bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multimodal characterization of antigen-specific CD8+T cells across SARS-CoV-2 vaccination and infection
Authors: Zhang Bingjie , Upadhyay Rabi , Hao Yuhan , Samanovic Marie I. , Herati Ramin S. , Blair John , Axelrad Jordan , Mulligan Mark J. , Littman Dan R. , Satija Rahul 
Published: January 2023

ABSTRACTThe human immune response to SARS-CoV-2 antigen after infection or vaccination is defined by the durable production of antibodies and T cells. Population-based monitoring typically focuses on antibody titer, but there is a need for improved characterization and quantification of T cell responses. Here, we utilize multimodal sequencing technologies to perform a longitudinal analysis of circulating human leukocytes collected before and after BNT162b2 immunization. Our data reveal distinct subpopulations of CD8+T cells which reliably appear 28 days after prime vaccination (7 days post boost). Using a suite of cross-modality integration tools, we define their transcriptome, accessible chromatin landscape, and immunophenotype, and identify unique biomarkers within each modality. By leveraging DNA-oligo-tagged peptide-MHC multimers and T cell receptor sequencing, we demonstrate that this vaccine-induced population is SARS-CoV-2 antigen-specific and capable of rapid clonal expansion. Moreover, we also identify these CD8+populations in scRNA-seq datasets from COVID-19 patients and find that their relative frequency and differentiation outcomes are predictive of subsequent clinical outcomes. Our work contributes to our understanding of T cell immunity, and highlights the potential for integrative and multimodal analysis to characterize rare cell populations.
CAM5, WRKY53, and TGA5 regulate defense gene expression mediated by the volatile organic compound ethyl vinyl ketone
Authors: Gong Junqing , Guo Zhujuan , Wang Zhaoyuan , Yao Lijuan , Zhao Chuanfang , Lin Sheng , Ma Songling , Shen Yingbai 
Published: January 2023

AbstractPlants produce ethyl vinyl ketone (evk) in response to biotic stress, but the evk’s identification and downstream defense response remain unclear. In this paper, it is predicted by docking for the first time that evk can be recognized by RBOH protein and assist the electron transfer of RBOHD/RBOHF by binding to its FAD or NADPH binding site. Here, we show that evk treatment increased H2O2and intracellular calcium concentrations inArabidopsis thalianamesophyll cells, as observed by confocal laser scanning microscopy and non-invasive micro-test technology, and that H2O2signaling functioned upstream of Ca2+signaling. Yeast two-hybrid, firefly luciferase complementation imaging, andin vitropull-down assays demonstrated that the ACA8 (AUTOINHIBITED Ca2+-ATPASE, ISOFORM 8)–CML8 (CALMODULIN-LIKE 8) interaction promoted Ca2+efflux to return Ca2+levels to the resting state. Evk treatment led to the antagonism of salicylic acid (SA) and jasmonic acid (JA). CALMODULIN 5 (CAM5) positively regulatesWRKY53expression, and CAM5 and WRKY53 positively regulate SA-related gene expression. These proteins physically interact and form a complex that is unlocked by Ca2+to release WRKY53. An electrophoretic mobility shift assay and dual-luciferase reporter assay demonstrated that WRKY53 and TGA5 cooperate to enhance the expression of the defense genePATHOGENESIS-REALTED 1(PR1) and that WRKY53 enhances the binding of TGA5 to thePR1promoter. This paper proposes a framework that evk, as a RES substance, can achieve plant’s ‘REScue’ through complete defense response.
Sugar restriction and blood ingestion shape divergent immune defense trajectories in the mosquitoAedes aegypti
Authors: Magistrado Dom , El-Dougdoug Noha K. , Short Sarah M. 
Published: January 2023

