bluuebunny/crossref_metadata_2025_split huggingface dataset:
The geography of metacommunities: landscape characteristics drive geographic variation in the assembly process through selecting species pool attributes
Authors: Khattar Gabriel , Peres-Neto Pedro 
Published: June 2023

AbstractMetacommunity ecology traditionally disregards that the dominant life-histories observed in species pools are selected by the characteristics of landscapes where the assembly process takes place. Recognizing the importance of this relationship is relevant because it integrates macroecological principles into metacommunity theory, generating a greater understanding about the ecological causes underlying broad-scale geographic variation in the relative importance of assembly mechanisms. To demonstrate that, we employed simulation models in which species pools with the same initial distribution of niche breadths and dispersal abilities interacted in landscapes with contrasting characteristics. By assessing the traits of species that dominated the metacommunity in each landscape type, we determined how different landscape characteristics select for different life-history strategies at the metacommunity level. We also analyzed the simulated data to derive predictions about the causal links between landscape characteristics, dominant life-histories in species pools, and their mutual influence on empirical inferences about the assembly process. We provide empirical support to these predictions by contrasting the assembly process of moth metacommunities in a tropical versus a temperate mountainous landscape. Collectively, our simulation models and empirical analyses illustrate how our framework can be formalized as an inferential tool for investigating the geography of metacommunity assembly.
Vascular Endothelial Barrier Protection Prevents Atrial Fibrillation by Preserving Cardiac Nanostructure
Authors: Mezache Louisa , Soltisz Andrew , Johnstone Scott R. , Isakson Brant E. , Veeraraghavan Rengasayee 
Published: June 2023

ABSTRACTAtrial fibrillation (AF) is the most common cardiac arrhythmia, affecting ∼3% of the US population. It is widely associated with inflammation, vascular dysfunction, and elevated levels of the vascular leak-inducing cytokine, vascular endothelial growth factor (VEGF). The mechanism underlying AF is not well understood and current treatments are limited to managing this progressive disease, rather than arresting the underlying pathology. We previously identified edema-induced disruption of sodium channel (NaV1.5) –rich intercalated disk (ID) nanodomains as a novel mechanism for AF initiation secondary to acute inflammation. Therefore, we hypothesized that protecting the vascular barrier can prevent vascular leak-induced atrial arrhythmias. We identified two molecular targets for vascular barrier protection, connexin43 (Cx43) hemichannels and pannexin-1 (Panx1) channels, which have been implicated in cytokine-induced vascular leak. AF incidence was increased in untreated mice exposed to VEGF relative to vehicle controls. VEGF also increased the average number of AF episodes. VEGF shifted NaV1.5 signal to longer distances from Cx43 gap junctions (GJs), measured by a distance transformation-based spatial analysis of 3D confocal images of IDs. Similar effects were observed with NaV1.5 localized near mechanical junctions (MJs) composed of N-cad. Blocking connexin43 hemichannels (αCT11 peptide) or Panx1 channels (PxIL2P peptide) significantly reduced the duration of AF episodes compared to VEGF alone with no treatment. Concurrently, both peptide therapies preserved NaV1.5 distance from GJs to control levels and reduced MJ-adjacent intermembrane distance in these hearts. Notably, similar antiarrhythmic efficacy was also achieved with clinically-relevant small molecule inhibitors of Cx43 and Panx1.
Non-Consummatory Behavior Signals Predict Aversion-Resistant Alcohol Drinking in Head-Fixed Mice
Authors: Timme Nicholas M. , Ardinger Cherish E. , Weir Seth D. C. , Zelaya-Escobar Rachel , Kruger Rachel , Lapish Christopher C. 
Published: June 2023

