bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unifying comprehensive genomics and transcriptomics in individual cells to illuminate oncogenic and drug resistance mechanisms
Authors: Marks Jeffrey R. , Zawistowski Jon S. , Salas-González Isai , Tate Tia A. , Morozova Tatiana V. , Blackinton Jeff G. , Arvapalli Durga M. , Velivela Swetha D. , Harton Gary L. , Gawad Charles , Weigman Victor J. , Hwang E. Shelley , West Jay A.A. 
Published: May 2022

ABSTRACTDiscovering transcriptional variation in the absence of underlying genomic contributions hinders understanding of molecular mechanisms of disease. To assess this coordination in individual cells, we leveraged a new workflow, ResolveOME, exploiting the attributes of primary template-directed amplification (PTA) to enable accurate, complete-genome assessment of single-nucleotide variation in conjunction with full-transcript RNA-seq.In cultured AML cells resistant to the FLT3 inhibitor quizartinib, we uncovered aFLT3missense mutation and matched transcript upregulation of AXL signal transduction and enhancer factor modulation driving resistance. In primary breast cancer cells, we detected oncogenicPIK3CAN345K mutations and heterogeneous classes of chromosomal loss and were empowered to interpret these genotypes with the crucial knowledge of cell identity and state derived from the transcriptome. The study reinforces the plasticity of the genome in conjunction with expected transcriptional modulation, leading to combinatorial alterations that affect cellular evolution that can be identified through application of this workflow to individual cells.
microbeSEG: A deep learning software tool with OMERO data management for efficient and accurate cell segmentation
Authors: Scherr Tim , Seiffarth Johannes , Wollenhaupt Bastian , Neumann Oliver , Schilling Marcel P. , Kohlheyer Dietrich , Scharr Hanno , Nöh Katharina , Mikut Ralf 
Published: May 2022

AbstractIn biotechnology, cell growth is one of the most important properties for the characterization and optimization of microbial cultures. Novel live-cell imaging methods are leading to an ever better understanding of cell cultures and their development. The key to analyzing acquired data is accurate and automated cell segmentation at the single-cell level. Therefore, we present microbeSEG, a user-friendly Python-based cell segmentation tool with a graphical user interface and OMERO data management. microbeSEG utilizes a state-of-the-art deep learning-based segmentation method and can be used for instance segmentation of a wide range of cell morphologies and imaging techniques, e.g., phase contrast or fluorescence microscopy. The main focus of microbeSEG is a comprehensible, easy, efficient, and complete workflow from the creation of training data to the final application of the trained segmentation model. We demonstrate that accurate cell segmentation results can be obtained within 45 minutes of user time. Utilizing public segmentation datasets or pre-labeling further accelerates the microbeSEG workflow. This opens the door for accurate and efficient data analysis of microbial cultures.
Characterization of metabolic changes associated with floral transition in Arabidopsis: RAFFINOSE SYNTHASE 5 contributes to determine the timing of floral transition
Authors: Praena Tamayo Jesús , Budzinski Ilara Gabriela Frasson , Delhomme Nicolas , Moritz Thomas , Madueño Francisco , Benlloch Reyes 
Published: May 2022

AbstractIntegration of environmental and endogenous cues triggers floral induction at the optimal time during the plant life cycle. Flowering is a tightly regulated process, which involves an intricated genetic network, as expected for a process crucial for plant fitness and survival. Individual metabolites are known to contribute to the determination of flowering time, including carbohydrates and hormones. However, a global analysis of metabolic changes associated with flowering was still lacking. We performed a metabolomic study to characterize global metabolic changes associated with photoperiodic floral induction. By using an inducible system, with the CONSTANS (CO) promoter driving the expression of CO fused to the rat glucocorticoid receptor (CO::GR), we induce flowering and identify metabolites that increase or decrease in leaves and apices during floral induction. Combining metabolomic with transcriptomic data, we identify that raffinose metabolism was altered in apices that are induced to flower. Loss-of-function mutants affecting RAFFINOSE SYNTHASE 5 (RS5), a key enzyme of the raffinose metabolism, show an early flowering phenotype. Also, RS5 expression changes during floral transition, suggesting a role for raffinose catabolism on the release of simple sugars at the apex. We propose that variation on the differential accumulation of raffinose and mono- and disaccharides during floral transition contributes to the induction of floral transition, by influencing expression of THEHALOSE-6-PHOSPHATE SYNTHASE 1 (TPS1) and SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 3 (SPL3), which affect expression of the florigen FLOWERING LOCUS T (FT).
DysRegNet: Patient-specific and confounder-aware dysregulated network inference
Authors: Kersting Johannes , Lazareva Olga , Louadi Zakaria , Baumbach Jan , Blumenthal David B. , List Markus 
Published: May 2022