AbstractImmune defense is comprised of 1) resistance: the ability to reduce pathogen load, and 2) tolerance: the ability to limit the disease severity induced by a given pathogen load. The study of tolerance in the field of animal immunity is fairly nascent in comparison to resistance. Consequently, studies which examine immune defense comprehensively (i.e., considering both resistance and tolerance in conjunction) are uncommon, despite their exigency in achieving a thorough understanding of immune defense. Furthermore, understanding tolerance in arthropod disease vectors is uniquely relevant, as tolerance is essential to the cyclical transmission of pathogens by arthropods. Here, we tested the effect(s) of dietary sucrose concentration (high or low) and blood meal (present or absent) on resistance and tolerance toEscherichia coliinfection in the yellow fever mosquitoAedes aegypti. Resistance and tolerance were measured concurrently and at multiple timepoints. We found that both blood and sucrose affected resistance. Mosquitoes from the low sugar treatment displayed enhanced resistance at all timepoints post-infection compared to those from the high sugar treatment. Additionally, blood-fed mosquitoes showed enhanced resistance compared to non-blood-fed mosquitoes, but only on day 1 post-infection. Sucrose had no effect on tolerance, but the effect of blood was significant and dynamic across time. Specifically, we show that consuming blood prior to infection ameliorates a temporal decline in tolerance that mosquitoes experience when provided with only sugar meals. Taken together, our findings indicate that different dietary components can have unique and sometimes temporally dynamic impacts on resistance and tolerance. Finally, our findings 1) highlight the value of experimental and analytical frameworks which consider the explicit testing of effects on both resistance and tolerance as separate, but equally important, components of immune defense, and 2) underscore the importance of including a temporal component in studies of immune defense.
Delineating genotypes and phenotypes of individual cells from long-read single cell transcriptomes
Authors: Shiau Cheng-Kai , Lu Lina , Kieser Rachel , Fukumura Kazutaka , Pan Timothy , Lin Hsiao-Yun , Yang Jie , Tong Eric L. , Lee GaHyun , Yan Yuanqing , Huse Jason T. , Gao Ruli 
Published: January 2023

AbstractSingle-cell nanopore sequencing of full-length mRNAs (scNanoRNAseq) is transforming singlecell multi-omics studies. However, challenges include computational complexity and dependence on short-read curation. To address this, we developed a comprehensive toolkit, scNanoGPS to calculate same-cell genotypes-phenotypes without short-read guidance. We applied scNanoGPS onto 23,587 long-read transcriptomes from 4 tumors and 2 cell lines. Standalone, scNanoGPS accurately deconvoluted error-prone long-reads into single-cells and single-molecules. Further, scNanoGPS simultaneously accessed both phenotypes (expressions/isoforms) and genotypes (mutations) of individual cells. Our analyses revealed that tumor and stroma/immune cells often expressed significantly distinct combinations of isoforms (DCIs). In a kidney tumor, we identified 924 genes with DCIs involved in cell-type-specific functions such asPDE10Ain tumor cells andCCL3in lymphocytes. Moreover, transcriptome-wide mutation analyses identified many cell-type-specific mutations includingVEGFAmutations in tumor cells andHLA-Amutations in immune cells, highlighting critical roles of different populations in tumors. Together, scNanoGPS facilitates applications of single-cell long-read sequencing.
A fundamental law underlying predictive remapping
Authors: Adeyefa-Olasupo Ifedayo-EmmanuEL 
Published: January 2023

ABSTRACTPredictive remapping (R) — the ability of cells in retinotopic brain structures to transiently exhibit spatiotemporal shifts beyond the spatial extent of their classical anatomical receptive fields — has been proposed as a primary mechanism that stabilizes an organism’s percept of the visual world around the time of a saccadic eye movement. Despite the well-documented effects ofR, a biologically plausible mathematical abstraction that specifies a fundamental law and the functional architecture that actively mediates this ubiquitous phenomenon does not exist. I introduce the Newtonian model ofR, where each modular component ofRmanifests as three temporally overlapping forces - a centripetal, convergentand translational force, that perturb retinotopic cells from their equilibrium extent. The resultant and transient influences of these forcesgives rise to a neuronal force field that governs the spatiotemporal dynamics ofR. This neuronal force field fundamentally obeys an inverse-distance law, akin to Newton’s law of universal gravitation [1] and activates retinotopic elastic fields (elφs). I posit that elφs are transient functional structures that are self-generated by a visual system during active vision and approximate the sloppiness (or degrees of spatial freedom) within which receptive fields are allowed to shift while ensuring that retinotopic organization does not collapse. The predictions of the proposed general model are borne out by the spatiotemporal changes in sensitivity to probe stimuli in human subjects around the time of a saccadic eye movement and qualitatively match neural signatures associated with predictive shifts in the receptive fields of cells in premotor and higher-order retinotopic brain structures.
A 3D adrenocortical carcinoma tumor platform for preclinical modeling of drug response and matrix metalloproteinase activity
Authors: Dedhia Priya H. , Sivakumar Hemamylammal , Rodriguez Marco A. , Nairon Kylie G. , Zent Joshua M. , Zheng Xuguang , Jones Katie , Popova Liudmila , Leight Jennifer L. , Skardal Aleksander 
Published: January 2023

