bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative analysis of kidney transplantation modeled using precision-cut kidney slices and kidney transplantation in pigs
Authors: Moor Matthias B. , Nordström Johan , Burmakin Mikhail , Raki Melinda , Al-Saad Samer , Nowak Greg , Wennberg Lars , Patrakka Jaakko , Olauson Hannes 
Published: January 2024

AbstractKidney transplants are at risk for so far unavoidable ischemia-reperfusion injury. Several experimental kidney transplantation models are available to study this injury, but all have their own limitations. Here, we describe precision-cut kidney slices (PCKS) as a novel model of kidney ischemia-reperfusion injury in comparison with pig and human kidney transplantation.Following bilateral nephrectomy in pigs, we applied warm ischemia (1h), cold ischemia (20h) and a reperfusion period (4h) to one whole kidney undergoing transplantation to a recipient pig and, in parallel, established PCKS undergoing ischemia and modeled reperfusion. Histopathological assessment revealed the presence of some but not all morphological features of tubular injury in PCKS as seen in pig kidney transplantation. RNAseq demonstrated that the majority of changes occurred after reperfusion only, with a partial overlap between PCKS and kidney transplantation, with some differences in transcriptional response attributable to systemic inflammatory responses and immune cell migration. Comparison of PCKS and pig kidney transplantation with RNAseq data from human kidney biopsies by gene set enrichment analysis revealed that both PCKS and pig kidney transplantation reproduced the post-reperfusion pattern of human kidney transplantation. In contrast, only post-cold ischemia PCKS and pig kidney partially resembled the gene set of human acute kidney injury.Overall, the present study established that a PCKS protocol can model kidney transplantation and its reperfusion-related damage on a histological and a transcriptomic level. PCKS may thus expand the toolbox for developing novel therapeutic strategies against ischemia-reperfusion injury.
Mitochondrially targeted deferasirox kills cancer cellsviasimultaneous iron deprivation and ferroptosis induction
Authors: Jadhav Sukanya B , Sandoval-Acuña Cristian , Pacior Yaiza , Klanicova Kristyna , Blazkova Kristyna , Sedlacek Radislav , Stursa Jan , Werner Lukas , Truksa Jaroslav 
Published: January 2024

AbstractIron chelation has been proposed as an anti-cancer approach; however, iron chelators are generally non-specific for cancer cells and rely on the higher sensitivity of malignant cells to iron deprivation and accumulation of the drug in tumor tissueviathe enhanced permeability and retention effect. Here, we present mitochondrially targeted deferasirox (mitoDFX), a redox-active iron chelator that deprives cells of biologically active iron, as evidenced by a decrease in [Fe-S] cluster and heme-containing proteins. Notably, mitoDFX also depletes the major cellular antioxidant glutathione and induces lipid peroxidation, both of which are hallmarks of ferroptosis, resulting in selective induction of cell death in cancer cells. In summary, targeting deferasirox into the mitochondria results in an agent that has a unique ability to elicit iron deprivation and produce toxic lipid peroxidesviaits redox activity, thus harnessing the dual nature of iron in a single molecule to combat cancer.
Energy Optimization Induces Predictive-coding Properties in a Multicompartment Spiking Neural Network Model
Authors: Zhang Mingfang(Lucy) , Bohte Sander M. 
Published: January 2024

AbstractPredictive coding is a prominent theoretical framework for understanding the hierarchical sensory processing in the brain, yet how it could be implemented in networks of cortical neurons is still unclear. While most existing works have taken a hand-wiring approach to creating microcircuits that match experimental results, recent work in applying an optimisation approach to rate-based artificial neural networks revealed that cortical connectivity might result from self-organisation given some fundamental computational principle, such as energy efficiency. As no corresponding approach has studied this in more plausible networks of spiking neurons, we here investigate whether predictive coding properties in a multi-compartment spiking neural network can emerge from energy optimisation. We find that a model trained with an energy objective in addition to a task-relevant objective is able to reconstruct internal representations given top-down expectation signals alone. Additionally, neurons in the energy-optimised model also show differential responses to expected versus unexpected stimuli, qualitatively similar to experimental evidence for predictive coding. These findings indicate that predictive-coding-like behaviour might be an emergent property of energy optimisation, providing a new perspective on how predictive coding could be achieved in the cortex.
Dorsal horn dendrite polarization during Spinal Cord Stimulation (SCS) predicted using the quasi-uniform-mirror assumption
Authors: Zannou Adantchede Louis , Koochesfahani Mojtaba Belali , Russo Marc , Bikson Marom 
Published: January 2024