AbstractA key facet of alcohol use disorder is continuing to drink alcohol despite negative consequences (so called “aversion-resistant drinking”). In this study, we sought to assess the degree to which head-fixed mice exhibit aversion-resistant drinking and to leverage behavioral analysis techniques available in head-fixture to relate non-consummatory behaviors to aversion-resistant drinking. We assessed aversion-resistant drinking in head-fixed female and male C57BL/6J mice. We adulterated 20% (v/v) alcohol with varying concentrations of the bitter tastant quinine to measure the degree to which mice would continue to drink despite this aversive stimulus. We recorded high-resolution video of the mice during head-fixed drinking, tracked body parts with machine vision tools, and analyzed body movements in relation to consumption. Female and male head-fixed mice exhibited heterogenous levels of aversion-resistant drinking. Additionally, non-consummatory behaviors, such as paw movement and snout movement, were related to the intensity of aversion-resistant drinking. These studies demonstrate that head-fixed mice exhibit aversion-resistant drinking and that non-consummatory behaviors can be used to assess perceived aversiveness in this paradigm. Furthermore, these studies lay the groundwork for future experiments that will utilize advanced electrophysiological techniques to record from large populations of neurons during aversion-resistant drinking to understand the neurocomputational processes that drive this clinically relevant behavior.
Astrocytes gate long-term potentiation in hippocampal interneurons
Authors: Shen Weida , Tang Yejiao , Yang Jing , Zhu Linjing , Zhou Wen , Xiang Liyang , Zhu Feng , Dong Jingyin , Xie Yicheng , Zeng Ling-Hui 
Published: June 2023

AbstractLong-term potentiation is involved in physiological processes such as learning and memory, motor learning and sensory processing, and pathological conditions such as addiction. In contrast to the extensive studies on the mechanism of long-term potentiation on excitatory glutamatergic synapses onto excitatory neurons (LTPE→E), the mechanism of LTP on excitatory glutamatergic synapses onto inhibitory neurons (LTPE→I) remains largely unknown. In the central nervous system, astrocytes play an important role in regulating synaptic activity and participate in the process of LTPE→E, but their functions in LTPE→Iremain incompletely defined., We studied the role of astrocytes in regulating LTPE→Iin the hippocampal CA1 region and their impact on cognitive function using electrophysiological, pharmacological, confocal calcium imaging, chemogenetics and behavior tests. We showed that LTPE→Iin the stratum oriens of hippocampal CA1 is astrocyte independent. However, in the stratum radiatum, synaptically released endocannabinoids increase astrocyte Ca2+via type-1 cannabinoid receptors, stimulate D-serine release, and potentiate excitatory synaptic transmission on inhibitory neurons through the activation of (N-methyl-D-aspartate) NMDA receptors. We also revealed that chemogenetic activation of astrocytes is sufficient for inducing NMDA-dependentde novoLTPE→Iin the stratum radiatum of the hippocampus. Furthermore, we found that disrupting LTPE→Iby knocking down γCaMKII in interneurons of the stratum radiatum resulted in dramatic memory impairment. Our findings suggest that astrocytes release D-serine, which activates NMDA receptors to regulate LTPE→I, and that cognitive function is intricately linked with the proper functioning of this LTPE→Ipathway.
Classification of patients with COVID-19 by blood RNA endotype: A prospective cohort study
Authors: Yoshimura Jumpei , Togami Yuki , Ebihara Takeshi , Mastumoto Hisatake , Mitsuyama Yumi , Sugihara Fuminori , Hirata Haruhiko , Okuzaki Daisuke , Ogura Hiroshi 
Published: June 2023

AbstractBackgroundAlthough the development of vaccines has considerably reduced the severity of COVID-19, its incidence is still high. Hence, a targeted approach based on RNA endotypes of a population should be developed to help design biomarker-based therapies for COVID-19.ObjectivesWe evaluated the major RNAs transcribed in blood cells during COVID-19 using PCR to further elucidate its pathogenesis and determine predictive phenotypes in COVID-19 patients.Study designIn a discovery cohort of 40 patients with COVID-19, 26,354 RNAs were measured on day 1 and day 7. Five RNAs associated with disease severity and prognosis were derived. In a validation cohort of 153 patients with COVID-19 treated in the intensive care unit, we focused on prolactin (PRL), and toll-like receptor 3 (TLR3) among RNAs, which have a strong association with prognosis, and evaluated the accuracy for predicting survival of PRL-to-TL3 ratios (PRL/TLR3) with the areas under the ROC curves (AUC). The validation cohort was divided into two groups based on the cut-off value in the ROC curve with the maximum AUC. The two groups were defined by high PRL/TLR3 (n=47) and low PRL/TLR3 groups (n=106) and the clinical outcomes were compared.ResultsIn the validation cohort, the AUC for PRL/TLR3 was 0.79, showing superior prognostic ability compared to severity scores such as APACHE II and SOFA. The high PRL/TLR3 group had a significantly higher 28-day mortality than the low PRL/TLR3 group (17.0% vs 0.9%, P<0.01).ConclusionsA new RNA endotype classified using high PRL/TLR3 was associated with mortality in COVID-19 patients.
A cytokinetic ring-driven cell rotation achieves Hertwig’s rule in early development
Authors: Middelkoop Teije C. , Neipel Jonas , Cornell Caitlin E. , Naumann Ronald , Pimpale Lokesh G. , Jülicher Frank , Grill Stephan W. 
Published: June 2023