AbstractAdrenocortical carcinoma (ACC) has a poor prognosis, and no new drugs have been identified in decades. The absence of drug development can partly be attributed to a lack of preclinical models. Both animal models and 2D cell cultures of ACC fail to accurately mimic the disease, as animal physiology is inherently different than humans, and 2D cultures fail to represent the crucial 3D architecture. Organoids and other small 3Din vitromodels of tissues or tumors can model certain complexities of humanin vivobiology; however, this technology has largely yet to be applied to ACC. In this study, we describe the generation of 3D tumor constructs from an established ACC cell line, NCI-H295R. NCI-H295R cells were encapsulated to generate 3D ACC constructs. Tumor constructs were assessed for biomarker expression, viability, proliferation, and cortisol production. In addition, matrix metalloproteinase (MMP) functionality was assessed directly using fluorogenic MMP-sensitive biosensors and through infusion of NCI-H295R cells into a metastasis-on-a-chip microfluidic device platform. ACC tumor constructs showed expression of biomarkers associated with ACC, including SF-1, Melan A, and inhibin α. Treatment of ACC tumor constructs with chemotherapeutics demonstrated decreased drug sensitivity compared to 2D cell culture. Since most tumor cells migrate through tissue using MMPs to break down extracellular matrix, we validated the utility of ACC tumor constructs by integrating fluorogenic MMP-sensitive peptide biosensors within the tumor constructs. Lastly, in our metastasis-on-a-chip device, NCI-H295R cells successfully engrafted in a downstream lung cell line-based construct, but invasion distance into the lung construct was decreased by MMP inhibition. These studies, which would not be possible using 2D cell cultures, demonstrated that NCI-H295R cells secreted active MMPs that are used for invasion in 3D. This work represents the first evidence of a 3D tumor constructs platform for ACC that can be deployed for future mechanistic studies as well as development of new targets for intervention and therapies.SignificanceThe paucity of preclinical research models has contributed to lack of progress in treatment of adrenocortical carcinoma (ACC). Three-dimensional modeling of ACC may provide novel insights for preclinical studies and advance ACC research.
Learning accelerates the evolution of slow aging but obstructs negligible senescence
Authors: Lenart Peter , Psalmon Sacha , Towbin Benjamin D. 
Published: January 2023

AbstractThe risk of dying tends to increase with age, but this trend is far from universal. For humans, mortality is high during infancy, declines during juvenile development, and increases during adulthood. For other species, mortality never increases, or even continuously declines with age, which has been interpreted as absent- or reverse-aging. We developed a mathematical model that suggests an alternative interpretation. The model describes the age-dependence of mortality as the sum of two opposite processes. The mortality risk due to physiological decline increases monotonously with age. But old individuals gain survival benefits through processes like growth and learning. This simple model fits mortality dynamics for all human age classes and for species across the tree of life. Simulations revealed an unexpected complexity by which learning impacts the evolution of aging. An ability to learn initially accelerated the evolution of slower aging but constrained the slowest possible rate of aging that can evolve. This constraint occurs when learning reduces mortality during the reproductive period to near negligible levels and thereby eliminates selection for a further slow-down of aging. In conclusion, learning accelerates the evolution of slower aging, but obstructs the evolution of negligible senescence for species with strong learning-associated survival benefits.
GABAergic signaling shapes multiple aspects ofDrosophilacourtship motor behavior
Authors: Amin Hoger , Nolte Stella S. , Swain Bijayalaxmi , von Philipsborn Anne C. 
Published: January 2023

AbstractInhibitory neurons are essential for nervous system function. GABA is the most important neurotransmitter for fast neuronal inhibition in vertebrates and invertebrates. GABAergic signaling in sex specific,fruitlessexpressing neuronal circuits ofDrosophilais required for multiple aspects of male courtship behavior. RNAi mediated knockdown of the GABA producing enzyme Gad1 and the ionotropic receptor Rdl in the ventral nerve cord causes uncoordinated and futile copulation attempts, defects in wing extension choice and severe alterations of courtship song. Altered song of GABA depleted males fails to stimulate female receptivity, but rescue of song patterning alone is not sufficient to rescue male mating success. Knockdown of Gad1 and Rdl in brain circuits abolishes courtship conditioning. We characterize the around 220 neurons coexpressing Gad1 and Fruitless in theDrosophilamale nervous system and propose inhibitory circuit motifs underlying key features of courtship behavior based on the observed phenotypes.
Bacillus subtilisRadA/Sms-mediated nascent lagging-strand unwinding at stalled or reversed forks is a two-step process: RadA/Sms assists RecA nucleation, and RecA loads RadA/Sms
Authors: Torres Rubén , Carrasco Begoña , Alonso Juan C. 
Published: January 2023