Gene regulation is frequently altered in diseases in unique and patient-specific ways. Hence, personalized strategies have been proposed to infer patient-specific gene-regulatory networks. However, existing methods do not scale well as they often require recomputing the entire network per sample. Moreover, they do not account for clinically important confounding factors such as age, sex, or treatment history. Finally, a user-friendly implementation for the analysis and interpretation of such net-works is missing.We present DysRegNet, a method for inferring patient-specific regulatory alterations (dysregulations) from bulk gene expression profiles. We compared DysRegNet to SSN, a well-known sample-specific network approach. We demonstrate that both SSN and DysRegNet produce interpretable and biologically meaningful networks across various cancer types. In contrast to SSN, DysRegNet can scale to arbitrary sample numbers and highlights the importance of confounders in network inference, revealing an age-specific bias in gene regulation in breast cancer. DysRegNet is available as a Python package (https://github.com/biomedbigdata/DysRegNet_package), and analysis results for eleven TCGA cancer types are available through an interactive web interface (https://exbio.wzw.tum.de/dysregnet).
Colour polymorphism associated with a gene duplication in male wood tiger moths
Authors: Brien Melanie N. , Orteu Anna , Yen Eugenie C. , Galarza Juan A. , Kirvesoja Jimi , Pakkanen Hannu , Wakamatsu Kazumasa , Jiggins Chris D. , Mappes Johanna 
Published: May 2022

AbstractColour is often used as an aposematic warning signal, with predator learning expected to lead to a single colour pattern within a population. However, there are many puzzling cases where aposematic signals are also polymorphic. The wood tiger moth,Arctia plantaginis, displays bright hindwing colours associated with unpalatability, and males have discrete colour morphs which vary in frequency between localities. In Finland, both white and yellow morphs can be found, and these colour morphs also differ in behavioural and life-history traits. Here, we show that male colour is linked to an extra copy of ayellowfamily gene that is only present in the white morphs. This white-specific duplication, which we namevalkea, is highly upregulated during wing development, and CRISPR knockouts validate the role ofvalkeain producing white wing colour. We also characterise the pigments responsible for yellow, white and black colouration, showing that yellow is partly produced by pheomelanins, while black is dopamine-derived eumelanin. Our results add to a growing number of studies on the genetic architecture of complex and seemingly paradoxical polymorphisms, and the role of gene duplications and structural variation in adaptive evolution.
Single cell transcriptional landscape of long non-coding RNAs orchestrating mouse heart development
Authors: Ramos Thaís A. R. , Kim Soo Young , Gillette Thomas G. , Hill Joseph A. , Lavandero Sergio , do Rêgo Thaís G. , Maracaja-Coutinho Vinicius 
Published: May 2022

AbstractLong non-coding RNAs (lncRNAs) comprise the most representative transcriptional units of the mammalian genome, and they’re associated with organ development that can be associated with the emergence of diseases, such as cardiovascular diseases. Thus, we used bioinformatic approaches, machine learning algorithms and statistical techniques to define lncRNAs involved in mammalian cardiac development. We used a single-cell transcriptome dataset generated from 4 embryonic and 4 postnatal stages. Our study identified 8 distinct cell types, novel marker transcripts (coding/lncRNAs) and also, differential expression and functional enrichment analysis reveal cardiomyocyte subpopulations associated with cardiac function; meanwhile modular co-expression analysis reveals cell-specific functional insights for lncRNAs during myocardial development, including a potential association with key genes related to disease and the “fetal gene program”. Our results evidence the role of particular lncRNAs in heart development, and highlights the usage of co-expression modular approaches in the cell-type functional definition.
NMDA-receptor-Fc-fusion constructs neutralize anti-NMDA receptor antibodies
Authors: Steinke Stephan , Kirmann Toni , Nerlich Jana , Weichard Iron , Kuhn Philip , Bullmann Torsten , Ritzau-Jost Andreas , Rizalar Filiz Sila , Prüss Harald , Haucke Volker , Geis Christian , Hust Michael , Hallermann Stefan 
Published: May 2022

