bluuebunny/crossref_metadata_2025_split huggingface dataset:
CRISPR-GRIT: Guide-RNAs with Integrated Repair Templates Enable Precise Multiplexed Genome Editing in the Diploid Fungal PathogenCandida albicans
Authors: Cotter Christopher J. , Trinh Cong T. 
Published: November 2023

AbstractCandida albicansis an opportunistic fungal pathogen that causes severe infections in immunocompromised individuals. Overuse of antifungals coupled with climate change has led to the rapid emergence of antifungal resistance. Thus, there is an urgent need to understand fungal pathogen genetics to develop new antifungal strategies. Genetic manipulation ofC. albicansis encumbered by its diploid chromosomes which require editing both alleles for elucidating gene function. Even though recent development of CRISPR-Cas systems has facilitated genome editing inC. albicans, large-scale functional genomic studies are still hindered by the necessity of co-transforming repair templates for homozygous knockouts. Here, we present CRISPR-GRIT, a repair template-integrated guide RNA design for expedited gene knockouts inC. albicans,and demonstrate its utility for multiplexed editing. We envision that this method can be employed for high-throughput library screens and identification of synthetic lethal pairs in bothC. albicansand other diploid organisms with strong homologous recombination machinery.
Mathematical model of a cell membrane
Authors: Gorkavyi Nick 
Published: November 2023

AbstractBimolecular cell membranes play a crucial role in many biological processes and possess a unique set of physical properties. Bimolecular membranes and monomolecular films can be considered as a “two-dimensional fluid” because the diffusion of molecules along the membrane or film is a hydrodynamic process. On the other hand, the bending of the cell membrane is controlled by its stiffness and elastic tension. The aim of this work is to adapt the Navier-Stokes hydrodynamic equations, obtained using the classical Chapman-Enskog method, to the case of two-dimensional membranes. The hydrodynamic equation system is complemented by an elasticity equation for the bending oscillations of the membrane. The obtained system of equations for the dynamics of the cell membrane is linearized for the case of disturbances with small amplitude. Dispersion equations for stable and unstable linear oscillations of cell membranes are investigated, and conditions for the onset of instabilities are derived.
Digital twinning of cardiac electrophysiology for congenital heart disease
Authors: Salvador Matteo , Kong Fanwei , Peirlinck Mathias , Parker David W. , Chubb Henry , Dubin Anne M. , Marsden Alison Lesley 
Published: November 2023

AbstractIn recent years, blending mechanistic knowledge with machine learning has had a major impact in digital healthcare. In this work, we introduce a computational pipeline to build certified digital replicas of cardiac electrophysiology in pediatric patients with congenital heart disease. We construct the patient-specific geometry by means of semi-automatic segmentation and meshing tools. We generate a dataset of electrophysiology simulations covering cell-to-organ level model parameters and utilizing rigorous mathematical models based on differential equations. We previously proposed Branched Latent Neural Maps (BLNMs) as an accurate and efficient means to recapitulate complex physical processes in a neural network. Here, we employ BLNMs to encode the parametrized temporal dynamics of in silico 12-lead electrocardiograms (ECGs). BLNMs act as a geometry-specific surrogate model of cardiac function for fast and robust parameter estimation to match clinical ECGs in pediatric patients. Identifiability and trustworthiness of calibrated model parameters are assessed by sensitivity analysis and uncertainty quantification.
Microfluidic device for simple diagnosis of plant growth condition by detecting miRNAs from filtered plant extracts
Authors: Kawakatsu Yaichi , Okada Ryo , Hara Mitsuo , Tsutsui Hiroki , Yanagisawa Naoki , Higashiyama Tetsuya , Arima Akihide , Baba Yoshinobu , Kurotani Ken-ichi , Notaguchi Michitaka 
Published: November 2023