AbstractWhile the mechanisms of Spinal Cord Stimulation are traditionally assumed to follow pacing of dorsal columns axons, the development of sub-paresthesia SCS and new waveforms has encouraged consideration of different cellular targets. Given their relative proximity to the stimulation electrodes and role in pain processing (e.g., synaptic processing and gate control theory), spinal cord dorsal horn interneurons may be direct targets of stimulation. We developed a novel computational modeling pipeline termed ‘quasi-uniform-mirror assumption’ and apply it to predict polarization of dorsal horn inter-neuron cell types (Islet type, Central type, Stellate/Radial, Vertical-like) to SCS. The quasi-uniform-mirror assumption allows prediction, for each cell type and location in the dorsal horn, the peak and axis of dendritic polarization as well as the impact of stimulation pulse width. For long pulse (dc), the peak polarization per mA of SCS with a bipolar montage were: Islet type 3.5 mV, Central type 2 mV, Stellate/Radial 1.4 mV, Vertical-like 2.5 mV. For Stellate/Radial the peak dendritic polarization was dorsal-ventral, and for Islet type Central peak dendrite polarization was in the rostral-caudal axis. For Islet type and Central type cells peak dendrite polarization was between stimulation electrodes, while for Stellate/Radial and Vertical-like peak dendrite polarization was under stimulation electrodes. The impact of pulse width depended on cell membrane time constants, which in the quasi-uniform-mirror assumption are uniform first-order. Assuming 1 ms time constant, for a 1 ms or 100 us pulse width, the peak dendrite polarization decreases (from the dc values) by ∼33% and ∼88%. These results suggest, for the conditions modeled, maximum polarization is of islet-cells in the superficial dorsal horn at locations between electrodes; applying 2 mA 1 ms pulse SCS, the peak islet-cell dendrite polarization is ∼4.7 mV. Polarizations of a few mV have been shown to modulate synaptic processing through sub-threshold mechanisms.
Apical cell expansion maintained by Dusky-like establishes a scaffold for corneal lens morphogenesis
Authors: Ghosh Neha , Treisman Jessica E. 
Published: January 2024

SummaryThe biconvex shape of theDrosophilacorneal lens, which enables it to focus light onto the retina, arises by organized assembly of chitin and other apical extracellular matrix components. We show here that the Zona Pellucida domain-containing protein Dusky-like is essential for normal corneal lens morphogenesis. Dusky-like transiently localizes to the expanded apical surfaces of the corneal lens-secreting cells, and in its absence, these cells undergo apical constriction and apicobasal contraction. Dusky-like also controls the arrangement of two other Zona Pellucida-domain proteins, Dumpy and Piopio, external to the developing corneal lens. Loss of eitherdusky-likeordumpydelays chitin accumulation and disrupts the outer surface of the corneal lens. Artificially inducing apical constriction with constitutively active Myosin light chain kinase is sufficient to similarly alter chitin deposition and corneal lens morphology. These results demonstrate the importance of cell shape for the morphogenesis of overlying apical extracellular matrix structures.
Stronger effect of temperature on body growth in cool than in warm populations suggests lack of local adaptation
Authors: Lindmark Max , Ohlberger Jan , Gårdmark Anna 
Published: January 2024