AbstractN-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common subtype of autoimmune encephalitis characterized by a complex neuropsychiatric syndrome ranging from memory impairment and psychosis to coma. Patients develop an intrathecal immune response against NMDARs with antibodies that presumably bind to the amino-terminal domain (ATD) of the GluN1 subunit. The therapeutic response to immunotherapy is often delayed and does not directly interfere with intrathecal synthesis of pathogenic antibodies. Therefore, new therapeutic approaches for fast neutralization of NMDAR antibodies are needed. Here, we developed fusion constructs consisting of the Fc part of immunoglobulin G and the ATDs of either GluN1 or GluN2B or both, GluN1 and GluN2B, subunits. Surprisingly, both subunits were required to generate high-affinity epitopes. The construct with both subunits efficiently prevented NMDAR binding of patient-derived monoclonal antibodies and of patient cerebrospinal fluid containing high-titer NMDAR antibodies. Furthermore, it inhibited the internalization of NMDARs in rodent dissociated neurons and human induced pluripotent stem cells (iPSC)-derived neurons. Finally, the construct stabilized NMDAR currents recorded in rodent neurons. Our results demonstrate that both GluN1 and GluN2B subunits contribute to the main immunogenic region of the NMDAR and provide a promising strategy for fast and specific treatment of NMDAR encephalitis, which can complement immunotherapy.
Increased glucose availability sensitizes pancreatic cancer to chemotherapy
Authors: Vaziri-Gohar Ali , Hue Jonathan J. , Graor Hallie G. , Abbas Ata , Zarei Mehrdad , Hajihassani Omid , Titomihelakis George , Feczko John , Rathore Moeez , Wang Rui , Zarei Mahsa , Goudarzi Maryam , Zhang Renliang , Willard Belinda , Zhang Li , Wang Gi-Ming , Tatsuoka Curtis , Salvino Joseph M. , Bederman Ilya , Brunengraber Henri , Lyssiotis Costas A. , Brody Jonathan R. , Winter Jordan M. 
Published: May 2022

SummaryPancreatic cancer (Pancreatic Ductal Adenocarcinoma; PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, leaving chemotherapy as the best available systematic treatment. The discovery of safe and available adjuncts that improve chemotherapeutic efficacy would potentially improve survival outcomes. We show that a hyperglycemic state enhances the efficacy of conventional single- and multi-agent chemotherapies against PDAC. Molecular analyses of tumors exposed to relatively high glucose levels revealed that a key metabolic pathway, glutathione biosynthesis, is diminished and underlies chemo-sensitization by enhancing oxidative injury to cancer cells. Inhibition of this pathway under normal conditions phenocopied a hyperglycemic state by enhancing chemotherapeutic efficacy in mouse PDAC, while rescuing the pathway under high glucose abrogated the anti-tumor effects observed with chemotherapy.
Glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors
Authors: Cao Shuting , Hung Yu-Wen , Wang Yi-Chang , Chung Yiyin , Qi Yue , Ouyang Ching , Zhong Xiancai , Hu Weidong , Coblentz Alaysia , Maghami Ellie , Sun Zuoming , Lin H. Helen , Ann David K. 
Published: May 2022

AbstractRationaleImmunosuppression in the tumor microenvironment (TME) is key to the pathogenesis of solid tumors. Tumor cell-intrinsic autophagy is critical for sustaining both tumor cell metabolism and survival. However, the role of autophagy in the host immune system that allows cancer cells to escape immune destruction remains poorly understood. Here, we determined if attenuated host autophagy is sufficient to induce tumor rejection through reinforced adaptive immunity. Furthermore, we determined whether dietary glutamine supplementation, mimicking attenuated host autophagy, is capable of promoting antitumor immunity.MethodsA syngeneic orthotopic tumor model in Atg5+/+ and Atg5flox/flox mice was established to determine the impact of host autophagy on the antitumor effects against mouse malignant salivary gland tumors (MSTs). Multiple cohorts of immunocompetent mice were used for oncoimmunology studies, including inflammatory cytokine levels, macrophage, CD4+, and CD8+ cells tumor infiltration at 14 days and 28 days after MST inoculation. In vitro differentiation and in vivo dietary glutamine supplementation were used to assess the effects of glutamine on Treg differentiation and tumor expansion.ResultsWe showed that mice deficient in the essential autophagy gene, Atg5, rejected orthotopic allografts of isogenic MST cells. An enhanced antitumor immune response evidenced by reduction of both M1 and M2 macrophages, increased infiltration of CD8+ T cells, elevated IFN-γ production, as well as decreased inhibitory Tregs within TME and spleens of tumor-bearing Atg5flox/flox mice. Mechanistically, ATG5 deficiency increased glutamine level in tumors. We further demonstrated that dietary glutamine supplementation partially increased glutamine levels and restored potent antitumor responses in Atg5+/+ mice.ConclusionsDietary glutamine supplementation exposes a previously undefined difference in plasticity between cancer cells, cytotoxic CD8+ T cells and Tregs.
Effects of Full-cycle Exposure to Difenoconazole in Parental Zebrafish on the Liver-gut Axis of F0 and F1 Generations
Authors: Zhu Tao , Wang Siwen , Li Dong 
Published: May 2022