AbstractPlants are exposed to a variety of environmental stress and starvation of inorganic phosphorus can be a major constraint in crop production. In plants, in response to phosphate deficiency in soil, miR399, a type of microRNA (miRNA), is upregulated. By detecting miR399, the early diagnosis of phosphorus deficiency stress in plants can be accomplished. However, general miRNA detection methods require complicated experimental manipulations. Therefore, simple and rapid miRNA detection methods are required for early plant nutritional diagnosis. For the simple detection of miR399, microfluidic technology is suitable for point-of-care applications because of its ability to detect target molecules in small amounts in a short time and with simple manipulation. In this study, we developed a microfluidic device to detect miRNAs from filtered plant extracts for the easy diagnosis of plant growth conditions. To fabricate the microfluidic device, verification of the amine-terminated glass as the basis of the device and the DNA probe immobilization method on the glass was conducted. In this device, the target miRNAs were detected by fluorescence of sandwich hybridization in a microfluidic channel. For plant stress diagnostics using a microfluidic device, we developed a protocol for miRNA detection by validating the sample preparation buffer, filtering, and signal amplification. Using this system, endogenous sly-miR399 in tomatoes, which is expressed in response to phosphorus deficiency, was detected before the appearance of stress symptoms. This early diagnosis system of plant growth conditions has a potential to improve food production and sustainability through cultivation management.
The clinician-AI interface: intended use and explainability in FDA-cleared AI devices for medical image interpretation
Authors: McNamara Stephanie L. , Yi Paul H. , Lotter William 
Published: November 2023

AbstractAs applications of AI in medicine continue to expand, there is an increasing focus on integration into clinical practice. An underappreciated aspect of clinical translation is where the AI fits into the clinical workflow, and in turn, the outputs generated by the AI to facilitate clinician interaction in this workflow. For instance, in the canonical use case of AI for medical image interpretation, the AI could prioritize cases before clinician review or even autonomously interpret the images without clinician review. A related aspect is explainability – does the AI generate outputs to help explain its predictions to clinicians? While many clinical AI workflows and explainability techniques have been proposed, a summative assessment of the current scope in clinical practice is lacking. Here, we evaluate the current state of FDA-cleared AI devices for medical image interpretation assistance in terms of intended clinical use, outputs generated, and types of explainability offered. We create a curated database focused on these aspects of the clinician-AI interface, where we find a high frequency of “triage” devices, notable variability in output characteristics across products, and often limited explainability of AI predictions. Altogether, we aim to increase transparency of the current landscape of the clinician-AI interface and highlight the need to rigorously assess which strategies ultimately lead to the best clinical outcomes.
The pleiotropic architecture of human impulsivity across biological scales
Authors: Mallard Travis T. , Tubbs Justin D. , Jennings Mariela , Zhang Yingzhe , Gustavson Daniel E. , Grotzinger Andrew D. , Westwater Margaret L. , Williams Camille M. , Fortgang Rebecca G. ,   23andMe Research Team, Elson Sarah L. , Fontanillas Pierre , Davis Lea K. , Raznahan Armin , Tucker-Drob Elliot M. , Choi Karmel W. , Ge Tian , Smoller Jordan W. , Palmer Abraham A. , Sanchez-Roige Sandra 
Published: November 2023

AbstractImpulsivity is a complex psychological construct that represents a core feature of many psychiatric and neurological conditions. Here, we used multivariate methods to formally model the genetic architecture of impulsivity in humans, advancing genomic discovery and revealing pervasive pleiotropy that largely counters theories of impulsivity as a unitary construct. We identified 18 loci and 93 genes with diverse effects in GWAS and TWAS analyses, respectively, including a hotspot at 17q21.31 that harbors genes involved in neurodevelopmental and neurodegenerative disorders. Downstream analyses revealed that heterogeneous signals were localized to specific biological correlates, including expression in brain tissue during fetal development and cortical alterations in the inferior frontal gyrus. Polygenic score analyses suggested that liability for different forms of impulsivity may differentiate across development, operating via broad pathways early in life but affecting diverse outcomes by adulthood. Collectively, our study generates new insights into the pleiotropic architecture of impulsivity, which provides a more comprehensive understanding of its multi-faceted biology.
Comparative Transcriptome Analysis of Acne vulgaris, Rosacea, and Hidradenitis Suppurativa Supports High Dose Dietary Zinc as a Therapeutic Agent
Authors: Li Li , Hajam Irshad , McGee Jean S. , Tang Zhengkuan , Zhang Ye , Badey Nikil , Mintzer Esther , Zhang Zhenrui , Liu George Y. , Church George M. , Wang Yu 
Published: November 2023

