bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carotid artery ultrasound for assessing fluid responsiveness in patients undergoing mechanical ventilation with low tidal volume and preserved spontaneous breathing
Authors: Zhou Kefan , Ran Shan , Guo Yixin , Ye Hongwei 
Published: December 2023

Abstract

Objective
This study aimed to investigate whether changes in carotid artery corrected flow time (ΔFTcbolus) and carotid artery peak flow velocity respiratory variation (ΔVpeakbolus) induced by the fluid challenge could reliably predict fluid responsiveness in mechanically ventilated patients with a tidal volume < 8 ml/kg PBW while preserving spontaneous breathing.

Methods
Carotid artery corrected flow time (FTc), carotid artery peak flow velocity respiratory variation (ΔVpeak), and hemodynamic data were measured before and after administration of 250 ml crystalloids. Fluid responsiveness was defined as a 10% or more increase in stroke volume index as assessed by noninvasive cardiac output monitoring (NICOM) after the fluid challenge.

Results
A total of 43 patients with acute circulatory failure were enrolled in this study. 43 patients underwent a total of 60 fluid challenges. ΔFTcbolus and ΔVpeakbolus showed a significant difference between the fluid responsiveness positive group (n = 35) and the fluid responsiveness negative group (n = 25). Spearman correlation test showed that ΔFTcbolus and ΔVpeakbolus with the relative increase in stroke volume index after fluid expansion (r = 0.5296, P < 0.0001; r = 0.3175, P = 0.0135). Multiple logistic regression analysis demonstrated that ΔFTcbolus and ΔVpeakbolus were significantly correlated with fluid responsiveness in patients with acute circulatory failure. The areas under the receiver operating characteristic curves (AUROC) of ΔFTcbolus and ΔVpeakbolus for predicting fluid responsiveness were 0.935 and 0.750, respectively. The optimal cut-off values of ΔFTcbolus and ΔVpeakbolus were 0.725 (sensitivity of 97.1%; specificity of 84%) and 4.21% (sensitivity of 65.7%; specificity of 80%), respectively.

Conclusion
In mechanically ventilated patients with a tidal volume < 8 ml/kg while preserving spontaneous breathing, ΔFTcbolus and ΔVpeakbolus could predict fluid responsiveness. The predictive performance of ΔFTcbolus was superior to ΔVpeakbolus.
Multi-target mode of action of Sulfodyne®, a stabilized Sulforaphane, against pathogenic effects of SARS-CoV-2 infection
Authors: Romeo Paul-Henri , Conquet Laurine , Messiaen Sébastien , Pascal Quentin , Moreno Stéphanie G. , Bravard Anne , Bernardino-Sgherri Jacqueline , Dereuddre-Bosquet Nathalie , Montagutelli Xavier , Grand Roger Le , Petit Vanessa , Ferri Federica 
Published: December 2023