AbstractTo explore the effects of long-term exposure to low-dose difenoconazole (DCZ) on lipid metabolism in the liver-gut axis, we exposed zebrafish embryos to ambient concentrations of DCZ for 120 days and comprehensively analyzed the metabolic and microbial networks of the F0 and F1 generations using biochemical, metabolomic and metagenomics approaches. The changes of biochemical indexes indicated that DCZ exposure inhibited lipid synthesis, lipolysis and lipid transport of F0 males and females. In addition, the composition of gut microbes in males and females was significantly changed, which corresponds to changes in biochemical parameters in liver, intestine and serum. Metabolome analysis showed that pathways related to amino acid metabolism, ATP-binding cassette transporters, carbohydrate metabolism, and energy metabolism were downregulated in the gut of males and females. At 120 days post-fertilization, lipid synthesis, lipolysis and lipid transport of F1 males was upregulated; the composition of microbiota and metabolome of the F1males gut was significantly altered. Overall, we found that long-term exposure to low doses of DCZ inhibited the liver-gut axis in males and females, and the liver-gut axis in F1 males were disturbed even in F1 generation without DCZ exposure.
HematoNet: Expert Level Classification of Bone Marrow Cytology Morphology in Hematological Malignancy with Deep Learning
Authors: Tripathi Satvik , Augustin Alisha Isabelle , Sukumaran Rithvik , Dheer Suhani , Kim Edward 
Published: May 2022

AbstractThere have been few efforts made to automate the cytomorphological categorization of bone marrow cells. For bone marrow cell categorization, deep-learning algorithms have been limited to a small number of samples or disease classifications. In this paper, we proposed a pipeline to classify the bone marrow cells despite these limitations. Data augmentation was used throughout the data to resolve any class imbalances. Then, random transformations such as rotating between 0° to 90°, zooming in/out, flipping horizontally and/or vertically, and translating were performed. The model used in the pipeline was a CoAtNet and that was compared with two baseline models, EfficientNetV2 and ResNext50. We then analyzed the CoAtNet model using SmoothGrad and Grad-CAM, two recently developed algorithms that have been shown to meet the fundamental requirements for explainability methods. After evaluating all three models’ performance for each of the distinct morphological classes, the proposed CoAtNet model was able to outperform the EfficientNetV2 and ResNext50 models due to its attention network property that increased the learning curve for the algorithm which was represented using a precision-recall curve.
In schizophrenia, the effects of the IL-6/IL-23/Th17 axis on health-related quality of life and disabilities are partly mediated by generalized cognitive decline and the symptomatome
Authors: Al-Musawi Ali Fattah , Al-Hakeim Hussein Kadhem , Al-Haboby Inas H. , Almulla Abbas F. , Maes Michael 
Published: May 2022

