bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liquid spherical shells are a non-equilibrium steady state
Authors: Bergmann Alexander M. , Bauermann Jonathan , Bartolucci Giacomo , Donau Carsten , Stasi Michele , Holtmannspötter Anna-Lena , Jülicher Frank , Weber Christoph A. , Boekhoven Job 
Published: February 2023

AbstractLiquid-liquid phase separation is the process in which two immiscible liquids demix. This spontaneous phenomenon yields spherical droplets that eventually coarsen to one large, stable droplet governed by the principle of minimal free energy. In chemically fueled phase separation, the formation of phase-separating molecules is coupled to a fuel-driven, nonequilibrium reaction cycle. Chemically fueled phase separation yields dissipative structures sustained by a continuous fuel conversion. Such dissipative structures are ubiquitous in biology but poorly understood as they are governed by non-equilibrium thermodynamics. Here, we bridge the gap between passive, close-to-equilibrium, and active, dissipative structures with chemically fueled phase separation. We observe that spherical, active droplets can transition into a new morphology—a liquid, spherical shell of droplet material. A spherical shell would be highly unstable at equilibrium. Only by continuously converting chemical energy, this dissipative structure can be sustained. We demonstrate the transition mechanism, which is related to the activation of a product outside of the droplet, and the deactivation within the droplets leading to gradients of droplet material. We characterize how far out of equilibrium the spherical shell state is and the chemical power necessary to sustain it. Our work suggests new avenues for assembling complex stable morphologies, which might already be exploited to form membraneless organelles by cells.
Narratives engage brain and body: bidirectional interactions during natural story listening
Authors: Madsen Jens , Parra Lucas C. 
Published: February 2023

SummaryIt is often said that the body and the mind are connected. Yet, direct evidence of a bidirectional link is elusive. We hypothesized a top-down effect of cognition on arousal, and predicted that auditory narratives will drive not only brain signals but also peripheral physiological signals. We find that auditory narratives entrained gaze variation, saccade initiation, pupil size, and heart rate. This is consistent with a top-down effect of cognition on autonomic function. We also hypothesized a bottom-up effect, whereby autonomic physiology affects arousal. Controlled breathing affected pupil size, and heart rate was entrained by controlled saccades. Additionally, fluctuations in heart rate preceded fluctuations of pupil size and brain signals. Gaze variation, pupil size and heart rate were all associated with anterior-central brain signals. Together this suggests bidirectional causal effects between peripheral autonomic function and central brain circuits involved in the control of arousal.HighlightsListening to narratives modulates eye movements.Heart rate fluctuations precede fluctuations in pupil size and anterior-central neural activity.Breathing modulates pupil size suggesting causal effect on central arousal.Rhythmic saccades can entrain heart beats.eTOCWhen we listen to a story our body is integrally involved in the experience. We provide evidence for a bidirectional and causal link between body and mind by analyzing brain signals, pupil size, heart rate and eye movements, while subjects listen to narratives and during interventions that control autonomic signals.
LCP1 Regulates Cell Motility in Chondrosarcoma and Correlates with Metastatic Potential and Poor Patient Outcomes
Authors: Watson Caleb , Martin John T. , Nakagawa Makoto , Guardino Nicholas , Zou Trudy , Peairs Emily , Krez Alexandra , Nadesan Puvi , Huang ZeYu , Ou Jianhong , Somarelli Jason A. , Alman Benjamin , Visgauss Julia D. 
Published: February 2023

AbstractChondrosarcoma (CSA) is the second most common primary malignancy of bone, whose aggressive potential and chemo-resistant nature result in extremely poor outcomes in patients with advanced disease. Grading and prognostication of these tumors remain a significant challenge for pathologists, and medical oncologists have no effective therapies to prevent or treat metastatic disease. In the present study, we sought to explore the pathogenesis and aggressive progression of chondrosarcoma by comparing gene expression differences from metastasizing and non-metastasizing CSA tumors. We hypothesized that metastasizing tumors have inherent differences that may be attributed to the dysregulation of specific oncogenic cell signaling pathways. RNA-Seq analysis from patient-derived low-passage cell lines of metastasizing and non-metastasizing tumors pinpointed the geneLCP1(lymphocyte cytosolic protein 1) as upregulated in CSA cells from metastasizing tumors. Analysis of a large clinical cohort of CSA demonstrated that increased expression ofLCP1correlated with poor patient survival.In vitroanalyses confirmed the ability of LCP1 to promote migration and invasion of CSA cells. These data support the key role of LCP1 on metastatic potential and poor prognosis in CSA. In conclusion, we confirm the ability of LCP1 to drive metastatic behavior and correlate with poor outcomes in patients.
Anabolic phenotype in cartilage-specific Mitogen-inducible gene-6 knockout mice is independent of Transforming growth factor-α
Authors: Hadzic Ermina , To Bethia , Pest Michael A. , Qin Ling , Beier Frank 
Published: February 2023