AbstractCells tend to divide along the direction in which they are longest, as famously stated by Oscar Hertwig in 1884 in his ‘long axis’ rule1,2. The orientation of the mitotic spindle determines the cell division axis3, and Hertwig’s long axis rule is usually ensured by forces stemming from microtubules4. Pulling on the spindle from the cell cortex can give rise to unstable behaviors5,6, and we here set out to understand how Hertwig’s long axis rule is realized in early embryonic divisions where cortical pulling forces are prevalent. We focus on earlyC. elegansdevelopment, where we compressed embryos to reveal that cortical pulling forces favor an alignment of the spindle with the cell’s short axis. Strikingly, we find that this misalignment is corrected by an actomyosin-based mechanism that rotates the entire cell, including the mitotic spindle. We uncover that myosin-driven contractility in the cytokinetic ring generates inward forces that align it with the short axis, and thereby the spindle with the long axis. A theoretical model together with experiments using slightly compressed mouse zygotes suggest that a constricting cytokinetic ring can ensure Hertwig’s long axis rule in cells that are free to rotate inside a confining structure, thereby generalizing the underlying principle.
Rapid Prototyping of Thermoplastic Microfluidic 3D Cell Culture Devices by Creating Regional Hydrophilicity Discrepancy
Authors: Bai Haiqing , Olson Kristen N. Peters , Pan Ming , Marshall Thomas , Singh Hardeep , Ma Jingzhe , Gilbride Paige , Yuan Yu-Chieh , Si Longlong , Maharjan Sushila , Huang Di , Qian Xiaohua , Livermore Carol , Zhang Yu Shrike , Xie Xin 
Published: June 2023

AbstractMicrofluidic three-dimensional cell culture devices that enable the recapitulation of key aspects of organ structures and functionsin vivorepresent a promising preclinical platform to improve translational success during drug discovery. Essential to these engineered devices is the spatial patterning of cells from different tissue types within a confined microenvironment. Traditional fabrication strategies lack the scalability, cost-effectiveness, and rapid prototyping capabilities required for industrial applications, especially for processes involving thermoplastic materials. Here, we introduce an approach to pattern fluid guides inside microchannels by establishing differential hydrophilicity using pressure-sensitive adhesives as masks and a subsequent selective coating with a biocompatible polymer. We identified optimal coating conditions using polyvinylpyrrolidone, which resulted in rapid and consistent hydrogel flow in both the open-chip prototype and the fully bonded device containing additional features for medium perfusion. We tested the suitability of our device for dynamic 3D cell culture by growing human hepatocytes in the device under controlled fluid flow for a 14-day period. Additionally, we demonstrated the potential of using our device for pharmaceutical high-throughput screening applications, such as predicting drug-induced liver injury. Our approach offers a facile strategy of rapid prototyping thermoplastic microfluidic organ chips with varying geometries, microstructures, and substrate materials.
Elucidating the heterogeneity of immunotherapy response and immune-related toxicities by longitudinal ctDNA and immune cell compartment tracking in lung cancer
Authors: Murray Joseph C. , Sivapalan Lavanya , Hummelink Karlijn , Balan Archana , White James R. , Niknafs Noushin , Rhymee Lamia , Pereira Gavin , Rao Nisha , Phallen Jillian , Leal Alessandro , Bartlett David L. , Marrone Kristen A. , Naidoo Jarushka , Levy Benjamin , Rosner Samuel , Hann Christine L. , Scott Susan C. , Feliciano Josephine , Lam Vincent K. , Ettinger David S. , Li Qing Kay , Illei Peter B. , Monkhorst Kim , Zaidi Ali H. , Scharpf Robert B. , Brahmer Julie R. , Velculescu Victor E. , Forde Patrick M. , Anagnostou Valsamo 
Published: June 2023