ABSTRACTAcne vulgaris, rosacea, and hidradenitis suppurativa are enduring inflammatory skin conditions that frequently manifest with akin clinical attributes, posing a considerable challenge for their distinctive diagnosis. While these conditions do exhibit certain resemblances, they also demonstrate distinct underlying pathophysiological mechanisms and treatment modalities. Delving into both the molecular parallels and disparities among these three disorders can yield invaluable insights for refined diagnostics, effective management, and targeted therapeutic interventions. In this report, we present a comparative analysis of transcriptomic data across these three diseases, elucidating differentially expressed genes and enriched pathways specific to each ailment, as well as those shared among them. We also identified high dose dietary zinc as a potential therapeutic agent and validated its efficacy in an acne mouse model.
Tripartite interactions of PKA catalytic subunit and C-terminal domains of cardiac Ca2+channel modulate its β-adrenergic regulation
Authors: Oz Shimrit , Sharon Tom , Subramaniam Suraj , Pallien Tamara , Katz Moshe , Tsemakhovich Vladimir , Tripathy Debi Ranjan , Sasson Giorgia , Chomsky-Hecht Orna , Vysochek Leonid , Schulz Maike , Fecher-Trost Claudia , Zühlke Kerstin , Bertinetti Daniela , Herberg Friedrich W. , Keren-Raifman Tal , Flockerzi Veit , Hirsch Joel A. , Klussmann Enno , Weiss Sharon , Dascal Nathan 
Published: November 2023

AbstractThe adrenergic nervous system augments cardiac contraction by increasing the activity of L-type voltage-gated CaV1.2 channels. Dysregulation of this process is linked to severe cardiac dysfunctions. The signaling cascade involves activation of β-adrenergic receptors, elevation of cAMP levels, separation of protein kinase A (PKA) regulatory subunit (PKAR) from catalytic subunit (PKAC), and phosphorylation of the inhibitory protein Rad leading to increased Ca2+influx. In cardiomyocytes, the core subunit of CaV1.2 (α1C) exists in two forms: full-length (FL) or proteolytically processed (truncated), lacking the distal C-terminus (dCT). Specificity and efficiency in the cascade are believed to emanate from unique protein-protein interactions, such as anchoring PKA (via PKAR) to α1Cby A-kinase anchoring proteins (AKAPs). However, most AKAPs do not interact with the truncated α1C, and their role in βAR regulation of cardiac CaV1.2 remains unclear. Here we show that PKAC, independently of PKAR or AKAPs, directly interacts with α1Cat two domains in α1C-CT: the proximal and distal C-terminal regulatory domains (PCRD and DCRD), which also interact with each other. Furthermore, we find that DCRD competes with PCRD and reduces its interaction with PKAC. The physiological consequences of these complex interactions are incompletely understood; our data suggest that they may fine-tune the βAR regulation of CaV1.2. We propose that the newly discovered interactions take part in governing colocalization of regulatory proteins within the βAR-CaV1.2 multimolecular signaling complexes in cardiomyocytes.
Translation variation across genetic backgrounds reveals a post-transcriptional buffering signature in yeast
Authors: Teyssonniere Elie M. , Shichino Yuichi , Friedrich Anne , Iwasaki Shintaro , Schacherer Joseph 
Published: November 2023