AbstractBody size is a key functional trait that has declined in many biological communities, partly due to changes in individual growth rates in response to climate warming. However, our understanding of growth responses in natural ecosystems is limited by relatively short time series without large temperature contrasts and unknown levels of adaptation to local temperatures across populations. In this study, we collated back-calculated length-at-age data for the fish Eurasian perch (Perca fluviatilis) from 10 populations along the Baltic Sea coast between 1953–2015 (142023 length-at-age measurements). We fitted individual-level growth trajectories using the von Bertalanffy growth equation, and reconstructed local temperature time series using generalized additive models fitted to three data sources. Leveraging a uniquely large temperature contrast due to climate change and artificial heating, we then estimated population-specific and global growth-temperature relationships using Bayesian mixed models, and evaluated if they conformed to local adaption or not. We found little evidence for local adaptation in the temperature-dependence of individual growth curves. Instead, population-specific curves mapped onto a global curve, resulting in body growth increasing with warming in cold populations but decreasing in warm populations. Understanding to which degree the effects of warming on growth and size are population-specific is critical for generalizing predictions of climate impacts on growth, which is a key biological trait affecting multiple levels of biological organisation from individuals to ecosystem functioning.
Estimation of Uncertainty and Location-specific Variation in Regional Food Web Interactions
Authors: Brothers Aaron , Santillán Vinicio , Quitián Marta , Neuschulz Eike Lena , Schleuning Matthias , Böhning-Gaese Katrin , Alvarez Orlando , Thron Christopher 
Published: January 2024

AbstractWe demonstrate a methodology for estimating uncertainties and intra-regional variations in bird-plant food web interactions, based on transect observations at multiple locations with the region. We model species-species interaction measurements at each location as Poisson random variables whose mean is proportional to the interaction strength at that location. We also model the location-dependent interaction strength as having uniform probability on an interval. A Bayesian approach is used to estimate this interaction strength interval based on measurements at specific locations. We present and discuss the implications of graphical representations to show how the estimated means and ranges of regional interaction strength (and the variances of these estimates) depend on measurements, in the case where measurements are taken at 3 locations. Among other properties, we show that taking the mean of three measured interaction frequencies will tend to underestimate the actual mean interaction strength, assuming a uniform interval model.The methodology is applied to a specific case of transect survey data for avian frugivore species’ interactions with fruit-bearing plants from three locations within each of six regions in Ecuador. We hypothesize that species within the same genus tend to substitute for each other out in different locations within the same region. We test this hypothesis by comparing the estimated location-dependent variances of species-species and genus-genus interactions. Results contraindicate the hypothesis: different species from the same genus tend to have higher interaction strengths in similar locations, i.e. “species in the same genus flock together.”We also find some evidence that fragmentation of the environment due to human activity, even if it does not reduce species diversity, may have a uniformizing effect so that the site-to-site variability in bird-fruit interactions is reduced.
Human induced pluripotent stem cell-derived cardiomyocytes to study inflammation-induced aberrant calcium transient
Authors: Tatekoshi Yuki , Chen Chunlei , Shapiro Jason , Chang Hsiang-Chun , Blancard Malorie , Lyra-Leite Davi , Burridge Paul W. , Feinstein Matthew , D’Aquila Richard , Hsue Priscilla , Ardehali Hossein 
Published: January 2024

AbstractHeart failure with preserved ejection fraction (HFpEF) is commonly found in persons living with HIV (PLWH) even when antiretroviral therapy (ART) suppresses HIV viremia. However, studying this condition has been challenging because an appropriate animal model is not available. In this paper, we studied calcium transient in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in culture to simulate the cardiomyocyte relaxation defect noted in of PLWH and HFpEF and to assess whether various drugs have an effect. We show that treatment of hiPSC-CMs with inflammatory cytokines (such as interferon-γ or TNF-α) impair their Ca2+uptake into sarcoplasmic reticulum and that SGLT2 inhibitors, clinically proven as effective for HFpEF, reverse this effect. Additionally, treatment with mitochondrial antioxidants (like mito-Tempo) and certain antiretrovirals resulted in the reversal of the effects of these cytokines on calcium transient. Finally, incubation of hiPSC-CMs with serum from HIV patients with and without diastolic dysfunction did not alter their Ca2+-decay time, indicating that the exposure to the serum of these patients is not sufficient to induce the decrease in Ca2+uptakein vitro. Together, our results indicate that hiPSC-CMs can be used as a model to study molecular mechanisms of inflammation-mediated abnormal cardiomyocyte relaxation and screen for potential new interventions.
Therapeutic targeting of KRAS mutation-driven tumorigenesis by extracellular vesicles loaded with small interfering RNA
Authors: Zhai Yanhua , Niu Shuiqin , Qiu Tao , Yi Yuan , Yan Yu , Hu Rui , He Xinjun , Xu Ke 
Published: January 2024