AbstractThe coronavirus disease 2019 (COVID-19) due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown that, except vaccination, few therapeutics options for its treatment or prevention are available. Among the pathways that can be targeted for COVID-19 treatment, the Keap1/Nrf2 pathway seems of high interest as it regulates redox homeostasis and inflammation that are altered during SARS-CoV-2 infection. Here, we use three potent activators of the Keap1/Nrf2 pathway and showed that Sulfodyne®, a stabilized natural Sulforaphane preparation with optimal bioavailability, had the highest antiviral activity in pulmonary or colonic epithelial cell lines even when added late after SARS-CoV-2 infection. This antiviral activity was not dependent on NRF2 activity but associated with action on ER stress and mTOR signaling that are activated during SARS-CoV-2 infection. Sulfodyne®also decreased the inflammatory response of epithelial cell lines infected by SARS-CoV-2 independently of SARS-CoV-2 replication and reduced the activation of human monocytes that are recruited after infection of epithelial cells by SARS-CoV-2. Administration of Sulfodyne®had little effects on SARS-CoV-2 replication in mice and hamsters infected with SARS-CoV-2 but significantly reduced weight loss and disease severity. Altogether, these results pinpoint the natural compound Sulfodyne®as a potent therapeutic agent of COVID-19 symptomatology.Author SummaryAccumulating evidence shows that oxidative stress coupled with the systemic inflammation contribute to COVID-19 pathogenesis. As the Keap1/Nrf2 pathway is the major regulator of redox homeostasis and promotes resolution of inflammation and as lung biopsies from COVID-19 patients showed a decreased NRF2 target gene signature, pharmacological agents that are known to activate NRF2 are good candidates for COVID-19 treatment. We show herein that Sulfodyne®, an NRF2 activator that consists in a stabilized Sulforaphane preparation with optimal bioavailability, impairs SARS-CoV-2 replication in colonic or pulmonary epithelial cells. We show that this antiviral activity of Sulfodyne®is not dependent of NRF2 activation, characterize the pathways associated with the Sulfodyne®antiviral activity and show that Sulfodyne®displays multiple actions that result in a decrease of the inflammation associated with SARS-CoV-2 infection. Finally, we show that Sulfodyne®decreases the pathogenesis of mice or hamster infected with SARS-CoV-2. Overall, this study provides mechanistic explanations of the action of Sulfodyne®during SARS-CoV-2 infection and suggests that Sulfodyne®is a potential therapeutic agent of COVID-19 pathogenesis.
The YARS Tyrosyl tRNA Synthetase Regulates Senescence Induction and Escape Through the Transcriptional Control of LIN9, a Member of the DREAM Complex
Authors: Coquelet Hugo , Leman Geraldine , Maarouf Amine , Petit Coralie , Toutain Bertrand , Henry Cécile , Boissard Alice , Guette Catherine , Lelièvre Eric , Vidi Pierre , Guillon Jordan , Coqueret Olivier 
Published: December 2023

ABSTRACTSenescence is a tumor suppressor mechanism triggered by oncogene expression and chemotherapy treatment. It orchestrates a definitive cessation of cell proliferation through the activation of the p53-p21 and p16-Rb pathways, coupled with the compaction of proliferative genes within heterochromatin regions. Some cancer cells have the ability to elude this proliferative arrest but the signaling pathways involved in circumventing senescence remain to be characterized. We have recently described that malignant cells capable of evading senescence have an increased expression of specific tRNAs, such as tRNA-Leu-CAA and tRNA-Tyr-GTA, alongside the activation of their corresponding tRNA ligases, namely LARS and YARS. We have previously shown that YARS promotes senescence escape by activating proliferation and cell cycle genes but its functions during this proliferative arrest remain largely unknown. In this study, we have continued to characterize the functions of YARS, describing non-canonical transcriptional functions of the ligase. Our results show that YARS is present in the nucleus of growing and senescent cells and interacts with the Trim28 transcriptional regulator. Importantly, YARS binds to the LIN9 promoter, a critical member of the Dream complex responsible for regulating cell cycle transcription. YARS facilitates the binding and the phosphorylation of the type II RNA polymerase and promotes the deposit of activating epigenetic marks on the LIN9 promoter. Consequently, during senescence escape, YARS promotes LIN9 expression and both proteins are necessary to induce the proliferation of emergent cells. These results underscore the unconventional transcriptional functions of YARS in promoting senescence escape by activating LIN9 and likely influencing the functions of the Dream complex.
The V-ATPase/ATG16L1 axis is controlled by the V1H subunit
Authors: Timimi Lewis , Wrobel Antoni G. , Chiduza George N. , Maslen Sarah L. , Torres-Méndez Antonio , Montaner Beatriz , Davis Colin , Skehel J. Mark , Rubinstein John L. , Schreiber Anne , Beale Rupert 
Published: December 2023

AbstractDefects in organellar acidification indicate compromised or infected compartments. Recruitment of the autophagy-related ATG16L1 complex to pathologically de-acidified compartments targets ubiquitin-like ATG8 molecules to perturbed membranes. How this process is coupled to pH gradient disruption is unclear. Here, we reveal a direct role for the V1H subunit of the V-ATPase proton pump in recruiting ATG16L1. The interaction between V1H and ATG16L1 occurs within assembled V-ATPases, but not dissociated V1complexes. This selectivity allows recruitment to be coupled to changes in V-ATPase assembly that follow pH dissipation. Cells lacking V1H undergo canonical macroautophagy but are unable to recruit ATG16L1 in response to influenza infection or ionophore drugs. We identify a loop within V1H that mediates ATG16L1 binding, which is absent in a neuronal isoform of V1H. Thus, V1H controls ATG16L1 recruitment in response to proton gradient dissipation, suggesting that the V-ATPase acts autonomously as a cell-intrinsic damage sensor.
Testicular mosaicism in non-mosaic postpubertal Klinefelter patients with focal spermatogenesis and in non-mosaic prepubertal Klinefelter boys
Authors: Gül Semir , Vloeberghs Veerle , Gies Inge , Goossens Ellen 
Published: December 2023