AbstractGene expression is known to vary among individuals, and this variability can impact the phenotypic diversity observed in natural populations. While the transcriptome and proteome have been extensively studied, little is known about the translation process itself. Here, we therefore performed ribosome and transcriptomic profiling on a genetically and ecologically diverse set of natural isolates of theSaccharomyces cerevisiaeyeast. Interestingly, we found that the Euclidean distances between each profile and the expression fold changes in each pairwise isolate comparison were higher at the transcriptomic level. This observation clearly indicates that the transcriptional variation observed in the different isolates is buffered through a phenomenon known as post-transcriptional buffering at the translation level. Furthermore, this phenomenon seemed to have a specific signature by preferentially affecting essential genes as well as genes involved in complex-forming proteins, and low transcribed genes. We also explored the translation of theS. cerevisiaepangenome and found that the accessory genes related to introgression events displayed similar transcription and translation levels as the core genome. By contrast, genes acquired through horizontal gene transfer events tended to be less efficiently translated. Together, our results highlight both the extent and signature of the post-transcriptional buffering.
Ventral hippocampal interneurons govern extinction and relapse of contextual associations
Authors: Lacagnina Anthony F. , Dong Tri N. , Iyer Rasika R. , Khan Saqib , Mohamed Mazen K , Clem Roger L. 
Published: November 2023

ABSTRACT/SUMMARYContextual associations are critical for survival but must be extinguished when new conditions render them nonproductive. By most accounts, extinction forms a new memory that competes with the original association for control over behavior, but the mechanisms underlying this competition remain largely enigmatic. Here we find the retrieval of contextual fear conditioning and extinction yield contrasting patterns of activity in prefrontal cortex and ventral hippocampus. Within ventral CA1, activation of somatostatin-expressing interneurons (SST-INs) occurs preferentially during extinction retrieval and correlates with differences in input synaptic transmission. Optogenetic manipulation of these cells but not parvalbumin interneurons (PV-INs) elicits bidirectional changes in fear expression following extinction, and the ability of SST-INs to gate fear is specific to the context in which extinction was acquired. A similar pattern of results was obtained following reward-based extinction. These data show that ventral hippocampal SST-INs are critical for extinguishing prior associations and thereby gate relapse of both aversive and appetitive responses.
Interpretable Inflammation Landscape of Circulating Immune cells
Authors: Jiménez-Gracia Laura , Maspero Davide , Aguilar-Fernández Sergio , Craighero Francesco , Ruiz Sara , Marchese Domenica , Caratù Ginevra , Elosua-Bayes Marc , Abdalfatah Mohamed , Sanzo-Machuca Angela , Corraliza Ana M. , Massoni-Badosa Ramon , Tran Hoang A. , Normand Rachelly , Nestor Jacquelyn , Hong Yourae , Kole Tessa , van der Velde Petra , Alleblas Frederique , Pedretti Flaminia , Aterido Adrià , Banchero Martin , Soriano German , Román Eva , van den Berge Maarten , Salas Azucena , Carrascosa Jose Manuel , Nebro Antonio Fernández , Domènech Eugeni , Cañete Juan , Tornero Jesús , Pérez-Gisbert Javier , Choy Ernest , Girolomoni Giampiero , Siegmund Britta , Julià Antonio , Serra Violeta , Elosua Roberto , Tejpar Sabine , Vidal Silvia , Nawijn Martijn C. , Marsal Sara , Vandergheynst Pierre , Villani Alexandra-Chloé , Nieto Juan C. , Heyn Holger 
Published: November 2023

AbstractInflammation is a biological phenomenon involved in a wide variety of physiological and pathological processes. Although a controlled inflammatory response is beneficial for restoring homeostasis, it can become unfavorable if dysregulated. In recent years, major progress has been made in characterizing acute and chronic inflammation in specific diseases. However, a global, holistic understanding of inflammation is still elusive. This is particularly intriguing, considering the crucial function of inflammation for human health and its potential for modern medicine if fully deciphered. Here, we leverage advances in the field of single-cell genomics to delineate the full spectrum of circulating immune cell activation underlying inflammatory processes during infection, immune-mediated inflammatory diseases and cancer. Our single-cell atlas of >2 million peripheral blood mononuclear cells from 356 patients and 18 diseases allowed us to learn a foundation model of inflammation in circulating immune cells. The atlas expanded our current knowledge of the biology of inflammation of acute (e.g. inflammatory bowel disease, sepsis) and chronic (e.g. cirrhosis, asthma, and chronic obstructive pulmonary disease) disease processes and laid the foundation to develop a precision medicine framework using unsupervised as well as explainable machine learning. Beyond a disease-centered classification, we charted altered activity of inflammatory molecules in peripheral blood cells, depicting functional biomarkers to further understand mechanisms of inflammation. Finally, we have laid the groundwork for developing precision medicine diagnostic tools for patients experiencing severe acute or chronic inflammation by learning a classifier for inflammatory diseases, presenting cells in circulation as a powerful resource for patient stratification.
Adolescent stress-induced behavioral deficits, ventral hippocampus redox dysregulation and excitatory/inhibitory imbalance related to schizophrenia
Authors: Santos-Silva Thamyris , Lopes Caio Fábio Baeta , Ülgen Doğukan Hazar , Guimarães Danielle Aparecida , Guimarães Francisco S. , Alberici Luciane Carla , Sandi Carmen , Gomes Felipe V. 
Published: November 2023