AbstractSchizophrenia patients show increased disabilities and lower quality of life (DisQoL). Nevertheless, there are no data whether, in schizophrenia, activation of the interleukin (IL)-6, IL-23, T helper (Th)-17 axis and lowered magnesium and calcium levels impact DisQoL scores. This study recruited 90 patients with schizophrenia (including 40 with deficit schizophrenia) and 40 healthy controls and assessed the World Health Association QoL instrument-Abbreviated version and Sheehan Disability scale, Brief Assessment of Cognition in Schizophrenia (BACS), IL-6, IL-23, IL-17, IL-21, IL-22, tumor necrosis factor (TNF)-α, magnesium and calcium. Regression analyses showed that a large part of the first factor extracted from the physical, psychological, social and environmental HR-QoL and interference with school/work, social life, and home responsibilities was predicted by a generalized cognitive deterioration (G-CoDe) index (a latent vector extracted from BACs scores), and the first vector extracted from various symptom domains (“symptomatome”), whereas the biomarkers had no effects. Partial Least Squares analysis showed that the IL6IL23Th17 axis and magnesium/calcium had highly significant total (indirect + direct) effects on HR-QoL/disabilities which were mediated by G-CoDe and the symptomatome (a first factor extracted from negative and positive symptoms). The IL6IL23Th17 axis explained 63.1% of the variance in a single latent trait extracted from G-CoDe, symptomatome, HR-QoL and disability data. The latter features are manifestations of a common core, namely the behavioral-cognitive-psycho-social worsening index, which is caused by the neuroimmunotoxic effects of the IL6IL23Th17 axis in subjects with lowered antioxidant defenses (magnesium and calcium) thereby producing damage to neuronal circuits underpinning deficit schizophrenia.
Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting restricts R-loop accumulation
Authors: Leszczynska Katarzyna B. , Dzwigonska Monika , Estephan Hala , Moehlenbrink Jutta , Bowler Elizabeth , Giaccia Amato J. , Mieczkowski Jakub , Kaminska Bozena , Hammond Ester M. 
Published: May 2022

ABSTRACTLocal hypoxia occurs in most solid tumors and is associated with aggressive disease and therapy resistance. Widespread changes in gene expression play a critical role in the biological response to hypoxia. However, most research has focused on hypoxia-inducible genes as opposed to those which are decreased in hypoxia. We demonstrate that chromatin accessibility is decreased in hypoxia, predominantly at gene promoters and specific pathways are impacted including DNA repair, splicing and the R-loop interactome. One of the genes with decreased chromatin accessibility in hypoxia wasDDX5, encoding the RNA helicase, DDX5, which showed reduced expression in various cancer cell lines in hypoxic conditions, tumor xenografts and in patient samples with hypoxic tumors. Most interestingly, we found that when DDX5 is rescued in hypoxia, replication stress and R-loop levels accumulate further, demonstrating that hypoxia-mediated repression of DDX5 restricts R-loop accumulation. Together these data support the hypothesis that a critical part of the biological response to hypoxia is the repression of multiple R-loop processing factors, however, as shown for DDX5, their role is specific and distinct.
HiCognition: a visual exploration and hypothesis testing tool for 3D genomics
Authors: Langer Christoph C. H. , Mitter Michael , Stocsits Roman R. , Gerlich Daniel W. 
Published: May 2022

AbstractThe 3D organization of the genome and epigenetic marks play important roles in gene expression, DNA repair, and chromosome segregation. Understanding how structure and composition of the chromatin fiber contribute to function requires integrated analysis of multiple genomics datasets from various techniques, experimental conditions, and cell states. Genome browsers facilitate such analysis, yet currently visualize only a few regions at a time and lack statistical functions that are often necessary to extract meaningful information. Here, we present HiCognition, a visual exploration and machine-learning tool based on a new genomic region set concept, which enables detection of patterns and associations between 3D chromosome conformation and collections of 1D genomics profiles of any type. By revealing how transcriptional activity and cohesin subunit isoforms contribute to chromosome conformation, we showcase how the flexible user interface and machine learning tools of HiCognition can help understand the relationship between structure and function of the genome.
Dynamic tripartite construct of interregional engram circuits underlies forgetting of extinction memory
Authors: Gu Xue , Wu Yan-Jiao , Zhu Jia-Jie , Wu Xin-Rong , Wang Qi , Yi Xin , Lin Ze-Jie , Jiao Zhi-Han , Xu Miao , Jiang Qin , Li Ying , Xu Nan-Jie , Zhu Michael Xi , Wang Lu-Yang , Xu Tian-Le , Li Wei-Guang 
Published: May 2022

AbstractFear extinction allows for adaptive control of learned fear responses but often fails, resulting in a renewal or spontaneous recovery of the extinguished fear, i.e., forgetting of the extinction memory readily occurs. Using an activity-dependent neuronal labeling strategy, we demonstrate that engram neurons for fear extinction memory are dynamically positioned in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral hippocampus (vHPC), which constitute an engram construct in the term of directional engram synaptic connectivity from the BLA or vHPC to mPFC, but not that in the opposite direction, for retrieval of extinction memory. Fear renewal or spontaneous recovery switches the extinction engram construct from an accessible to inaccessible state, whereas additional extinction learning or optogenetic induction of long-term potentiation restores the directional engram connectivity and prevents the return of fear. Thus, the plasticity of engram construct underlies forgetting of extinction memory.