ABSTRACTThe aim of the study is to investigate testicular mosaicism in non-mosaic postpubertal Klinefelter Syndrome patients and in non-mosaic prepubertal Klinefelter boys Testes of the males with non-mosaic Klinefelter Syndrome at different developmental stages were used.Immunohistochemical and fluorescent in situ hybridization analyses were applied for X chromosome ploidy in testis-specific cells in testicular biopsy samples from non-mosaic Klinefelter Syndrome patients.According to our findings, all analyzed spermatogonia in both postpubertal and prepubertal non-mosaic Klinefelter Syndrome patients have a 46,XY karyotype. However, while the Sertoli cells surrounding spermatogonia in postpubertal samples also have a 46,XY karyotype, the Sertoli cells surrounding spermatogonia in prepubertal samples have a 47,XXY karyotype. Peritubular myoid cells and Leydig cells may also have mosaicism in both postpubertal patients and prepubertal boys.In conclusion, we confirmed in situ using cell-specific markers that testicular mosaicism exists in non-mosaic Klinefelter Syndrome patients. Therefore, we hypothesize that focal spermatogenesis seen in some postpubertal Klinefelter Syndrome patients originates from euploid spermatogonia and Sertoli cells. Additionally, our findings suggest that only spermatogonia that have lost their X chromosome can survive. Furthermore, our data suggest that spermatogonia lose the extra X chromosome during fetal or neonatal life, while Sertoli cells lose it around puberty. These findings will lay the groundwork for new studies on exactly when and by which mechanism an extra X chromosome is lost in spermatogonia and Sertoli cells.
Stress-induced Rab11a-exosomes induce AREG-mediated cetuximab resistance in colorectal cancer
Authors: Mason John D. , Marks Ewan , Fan Shih-Jung , McCormick Kristie , Wilson Clive , Harris Adrian L. , Hamdy Freddie C. , Cunningham Chris , Goberdhan Deborah C. I. 
Published: December 2023

AbstractExosomes are secreted vesicles made intracellularly in the endosomal system. We have previously shown that exosomes are not only made in late endosomes, but also in recycling endosomes marked by the monomeric G-protein Rab11a. These vesicles, termed Rab11a-exosomes, are preferentially secreted under nutrient stress from several cancer cell types, including HCT116 colorectal cancer (CRC) cells. HCT116 Rab11a-exosomes have particularly potent signalling activities, some mediated by the Epidermal Growth Factor Receptor (EGFR) ligand, Amphiregulin (AREG). Mutant activating forms of KRAS, a downstream target of EGFR, are often found in advanced CRC. When absent, monoclonal antibodies, such as cetuximab, which target the EGFR and block the effects of EGFR ligands, such as AREG, can be administered. Patients, however, inevitably develop resistance to cetuximab, either by acquiring KRAS mutations or via non-genetic microenvironmental changes. Here we show that nutrient stress in several CRC cell lines causes the release of AREG-carrying Rab11a-exosomes. We demonstrate that while soluble AREG has no effect, much lower levels of AREG bound to Rab11a-exosomes from cetuximab-resistant KRAS-mutant HCT116 cells, can suppress the effects of cetuximab on KRAS-wild type Caco-2 CRC cells. Using neutralising anti-AREG antibodies and an intracellular EGFR kinase inhibitor, we show that this effect is mediated via AREG activation of EGFR, and not transfer of activated KRAS. Therefore, presentation of AREG on Rab11a-exosomes affects its ability to compete with cetuximab. We propose that this Rab11a-exosome-mediated mechanism contributes to the establishment of resistance in cetuximab-sensitive cells and may explain why in cetuximab-resistant tumours only some cells carry mutant KRAS.Graphical AbstractThis study highlights a clinically relevant mechanism in which stress-induced Rab11a-exosomes carrying the EGFR ligand, Amphiregulin (AREG) transfer drug resistance between genetically distinct colorectal cancer cells. Resistance to cetuximab, an anti-EGFR therapy, can be passed via Rab11a-exosomes from drug-resistant KRAS-mutant cells to previously drug-responsive KRAS-wild type cells. Unlike soluble AREG, Rab11a-exosome-associated AREG competes with cetuximab to activate EGFR signalling and promote EGFR-dependent outcomes, such as growth. This mechanism may support the co-operative evolution of clonal heterogeneity during tumour progression.
Dopamine-iron homeostasis interaction rescues mitochondrial fitness in Parkinson’s disease
Authors: Buoso Chiara , Seifert Markus , Lang Martin , Griffith Corey M. , Andújar Begoña Talavera , Rueda Maria Paulina Castelo , Fischer Christine , Doerrier Carolina , Talasz Heribert , Zanon Alessandra , Pramstaller Peter P. , Schymanski Emma L. , Pichler Irene , Weiss Guenter 
Published: December 2023

ABSTRACTImbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the pathogenesis of Parkinson’s disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and a PD patient with a mutation in the α-synuclein (SNCA) gene. In SH-SY5Y cells, dopamine treatment affected the expression of transmembrane iron transporters and cellular iron accumulation. Furthermore, dopamine supplementation led to decreased mitochondrial respiration and reduced mitochondrial fitness, including reduced mtDNA copy number and citrate synthase activity, increased oxidative stress and impaired aconitase activity. In dopaminergic neurons derived from a healthy control individual, dopamine showed comparable effects as observed in SH-SY5Y cells. The hiPSC-derived PD neurons harboring an endogenousSNCAmutation demonstrated altered mitochondrial iron homeostasis, reduced mitochondrial capacity along with increased oxidative stress and alterations of tricarboxylic acid cycle linked metabolic pathways compared with control neurons. Importantly, dopamine treatment of these PD neurons promoted a rescue effect by increasing mitochondrial respiration, activating antioxidant stress response, and normalizing altered metabolite levels linked to mitochondrial function. These observations provide evidence that dopamine affects iron homeostasis, intracellular stress responses and mitochondrial function in healthy cells, while dopamine supplementation can restore this disturbed regulatory network in PD cells.
Propagation of a rapid cell-to-cell H2O2signal over long distances in a monolayer of cardiomyocyte cells
Authors: Fichman Yosef , Rowland Linda , Nguyen Thi Thao , Chen Shi-Jie , Mittler Ron 
Published: December 2023

AbstractCell-to-cell communication plays a cardinal role in the biology of multicellular organisms. H2O2is an important cell-to-cell signaling molecule involved in the response of mammalian cells to wounding and other stimuli. We previously identified a signaling pathway that transmits wound-induced cell-to-cell H2O2signals within minutes over long distances, measured in centimeters, in a monolayer of cardiomyocytes. Here we report that this long-distance H2O2signaling pathway is accompanied by enhanced accumulation of cytosolic H2O2and altered redox state in cells along its path. We further show that it requires the production of superoxide, as well as the function of gap junctions, and that it is accompanied by changes in the abundance of hundreds of proteins in cells along its path. Our findings highlight the existence of a unique and rapid long-distance H2O2signaling pathway that could play an important role in different inflammatory responses, wound responses/healing, cardiovascular disease, and/or other conditions.HighlightsWounding induces an H2O2cell-to-cell signal in a monolayer of cardiomyocytes.The cell-to-cell signal requires H2O2and O2·-accumulation along its path.The signal propagates over several centimeters changing the redox state of cells.Changes in the abundance of hundreds of proteins accompanies the signal.The cell-to-cell signal requires paracrine and juxtacrine signaling.Graphical Abstract
Essential magnetosome proteins MamI and MamL from magnetotactic bacteria interact in mammalian cells
Authors: Sun Qin , Yu Liu , Donnelly Sarah C. , Fradin Cecile , Thompson R. Terry , Prato Frank S. , Goldhawk Donna E. 
Published: December 2023