AbstractPurposeAlthough immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect -especially in the setting of stable disease-call for the development of molecularly-informed real-time minimally invasive predictive biomarkers. In addition to capturing tumor regression, liquid biopsies may be informative in evaluating immune-related adverse events (irAEs).Experimental designWe investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response for each patient. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles.ResultsMolecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank p=0.0003) and overall survival (log-rank p=0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, peripheral blood T-cell repertoire reshaping, assessed by significant TCR clonotypic expansions and regressions were noted on-treatment.ConclusionsMolecular responses assist with interpretation of heterogeneous clinical responses especially for patients with stable disease. Our complementary assessment of the tumor and immune compartments by liquid biopsies provides an approach for monitoring of clinical benefit and immune-related toxicities for patients with NSCLC receiving immunotherapy.Statement of translational relevanceLongitudinal dynamic changes in cell-free tumor load and reshaping of the peripheral T-cell repertoire capture clinical outcomes and immune-related toxicities during immunotherapy for patients with non-small cell lung cancer.
Neurological Imaging Order Selection Using Natural Language Processing and a Support Vector Classifier
Authors: Mehta Videet , Dharia Rohan , Desai Nilesh 
Published: June 2023

AbstractPurposeTo develop an algorithm for automated medical imaging order selection based on provider-input signs and symptoms using natural language processing and machine learning. The aim is to reduce the frequency of inappropriate physician imaging orders, which currently accounts for 25.7% of cases, and thereby mitigate potential patient health concerns.Materials and MethodsThe study was conducted retrospectively with a four-step analysis process. The data used for training in the study consisted of anonymized imaging records and associated provider-input symptoms for CT and MRI orders in 40,667 patients from a tertiary children’s hospital. First, the data were normalized using keyword filtering and lemmatization. Second, an entity-embedding ML model converted the symptoms to high-dimensional numerical vectors suitable for model comprehension, which we used to balance the dataset through k-nearest-neighbor-based synthetic sampling. Third, a Support Vector Classifier (ML model) was trained and hyperparameter-tuned using the embedded symptoms to predict modality (CT/MRI), contrast (with/without), and anatomical region (head, neck, etc.) for the imaging orders. Finally, a web application was developed to package the model, which analyzes user-input symptoms and outputs the predicted order.ResultsThe model was found to have a final overall accuracy of 93.2% on a 4,704-case test set (p <0.001). The AUCs for the eight classes ranged from 96% to 100%, and the average F1-score was 0.92.ConclusionThis algorithm looks to act as a clinical decision support tool to help augment the present physician imaging order selection accuracy and improve patient health.
Unraveling antiviral efficacy of multifunctional immunomodulatory triterpenoids against SARS-COV-2 targeting main protease and papain-like protease
Authors: Choudhary Shweta , Nehul Sanketkumar , Singh Ankur , Panda Prasan Kumar , Kumar Pravindra , Sharma Gaurav Kumar , Tomar Shailly 
Published: June 2023

AbstractThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be over, but its variants continue to emerge, and patients with mild symptoms having long COVID is still under investigation. SARS-CoV-2 infection leading to elevated cytokine levels and suppressed immune responses set off cytokine storm, fatal systemic inflammation, tissue damage, and multi-organ failure. Thus, drug molecules targeting the SARS-CoV-2 virus-specific proteins or capable of suppressing the host inflammatory responses to viral infection would provide an effective antiviral therapy against emerging variants of concern. Evolutionarily conserved papain-like protease (PLpro) and main protease (Mpro) play an indispensable role in the virus life cycle and immune evasion. Direct-acting antivirals targeting both these viral proteases represent an attractive antiviral strategy that is also expected to reduce viral inflammation. The present study has evaluated the antiviral and anti-inflammatory potential of natural triterpenoids: azadirachtin, withanolide_A, and isoginkgetin. These molecules inhibit the Mpro and PLpro proteolytic activities with half-maximal inhibitory concentrations (IC50) values ranging from 1.42 to 32.7 µM. Isothermal titration calorimetry (ITC) analysis validated the binding of these compounds to Mpro and PLpro. As expected, the two compounds, withanolide_A and azadirachtin, exhibit potent anti-SARS-CoV-2 activity in cell-based assays, with half- maximum effective concentration (EC50) values of 21.73 µM and 31.19 µM, respectively. The anti-inflammatory role of azadirachtin and withanolide_A when assessed using HEK293T cells were found to significantly reduce the levels of CXCL10, TNFα, IL6, and IL8 cytokines, which are elevated in severe cases of COVID-19. Interestingly, azadirachtin and withanolide_A were also found to rescue the decreased type-I interferon response (IFN-α1). The results of this study clearly highlight the role of triterpenoids as effective antiviral molecules that target SARS-CoV-2 specific enzymes and also host immune pathways involved in virus mediated inflammation.
Immortalization and transformation of primary cells mediated by engineered ecDNAs
Authors: Pradella Davide , Zhang Minsi , Gao Rui , Yao Melissa A. , Gluchowska Katarzyna M. , Florez Ylenia Cendon , Mishra Tanmay , Rocca Gaspare La , Weigl Moritz , Jiao Ziqi , Nguyen Hieu H.M. , Grimm Felix , Lisi Marta , Mastroleo Chiara , Chen Kevin , Luebeck Jens , Bafna Vineet , Antonescu Cristina R. , Ventura Andrea 
Published: June 2023

ABSTRACTFocal gene amplifications are among the most common cancer-associated mutations, but their evolution and contribution to tumorigenesis have proven challenging to recapitulate in primary cells and model organisms. Here we describe a general approach to engineer large (>1 Mbp) focal amplifications mediated by extrachromosomal circular DNAs (ecDNAs, also known as “double minutes”) in a spatiotemporally controlled manner in cancer cell lines and in primary cells derived from genetically engineered mice. With this strategy, ecDNA formation can be coupled with expression of fluorescent reporters or other selectable markers to enable the identification and tracking of ecDNA-containing cells. We demonstrate the feasibility of this approach by engineering MDM2-containing ecDNAs in near-diploid human cells, showing that GFP expression can be used to track ecDNA dynamics under physiological conditions or in the presence of specific selective pressures. We also apply this approach to generate mice harboring inducibleMyc- andMdm2-containing ecDNAs analogous to those spontaneously occurring in human cancers. We show that the engineered ecDNAs rapidly accumulate in primary cells derived from these animals, promoting proliferation, immortalization, and transformation.
Genome reduction occurred in earlyProchlorococcuswith an unusually low effective population size
Authors: Zhang Hao , Hellweger Ferdi L. , Luo Haiwei 
Published: June 2023

AbstractIn the oligotrophic sunlit ocean, the most abundant free-living planktonic bacterial lineages evolve convergently through genome reduction. The cyanobacteriumProchlorococcusresponsible for 10% global oxygen production is a prominent example. The dominant theory known as ‘genome streamlining’ posits that they have extremely large effective population sizes (Ne) such that selection for metabolic efficiency acts to drive genome reduction. Because genome reduction largely took place anciently, this theory builds on the assumption that their ancestors’Newas similarly large. ConstrainingNefor ancient ancestors is challenging because experimental measurements of extinct organisms are impossible and alternatively reconstructing ancestralNewith phylogenetic models gives large uncertainties. Here, we develop a new strategy that leverages agent-based modeling to simulate the change ofNeproxy for ancient ancestors, the genome-wide ratio of radical to conservative nonsynonymous nucleotide substitution rate (dR/dC), in response to the change ofNe. Surprisingly, this proxy shows expected increases with decreases ofNeonly whenNefalls to about 10k – 100k or lower, magnitudes characteristic ofNeof obligate endosymbiont species where drift drives genome reduction. We therefore conclude that drift, rather than selection, is the primary force that droveProchlorococcusgenome reduction.
WITHDRAWN: How rate information is collectively coded in input to the cerebellum: a hypothesis and simulation
Authors: Gilbert Mike , Rasmussen Anders 
Published: June 2023

Withdrawal StatementThe authors have withdrawn their manuscript owing to the fact that it is a previous draft of the paper titled: “What if…? The granular layer, the input layer of the cerebellar network: a theory”. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.