AbstractRASis a well-known oncogene contributing to significant proportion of cancer incidences, yet it remains as an undruggable target to majority of therapeutic modalities. Here, we explored the potential of extracellular vesicles (EVs) for therapeutic targeting ofKRASmutation-driven tumorigenesis. EVs loaded with small interfering RNA (siRNA) againstKRASsuccessfully inhibited tumor xenograft growth when injected intratumorally in mice models. Intriguingly, when injected intravenously, EVs were still able to accumulate in tumors and deliverKRAStargeting siRNA payload in sufficient amount to show tumor growth inhibition. Therefore, EV-siRNA platform show great promises for therapeutic targeting ofKRASmutations and other undruggable targets.
Cell-autonomous and non-cell-autonomous effects of arginase-II on cardiac aging
Authors: Potenza Duilio M. , Cheng Xin , Ajalbert Guillaume , Brenna Andrea , Giraud Marie-Noelle , Frobert Aurelien , Cook Stephane , Mertz Kirsten D. , Yang Zhihong , Ming Xiu-Fen 
Published: January 2024

AbstractAging is a predominant risk factor for heart disease. Aging heart reveals low-grade chronic inflammation, cell apoptosis, cardiac fibrosis, and increased vulnerability to ischemic injury. The underlying molecular mechanisms responsible for the cardiac aging phenotype and its susceptibility to injury are far from being fully understood. Although previous literature reports a role of the mitochondrial enzyme arginase-II (Arg-II) in development of heart failure, contradictory results are reported and no systematic analysis of cellular expression and localization of Arg-II in the heart has been performed. Whether and how Arg-II participates in cardiac aging are still unknown. In this study, we demonstrate, to our surprise, that Arg-II is not expressed in cardiomyocytes from aged mice and human patients, but upregulated in non-myocytes of the aging heart, including macrophages, fibroblasts, endothelial cells. Mice with genetic deficiency ofarg-ii(arg-ii-/-) are protected from age-associated cardiac inflammation, myocyte apoptosis, interstitial and perivascular fibrosis, endothelial-mesenchymal transition (EndMT), and susceptibility to ischemic injury. Further experiments show that Arg-II mediates IL-1β release from macrophages of old mice, contributing to the above-described cardiac aging phenotype. In addition, Arg-II enhances mitochondrial reactive oxygen species (mtROS) and activates cardiac fibroblasts that is inhibited by inhibition of mtROS. Thus, our study demonstrates a non-cell-autonomous effect of Arg-II on cardiomyocytes, fibroblasts, and endothelial cells mediated by IL-1β from aging macrophages as well as a cell-autonomous effect of Arg-II through mtROS in fibroblasts contributing to cardiac aging phenotype.
Comprehensive characterization of the viscoelastic properties of Bovine Submaxillary Mucin (BSM) hydrogels and the effect of additives
Authors: Rulff Hanna , Schmidt Robert F. , Wei Ling-Fang , Fentker Kerstin , Kerkhoff Yannic , Mertins Philipp , Mall Marcus A. , Lauster Daniel , Gradzielski Michael 
Published: January 2024

ABSTRACTThis study presents a comprehensive characterization of the viscoelastic and structural properties of Bovine Submaxillary Mucin (BSM), which is widely used as a commercial source to conduct mucus-related research. We conducted concentration studies of BSM and examined the effects of various additives - NaCl, CaCl2, lysozyme, and DNA - on its rheological behavior. A notable connection between BSM concentration and viscoelastic properties was observed, particularly under varying ionic conditions. The rheological spectra could be well-described by a fractional Kelvin-Voigt Model with a minimum of model parameters. A detailed proteomics analysis provided insight into the molecular interactions within BSM, showing MUC19 as main component. Cryo-scanning electron microscopy allowed to visualize the network structure in relation to the rheological data. By elucidating the complex interplay between mucin concentration, environmental conditions, and viscoelastic properties, this research significantly contributes to the field of mucus research and lays an important basis for its further advancement.
The landscape of immune dysregulation in pediatric sepsis at a single-cell resolution
Authors: Alhamdan Fahd , Koutsogiannaki Sophia , Yuki Koichi 
Published: January 2024