AbstractTo detect cellular activities deep within the body using magnetic resonance platforms, magnetosomes are the ideal model of genetically-encoded nanoparticles. These membrane-bound iron biominerals produced by magnetotactic bacteria are highly regulated by approximately 30 genes; however, only a few magnetosome genes are essential and may constitute the root structure upon which biominerals form. To test this, essential magnetosome genesmamIandmamLwere expressed as fluorescent fusion proteins in mammalian cells. Localization and potential protein-protein interaction(s) were investigated using confocal microscopy and fluorescence correlation spectroscopy (FCS). Enhanced green fluorescent protein (EGFP)-MamI and the red fluorescent Tomato-MamL displayed distinct intracellular localization, with net-like and punctate fluorescence, respectively. Remarkably, co-expression revealed co-localization of both fluorescent fusion proteins in the same punctate pattern. An interaction between MamI and MamL was confirmed by co-immunoprecipitation. In addition, changes in EGFP-MamI distribution were accompanied by acquisition of intracellular mobility which all Tomato-MamL structures displayed. Truncation of the MamL C-terminal cationic peptide partially disrupted MamI-MamL colocalization but not mobility. Analysis of extracts from these cells by FCS was consistent with an interaction between fluorescent fusion proteins, including an increase in particle radius. Co-localization and interaction of MamI and MamL demonstrate that these essential magnetosome proteins may have a role in assembly of the magnetosome in any cell type.
Taste Experience Enhances Cortical Response Reliability during Latent Enhancement of Taste Aversion Learning
Authors: Flores Veronica Lee , Lin Jian-You 
Published: December 2023

AbstractLearning is not as simple as the association of paired stimuli in a vacuum. For example, benign experience with a taste stimulus weakens future conditioned taste aversions (CTA) to that taste—a phenomenon known as latent inhibition—and enhances later CTA to a novel taste (latent enhancement [LE]; Flores et al., 2016; Flores et al., 2018). Our recent investigations on how benign taste experience impacts cortical responses revealed an increase in the discriminability/salience of Gustatory Cortical (GC) responses to a new taste following experience offering a clue into potential underlying mechanisms for LE on CTA (Flores et al., 2022). Here, we predict that the previously reported increase in response discriminability following taste experience is associated with a reduction of variability that has been shown to promote learning. Our results support this prediction and reveal enhanced trial-to-trial consistency of single-neuron sucrose responses and coherent activity across ensemble neurons before CTA learning. Connecting this result to learning, we further show that the distinction between pre- and post-CTA sucrose responses are indeed greater in rats with prior benign taste experience. Overall, these results suggest that following benign experience, taste coding in GC becomes more reliable (at both the single-neuron and ensemble levels) providing a potential mechanism which may contribute to the stronger CTA acquisition seen in LE of learning.Significance StatementAnimals and humans readily learn the consequences of consuming a specific taste and react by changing their behaviors. We have shown that even seemingly inconsequential and benign taste experiences – which are arguably more common - can enhance taste behavior and learning. The work presented here is the first to evaluate how benign experience alters learning-related cortical processing dynamics usingin-vivoelectrophysiology in freely behaving rats. We report that benign taste experience alters cortical plasticity which underlies the enhancement of learning. This unravels a new area of chemosensory research and may shed light on how daily taste experiences impact the neural dynamics of future taste consumption and learning.
Oscillations in a Spatial Oncolytic Virus Model
Authors: Baabdulla Arwa Abdulla , Hillen Thomas 
Published: December 2023

AbstractVirotherapy treatment is a new and promising target therapy that selectively attacks cancer cells without harming normal cells. Mathematical models of oncolytic viruses have shown predator-prey like oscillatory patterns as result of an underlying Hopf bifurcation. In a spatial context, these oscillations can lead to different spatio-temporal phenomena such as hollow-ring patterns, target patterns, and dispersed patterns. In this paper we continue the systematic analysis of these spatial oscillations and discuss their relevance in the clinical context. We consider a bifurcation analysis of a spatially explicit reaction-diffusion model to find the above mentioned spatio-temporal virus infection patterns. The desired pattern for tumor eradication is the hollow ring pattern and we find exact conditions for its occurrence. Moreover, we derive the minimal speed of travelling invasion waves for the cancer and for the oncolytic virus. Our numerical simulations in 2-D reveal complex spatial interactions of the virus infection and a new phenomenon of a periodic peak splitting. An effect that we cannot explain with our current methods.