AbstractBackground/ObjectiveOsteoarthritis (OA) is a whole joint disorder with no disease modifying treatment currently available. The Epidermal Growth Factor Receptor (EGFR) signaling pathway plays an important role in cartilage/bone development and its ligand transforming growth factor-α(TGl·α) is upregulated in OA. In contrast, Mitogen-inducible gene 6 (Mig6) is a negative regulator of EGFR, and our studies demonstrate that cartilage-specific Mig-6 deletion results in anabolic effects on cartilage and formation of chondro-osseus nodules (CON). We aimed to attenuate EGFR signaling by inhibiting TGFαproduction in cartilage-specific Mig6 deficient mice, to test whether this would prevent the formation of CONs.MethodsWe generated double knockout mice by crossing cartilage-specificMig-6fl/flCol2a1-Cre+/-and whole-bodyTgfa+/-mice to generate experimental and control wild-type mice. Knee and elbow sections were stained with toluidine blue to examine articular cartilage thickness and cell density, and tartrate-resistant acid phosphatase for osteoclast activity. Additionally, immunohistochemistry was completed to analyze phospho-EGFR and SOX9.ResultsMig-6 deficient mice display cartilage thickening and CONs at 12 weeks in both the elbow and knee joints, which is independent of TGFαligand presence. Similarly, articular cartilage cell density is increased inMig-6fl/flCol2a1-Cre+/-Tgfa-/-andMig-6fl/flCol2al-Cre+/-mice, but notTgfa-/-mice, and displays increased SOX9 and phospho-EGFR staining.ConclusionThe articular cartilage displays increased thickness, increased cell density, and CON formation independent of the presence of TGFα, suggesting the anabolic phenotype in the Mig6-deficient mice is independent of TGFα/EGFR binding. The anabolic phenotype may be due to an alternative EGFR ligand activation, or perhaps due to other non-EGFR specific mechanism. More research is required to elucidate the exact pathway responsible for the anabolic effects.
Extracellular Vesicles from Inflammation-Primed Adipose-Derived Stem Cells Enhance Achilles Tendon Repair by Reducing Inflammation and Promoting Intrinsic Healing
Authors: Shen Hua , Lane Ryan A. 
Published: February 2023

AbstractAchilles tendon rupture is a common sports-related tendon injury. Even with advanced clinical treatments, many patients suffer from long-term pain and reduced function. These unsatisfactory outcomes result primarily from an imbalanced injury response with excessive inflammation and inadequate regeneration. Prior studies showed that extracellular vesicles from inflammation-primed adipose-derived stem cells (iEVs) can attenuate inflammation in the early phase of tendon healing. However, the effect of iEVs on tendon inflammation and regeneration in the later phases of tendon healing and the underlying mechanism remain to be determined. Accordingly, this study investigated the mechanistic roles of iEVs in regulating tendon response to injury using a mouse Achilles tendon injury and repair model in vivo and iEV-macrophage and iEV-tendon cell co-culture models in vitro. Results showed that iEVs promoted tendon anti-inflammatory gene expression and reduced mononuclear cell infiltration in the remodeling phase of tendon healing. iEVs also increased injury site collagen deposition and promoted tendon structural recovery. As such, mice treated with iEVs showed less peritendinous scar formation, much lower incidence of postoperative tendon gap or rupture, and faster functional recovery compared to untreated mice. Further in vitro study revealed that iEVs both inhibited macrophage inflammatory response and increased tendon cell proliferation and collagen production. The iEV effects were partially mediated by miR-147-3p, which blocks the toll-like receptor 4/NF-κB signaling pathway that activates macrophage M1 polarization. The combined results demonstrated that iEVs are a promising therapeutic agent, which can enhance tendon repair by attenuating inflammation and promoting intrinsic healing.Significance statementUsing a clinically relevant mouse Achilles tendon injury and repair model, this study revealed that iEVs, a biological product generated from inflammation-primed adipose-derived stem cells, can directly target both macrophages and tendon cells and enhance tendon structural and functional recovery by limiting inflammation and promoting intrinsic healing. Results further identified miR-147-3p as one of the active components of iEVs that modulate macrophage inflammatory response by inhibiting toll-like receptor 4/NF-κB signaling pathway. These promising findings paved the road toward clinical application of iEVs in the treatment of tendon injury and other related disorders.
Understanding the Free Energy Landscape of Phase Separation in Lipid Bilayers using Molecular Dynamics
Authors: Poruthoor Ashlin J. , Sharma Akshara , Grossfield Alan 
Published: February 2023

