lowlight conditions. However, a significantly decreased photosynthesis rate was observed under lowlight condition of the sun-grown species compared to highlight condition. In addition, our leaf anatomical analyses reveal that while all the five species show different anatomical structures under distinct light conditions, the shade-grown species possess lower degree of phenotypic plasticity relative the sun-grown species. Further comparisons of the transcriptome profiling show that all the five species exhibit gene expression divergence among different light conditions. The differentially expressed genes identified in the five species are functionally related to photosynthesis, secondary metabolites and other basic metabolisms. More importantly, differential regulation of the photosynthesis- and photomorphogenesis-related genes are potentially correlated with the phenotypic responses to distinct light conditions of the five species. Our study provides new insights on how the sun- and shade-grown woody species respond to shade and sunlight environments.
RiboXYZ: A comprehensive database for visualizing and analyzing ribosome structures
Authors: Kushner Artem , Petrov Anton , Duc Khanh Dao 
Published: August 2022

AbstractRecent advances in Cryo-EM led to a surge of ribosome structures deposited over the past years, including structures from different species, conformational states, or bound with different ligands. Yet, multiple conflicts of nomenclature make the identification and comparison of structures and ortholog components challenging. We present RiboXYZ (available at https://ribosome.xyz), a database that provides organized access to ribosome structures, with several tools for visualisation and study. The database is up-to-date with the Protein Data Bank (PDB) but provides a standardized nomenclature that allows for searching and comparing ribosomal components (proteins, RNA, ligands) across all the available structures. In addition to structured and simplified access to the data, the application has several specialized visualization tools, including the identification and prediction of ligand binding sites, and 3D superimposition of ribosomal components. Overall, RiboXYZ provides a useful toolkit that complements the PDB database, by implementing the current conventions and providing a set of auxiliary tools that have been developed explicitly for analyzing ribosome structures. This toolkit can be easily accessible by both experts and non-experts in structural biology so that they can search, visualize and compare structures, with various potential applications in molecular biology, evolution, and biochemistry.
NS5A domain I antagonises PKR to facilitate the assembly of infectious hepatitis C virus particles
Authors: Chen Shucheng , Harris Mark 
Published: August 2022

AbstractHepatitis C virus NS5A is a multifunctional phosphoprotein comprised of three domains (DI, DII and DIII). DI and DII have been shown to function in genome replication, whereas DIII has a role in virus assembly. We previously demonstrated that DI in genotype 2a (JFH1) also plays a role in virus assembly, exemplified by the P145A mutant which exhibited no defect in genome replication, but blocked infectious virus production (1). Here we extend this analysis to identify two other conserved and surface exposed residues proximal to P145 (C142 and E191) that shared the same phenotype. Further analysis revealed changes in the abundance of dsRNA, the size and distribution of lipid droplets (LD) and the co-localisation between NS5A and LDs in cells infected with these mutants, compared to wildtype. In parallel, to investigate the mechanism(s) underpinning this role of DI, we assessed the involvement of the interferon-induced double-stranded RNA-dependent protein kinase (PKR). In PKR-knockout cells, C142A and E191A exhibited levels of infectious virus production, LD size and co-localisation between NS5A and LD that were indistinguishable from wildtype. Co-immunoprecipitation and in vitro pulldown experiments confirmed that wildtype NS5A domain I (but not C142A or E191A) interacted with PKR. We further showed that the assembly phenotype of C142A and E191A was restored by ablation of interferon regulatory factor-1 (IRF1), a downstream effector of PKR. These data suggest a novel interaction between NS5A DI and PKR that functions to evade an antiviral pathway that blocks virus assembly through IRF1.Author summaryThe non-structural 5A protein (NS5A) of hepatitis C virus (HCV) plays a critical role in both virus genome replication and the assembly of infectious virus particles. NS5A is a target for potent and highly efficacious direct acting antivirals used extensively for HCV treatment. NS5A comprises 3 domains. Here, we show that the N-terminal domain I (DI) plays a role in virus assembly. Mutations in DI block both virus assembly and the perturbation of lipid droplet morphology that is a hallmark of HCV infection. Strikingly, this phenotype is abrogated by silencing of the cellular cytoplasmic double-stranded RNA sensor, PKR, a key antiviral factor. These mutations have therefore uncovered a hitherto uncharacterised antiviral pathway controlled by PKR which functions to block assembly of infectious virus particles.