AbstractRedox dysregulation has been proposed as a convergent point of childhood trauma and the emergence of psychiatric disorders, such as schizophrenia (SCZ). However, the impact of severe stressors during adolescence on the ventral hippocampus (vHip) redox states and their functional consequences, including behavioral and electrophysiological changes related to SCZ, are not entirely understood. After exposing adolescent animals to physical stress (postnatal day, PND31–40), we explored social and cognitive behaviors (PND47–49) and the activity of pyramidal glutamate neurons, the number of parvalbumin (PV) interneurons, and the transcriptomic signature of the vHip (PND51). We also evaluated the impact of stress on the redox system one and ten days after stress, while glutathione levels were measured in the vHip and serum following the behavioral test. Adolescent-stressed animals exhibited loss of sociability, cognitive impairment, and vHip excitatory/inhibitory (E/I) imbalance. Genome-wide transcriptional profiling unveiled the impact of stress on synaptic and redox system-related genes. Stress impacted mitochondrial respiratory function, leading to changes in reactive oxygen species levels in the vHip. Glutathione (GSH) and glutathione disulfide (GSSG) levels were elevated in the serum of stressed animals, while GSSG was also increased in the vHip and negatively correlated with sociability. Additionally, PV interneuron deficits in the vHip caused by adolescent stress were associated with oxidative stress. Our results highlight the negative impact of adolescent stress on vHip redox regulation and mitochondrial function, which are partially associated with E/I imbalance and behavioral abnormalities related to SCZ.
Expression and fusogenic activity of SARS CoV-2 Spike protein displayed in the HSV-1 Virion
Authors: Desai Prashant J. 
Published: November 2023

AbstractSevere acute respiratory syndrome coronavirus (SARS-CoV) is a zoonotic pathogen that can cause severe respiratory disease in humans. The new SARS-CoV-2 is the cause of the current global pandemic termed coronavirus disease 2019 (COVID-19) that has resulted in many millions of deaths world-wide. The virus is a member of the Betacoronavirus family, its genome is a positive strand RNA molecule that encodes for many genes which are required for virus genome replication as well as for structural proteins that are required for virion assembly and maturation. A key determinant of this virus is the Spike (S) protein embedded in the virion membrane and mediates attachment of the virus to the receptor (ACE2). This protein also is required for cell-cell fusion (syncytia) that is an important pathogenic determinant. We have developed a pseudotyped herpes simplex virus type 1 (HSV-1) recombinant virus expressing S protein in the virion envelop. This virus has also been modified to express a Venus fluorescent protein fusion to VP16, a virion protein of HSV-1. The virus expressing Spike can enter cells and generates large multi-nucleated syncytia which are evident by the Venus fluorescence. The HSV-1 recombinant virus is genetically stable and virus amplification can be easily done by infecting cells. This recombinant virus provides a reproducible platform for Spike function analysis and thusaddsto the repertoire of pseudotyped viruses expressing Spike.Impact StatementThe isolation of a pseudotyped herpes simplex virus type 1 (HSV-1) virus using the Spike protein is new and innovative. This virus can be used to study entry and fusion events mediated by the S protein as well as test antibodies for their ability to neutralize this particle. In addition, these virions can be used for screening antibody specificity using the S protein displayed in its natural membrane bound conformation.