ABSTRACTLiquid-liquid phase separation (LLPS) inside the cell often results in biological condensates that can critically impact cell homeostasis. Such phase separation events occur in multiple parts of cells, including the cell membranes, where the so-called “lipid raft” hypothesis posits the formation of ordered domains floating in a sea of disordered lipids. The resulting lipid domains often have functional roles. However, the thermodynamics of lipid phase separation and their resulting mechanistic effects on cell function and dysfunction are poorly understood. Understanding such complex phenomena in cell membranes, with their diverse lipid compositions, is exceptionally difficult. For this reasons, simple model systems that can recapitulate similar behavior are widely used to study this phenomenon. Despite these simplifications, the timescale and and length scales of domain formation pose a challenge for molecular dynamics (MD) simulations. Thus, most MD studies focus on spontaneous lipid phase separation — essentially measuring the sign (but not the amplitude) of the free energy change upon separation — rather than directly interrogating the thermodynamics. Here, we propose a proof-of-concept pipeline that can directly measure this free energy by combining coarse-grained MD with enhanced sampling protocols using a novel collective variable. This approach will be a useful tool to help connect the thermodynamics of phase separation with the mechanistic insights already available from molecular dynamics simulations.SIGNIFICANCEStandard molecular dynamics simulations can determine the sign the free energy change upon phase separation, but not the amplitude. We present a new method to determine the phase separation free energy for lipid membranes, based on a enhanced sampling using the weighted ensemble method combined with a novel collective variable, validated using coarse-grained simulations applied to several simple systems. The new method will be valuable as a way to develop models that connect molecular-level structural features to the thermodynamics of phase separation.
Elamipretide Improves ADP Sensitivity in Aged Mitochondria by Increasing Uptake through the Adenine Nucleotide Translocator (ANT)
Authors: Pharaoh Gavin , Kamat Varun , Kannan Sricharan , Stuppard Rudolph S. , Whitson Jeremy , Martin-Perez Miguel , Qian Wei-Jun , MacCoss Michael J. , Villen Judit , Rabinovitch Peter , Campbell Matthew D. , Sweet Ian R. , Marcinek David J. 
Published: February 2023

SUMMARYAging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment,in vivoheart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function.Abstract FigureGraphical Abstract.ELAM Binds Directly to ANT and ATP Synthase and ELAM Treatment Improves ADP Sensitivity, Increases ATP Production, and Improves Physiological Function in Old Muscles.ADP (adenosine diphosphate), ATP (adenosine triphosphate), VDAC (voltage-dependent anion channel), ANT (Adenine nucleotide translocator), H+(proton), ROS (reactive oxygen species), NADH (nicotinamide adenine dinucleotide), FADH2(flavin adenine dinucleotide), O2(oxygen), ELAM (elamipretide), −SH (free thiol), −SSG (glutathionylated protein).
dGAE(297-391) tau fragment promotes formation of CTE-like full-length tau filaments
Authors: Kitoka Kristine , Lends Alons , Kucinskas Gytis , Bula Anna Lina , Krasauskas Lukas , Smirnovas Vytautas , Zilkova Monika , Kovacech Branislav , Skrabana Rostislav , Hritz Jozef , Jaudzems Kristaps 
Published: February 2023

AbstractThe microtubule-associated protein tau forms disease-specific filamentous aggregates in several different neurodegenerative diseases. In order to understand how tau undergoes misfolding into a specific filament type and to control this process for drug development purposes, it is crucial to studyin vitrotau aggregation methods and investigate the structures of the obtained filaments at the atomic level. Here, we used the tau fragment dGAE, which aggregates spontaneously, to seed the formation of full-length tau filaments. The structures of dGAE and full-length tau filaments were investigated by solid-state MAS NMR, showing that dGAE allows propagation of a chronic traumatic encephalopathy (CTE)-like fold to the full-length tau. The obtained filaments efficiently seeded tau aggregation in HEK293T cells. This work demonstrates thatin vitropreparation of disease-specific types of full-length tau filaments is feasible.
Data-driven filtering for denoising of TCRpMHC single-cell data: a benchmark
Authors: Povlsen Helle Rus , Montemurro Alessandro , Jessen Leon Eyrich , Nielsen Morten 
Published: February 2023

AbstractPairing of the T cell receptor (TCR) with its cognate peptide-MHC (pMHC) is a cornerstone in T cell-mediated immunity. Recently, single-cell sequencing coupled with DNA-barcoded MHC multimer staining has enabled high-throughput studies of T cell specificities. However, the immense variability of TCR-pMHC interactions combined with the relatively low signal-to-noise ratio in the data generated using current technologies are complicating these studies. Several approaches have been proposed for denoising single-cell TCR-pMHC specificity data. Here, we present a benchmark evaluating two such denoising methods, ICON and ITRAP. We applied and evaluated the methods on publicly available immune profiling data provided by 10x Genomics. We find that both methods identified approximately 75% of the raw data as noise. We analyzed both internal metrics developed for the purpose and performance on independent data using machine learning methods trained on the raw and denoised 10x data. We find an increased signal-to-noise ratio comparing the denoised to the raw data for both methods, and demonstrate an overall superior performance of the ITRAP method in terms of both data consistency and performance. In conclusion, this study demonstrates that Improving the data quality by optimizing signal yield from high throughput studies of TCRpMHC-specificity is paramount in increasing our understanding of T cell-mediated immunity.
Climate, caribou and human needs linked by analysis of Indigenous and scientific knowledge
Authors: Gagnon Catherine A. , Hamel Sandra , Russell Don E. , Andre James , Buckle Annie , Haogak David , Pascal Jessi , Schafer Esau , Powell Todd , Svoboda Michael Y. , Berteaux Dominique 
Published: February 2023