AbstractReplication fork rescue requiresBacillus subtilisRecA, its negative (SsbA) and positive (RecO) mediators, and fork-processing (RadA/Sms). To understand how they work to promote fork remodeling, reconstituted branched replication intermediates were used. We show that RadA/Sms (or its variant RadA/Sms C13A) binds to the 5′-tail of a reversed fork with longer nascent lagging-strand and unwinds it in the 5′→3′ direction, but RecA and its mediators limit unwinding. RadA/Sms cannot unwind a reversed fork with a longer nascent leading-strand, or a gapped stalled fork, but RecA interacts with and activates unwinding. Here, the molecular mechanism by which RadA/Sms, in concert with RecA, in a two-step reaction, unwinds the nascent lagging-strand of reversed or stalled forks is unveiled. First, RadA/Sms, as amediator, contributes to SsbA displacement from the forks, and nucleates RecA onto single-stranded DNA. Then, RecA, as aloader, interacts with and recruits RadA/Sms onto the nascent lagging strand of these DNA substrates to unwind them. Within this process, RecA limits RadA/Sms self-assembly to control fork processing, and RadA/Sms prevents RecA from provoking unnecessary recombination.
TSD: Transformers for Seizure Detection
Authors: Ma Yongpei , Liu Chunyu , Ma Maria Sabrina , Yang Yikai , Truong Nhan Duy , Kothur Kavitha , Nikpour Armin , Kavehei Omid 
Published: January 2023

AbstractEpilepsy is a common neurological disorder that sub-stantially deteriorates patients’ safety and quality of life. Electroencephalogram (EEG) has been the golden-standard technique for diagnosing this brain disorder and has played an essential role in epilepsy monitoring and disease management. It is extremely laborious and challenging, if not practical, for physicians and expert humans to annotate all recorded signals, particularly in long-term monitoring. The annotation process often involves identifying signal segments with suspected epileptic seizure features or other abnormalities and/or known healthy features. Therefore, automated epilepsy detection becomes a key clinical need because it can greatly improve clinical practice’s efficiency and free up human expert time to attend to other important tasks. Current automated seizure detection algorithms generally face two challenges: (1) models trained for specific patients, but such models are patient-specific, hence fail to generalize to other patients and real-world situations; (2) seizure detection models trained on large EEG datasets have low sensitivity and/or high false positive rates, often with an area under the receiver operating characteristic (AUROC) that is not high enough for potential clinical applicability.This paper proposes Transformers for Seizure Detection, which we refer to as TSD in this manuscript. A Transformer is a deep learning architecture based on an encoder-decoder structure and on attention mechanisms, which we apply to recorded brain signals. The AUROC of our proposed model has achieved 92.1%, tested with Temple University’s publically available electroencephalogram (EEG) seizure corpus dataset (TUH). Additionally, we highlight the impact of input domains on the model’s performance. Specifically, TSD performs best in identifying epileptic seizures when the input domain is a time-frequency. Finally, our proposed model for seizure detection in inference-only mode with EEG recordings shows outstanding performance in classifying seizure types and superior model initialization.
Molecular portraits of colorectal cancer morphological regions
Authors: Budinská Eva , Hrivňáková Martina , Ivkovic Tina Catela , Madrzyk Marie , Nenutil Rudolf , Bencsiková Beatrix , Tukmachi Dagmar Al , Ručková Michaela , Dubská Lenka Zdražilová , Slabý Ondřej , Feit Josef , Dragomir Mihnea-Paul , Linhartova Petra Borilova , Tejpar Sabine , Popovici Vlad 
Published: January 2023