AbstractRecognizing immune dysregulation as a hallmark of sepsis pathophysiology, leukocytes have attracted major attention of investigation. While adult and pediatric sepsis are clinically distinct, their immunological delineation remains limited. Breakthrough of single cell technologies facilitated the characterization of immune signatures. We tackled to delineate immunological profiles of pediatric sepsis at a single-cell level by analyzing blood samples from six septic children, at both acute and recovery phases, and four healthy children. 16 single-cell transcriptomic datasets (96,156 cells) were analyzed and compared to adult sepsis dataset. We showed a unique shift in neutrophil subpopulations and functions between acute and recovery phases, along with examining the regulatory role of resistin. Neutrophil signatures were comparable between adult and pediatric sepsis. Innate-like CD4 T cells were predominantly and uniquely observed in acute phase of pediatric sepsis. Our study provides a thorough and comprehensive understanding of immune dysregulation in pediatric sepsis.
Emergence of neocortical function in heterotopic neurons
Authors: Roig-Puiggros Sergi , Guyoton Maëlle , Suchkov Dmitrii , Fortoul Aurélien , Fièvre Sabine , Matteucci Giulio , Maino Emma , Foucher Charlie G. , Fuciec Daniel , Klingler Esther , Francis Fiona , Minlebaev Marat , El-Boustani Sami , Watrin Françoise , Manent Jean-Bernard , Jabaudon Denis 
Published: January 2024

AbstractBrains come in various sizes and shapes, yet how neuronal position constrains the type of circuits that they can form remains largely unknown. The spatial layout of anatomical structures with corresponding functions varies widely across species (J-4). Also, during evolution, anatomical structures have duplicated and then diverged to generate new circuits and functions (5,6). Thus, it is critical to understand how the position of neurons constrains their integration into circuits and, ultimately, their function. To address this question, we studiedEmlJknockout mice in which subsets of neocortical neurons form a new structure below the neocortex termed heterotopia (Ht). We examined how this new location affects the molecular identity, topography, input-output circuit connectivity, electrophysiology, and functional properties of these neurons. Our results reveal a striking conservation of the cellular features and circuit properties of Ht neurons, despite their abnormal location and misorientation. Supporting this observation, these neurons were able to functionally substitute for overlying neocortical neurons in a behaviorally relevant task when the latter were optogenetically silenced. Hence, specific neuronal identities and associated function can be reproduced in altered anatomical settings, revealing a remarkable level of self-organization and adaptability of neocortical circuits.
Toward subtask decomposition-based learning and benchmarking for genetic perturbation outcome prediction and beyond
Authors: Gao Yicheng , Wei Zhiting , Dong Kejing , Yang Jingya , Chuai Guohui , Liu Qi 
Published: January 2024

AbstractDeciphering cellular responses to genetic perturbations is fundamental for a wide array of biomedical applications, ranging from uncovering gene roles and interactions to unraveling effective therapeutics. Accurately predicting the transcriptional outcomes of genetic perturbations is indispensable for optimizing experimental perturbations and deciphering cellular response mechanisms; however, three scenarios present principal challenges, i.e., predicting single genetic perturbation outcomes, predicting multiple genetic perturbation outcomes and predicting genetic outcomes across cell lines. In this study, we introduceSubTAsk decompositionModeling for geneticPerturbation prediction (STAMP), a conceptually novel computational strategy for genetic perturbation outcome prediction and downstream applications. STAMP innovatively formulates genetic perturbation prediction as a subtask decomposition (STD) problem by resolving three progressive subtasks in a divide-and-conquer manner, i.e., identifying differentially expressed gene (DEG) postperturbations, determining the regulatory directions of DEGs and finally estimating the magnitudes of gene expression changes. In addition to facilitating perturbation prediction, STAMP also serves as a robust and generalizable benchmark guide for evaluating various genetic perturbation prediction models. As a result, STAMP exhibits a substantial improvement in terms of its genetic perturbation prediction ability over the existing approaches on three subtasks and beyond, including revealing the ability to identify key regulatory genes and pathways on small samples and to reveal precise genetic interactions. Overall, STAMP serves as a fundamentally novel and effective prediction and generalizable benchmarking strategy that can facilitate genetic perturbation prediction, guide the design of perturbation experiments, and broaden the understanding of perturbation mechanisms.