AbstractHeterogeneity of colorectal carcinoma (CRC) represents a major hurdle towards personalized medicine. Efforts based on whole tumor profiling demonstrated that the CRC molecular subtypes were associated with specific tumor morphological patterns representing tumor subregions. We hypothesize that whole- tumor molecular descriptors depend on the morphological heterogeneity with significant impact on current molecular predictors.We investigated intra-tumor heterogeneity by morphology-guided transcriptomics to better understand the links between gene expression and tumor morphology represented by six morphological patterns (morphotypes): complex tubular, desmoplastic, mucinous, papillary, serrated, and solid/trabecular. Whole-transcriptome profiling by microarrays of 202 tumor regions (morphotypes, tumor-adjacent normal tissue, supportive stroma, and matched whole tumors) from 111 stage II-IV CRCs identified morphotype-specific gene expression profiles and molecular programs and differences in their cellular buildup. The proportion of cell types (fibroblasts, epithelial and immune cells) and differentiation of epithelial cells were the main drivers of the observed disparities with activation of EMT and TNF-α signaling in contrast to MYC and E2F targets signaling, defining major gradients of changes at molecular level. Several gene expression-based (including single-cell) classifiers, prognostic and predictive signatures were examined to study their behavior across morphotypes. Most exhibited important morphotype-dependent variability within same tumor sections, with regional predictions often contradicting the whole-tumor classification.The results show that morphotype-based tumor sampling allows the detection of molecular features that would otherwise be distilled in whole tumor profile, while maintaining histopathology context for their interpretation. This represents a practical approach at improving the reproducibility of expression profiling and, by consequence, of gene-based classifiers.
A Comprehensive Atlas of Perineuronal Net Distribution and Colocalization with Parvalbumin in the Adult Mouse Brain
Authors: Lupori Leonardo , Totaro Valentino , Cornuti Sara , Ciampi Luca , Carrara Fabio , Grilli Edda , Viglione Aurelia , Tozzi Francesca , Putignano Elena , Mazziotti Raffaele , Amato Giuseppe , Gennaro Claudio , Tognini Paola , Pizzorusso Tommaso 
Published: January 2023

AbstractPerineuronal nets (PNNs) surround specific neurons in the brain and are involved in various forms of plasticity and clinical conditions. However, our understanding of the PNN role in these phenomena is limited by the lack of highly quantitative maps of PNN distribution and association with specific cell types. Here, we present the first comprehensive atlas of PNN distribution (in Allen Brain Atlas coordinates) and colocalization with parvalbumin (PV) cells for over 600 regions of the adult mouse brain. Data analysis showed that PV expression is a good predictor of PNN aggregation. In the cortex, PNNs are dramatically enriched in layer 4 of all primary sensory areas in correlation with thalamocortical input density, and their distribution mirrors intracortical connectivity patterns. Gene expression analysis identified many PNN correlated genes. Strikingly, PNN anticorrelated transcripts were enriched in synaptic plasticity genes, generalizing PNN role as circuit stability factors. Overall, this atlas offers novel resources for understanding the organizational principles of the brain extracellular matrix.
Redox-mediated activation of ATG3 promotes ATG8 lipidation and autophagy progression in Chlamydomonas
Authors: Mallén-Ponce Manuel J. , Pérez-Pérez María Esther 
Published: January 2023

AbstractAutophagy is one of the main degradative pathways used by eukaryotic organisms to eliminate useless or damaged intracellular material in order to maintain cellular homeostasis under stress conditions. Mounting evidence indicates a strong interplay between the generation of ROS and the activation of autophagy. Although a tight redox regulation of autophagy has been shown in several organisms including microalgae, the molecular mechanisms underlying this control remain poorly understood. In this study, we have performed an in-depthin vitroandin vivoredox characterization of ATG3, an E2-activating enzyme involved in ATG8 lipidation and autophagosome formation, from two evolutionary distant unicellular model organisms: the green microalgaChlamydomonas reinhardtiiand the budding yeastSaccharomyces cerevisiae. Our results indicated that ATG3 activity from both organisms is subjected to redox regulation since these proteins require reducing equivalents to transfer ATG8 to the phospholipid phosphatidylethanolamine. We established the catalytic Cys of ATG3 as redox target in algal and yeast proteins, and showed that the oxidoreductase thioredoxin efficiently reduces ATG3. Moreover,in vivostudies revealed that the redox state of ATG3 fromChlamydomonas reinhardtiiundergoes profound changes in the absence of photoprotective carotenoids, a stress condition that activates autophagy in algae.