AbstractMigratory tundra caribou are ecologically and culturally critical in the circumpolar North. However, they are declining almost everywhere in North America, likely due to natural variation exacerbated by climate change and human activities. Yet, the interconnectedness between climate, caribou, and human well-being has received little attention. To address this gap, we bridged Indigenous and scientific knowledge in a single model, using as example the Porcupine caribou herd social-ecological system. Our analysis, involving 688 (fall season) and 616 (spring season) interviews conducted over nine years with 405 (fall season) and 390 (spring season) Indigenous hunters from nine communities, demonstrates that environmental conditions, large-scale temporal changes associated with caribou demography, and cultural practices affect hunters’ capacity to meet their needs in caribou. Our quantitative approach bolsters our understanding of the complex relationships between ecosystems and human welfare in environments exposed to rapid climate change, and shows the benefits of long-term participatory research methods implemented by Indigenous and scientific partners.
Three-dimensional spatial quantitative analysis of cardiac lymphatics in the mouse heart
Authors: Phillips Evan H. , Bindokas Vytautas P. , Jung Dahee , Teamer Jay , Kitajewski Jan K. , Solaro R. John , Wolska Beata M. , Lee Steve Seung-Young 
Published: February 2023

ABSTRACTObjective3D microscopy and image data analysis are necessary for studying the morphology of cardiac lymphatic vessels (LyVs) and association with other cell types. We aimed to develop a methodology for 3D multiplexed lightsheet microscopy and highly sensitive and quantitative image analysis to identify pathological remodeling in the 3D morphology of LyVs in young adult mouse hearts with familial hypertrophic cardiomyopathy (HCM).MethodsWe developed a 3D lightsheet microscopy workflow providing a quick turn-around (as few as 5-6 days), multiplex fluorescence detection, and preservation of LyV structure and epitope markers. Hearts from non-transgenic (NTG) and transgenic (TG) HCM mice were arrested in diastole, retrograde perfused, immunolabeled, optically cleared, and imaged. We built an image processing pipeline to quantify LyV morphological parameters at the chamber and branch levels.ResultsChamber-specific pathological alterations of LyVs were identified, but most significantly in the right atrium (RA). TG hearts had a higher volume fraction of ER-TR7+fibroblasts and reticular fibers. In the RA, we found associations between ER-TR7+volume fraction and both LyV segment density and median diameter.ConclusionsThis workflow and study enabled multi-scale analysis of pathological changes in cardiac LyVs of young adult mice, inviting ideas for research on LyVs in cardiac disease.
The eco-evolution and biodiversity in antagonistic and mutualistic interactive populations
Authors: Wang Lingzi , Pontarp Mikael 
Published: February 2023

AbstractUnderstanding environmental and ecological effects on ecosystem structure, function, and dynamics is crucial. However, our comprehension of such effects remains challenging due to the complex interplay of abiotic environment, ecological relationships among species, and coevolution within and across trophic levels. Here, we set out to investigate a wide range of combined ecoevolutionary responses in a plant-insect ecosystem. We study ecological population dynamics, coevolution and functional diversity in response to changes in (1) abiotic-biotic interactions, (2) within-trophic-level competitive interactions, and (3) between-trophic-level antagonistic and mutualistic interactions. We developed an eco-evolutionary and functional trait-based model to simulate environmental and ecologically mediated responses to these interactions. We show that mutualistic interactions render a positive feedback loop of increased population sizes followed by selection for even stronger biotic ecological interactions instead of abiotic interactions. Antagonistic interactions have the opposite effect and adaptation to abiotic environment becomes more important. Furthermore, our study reveals that benign conditions (high ecological opportunities, low within-trophic-level competition, and strong interactions between plants and insects) facilitate functional diversity, whereas harsh conditions impede diversity. These findings provide valuable insights into mechanisms that underlie fundamental eco-evolutionary responses to current environmental and ecological changes, offering potential contributions to ecosystem conservation facing urgent challenges.
TheThCre:mTmGmouse has sparse expression in the sympathetic nervous system
Authors: Tian Tina , Ward Patricia J 
Published: February 2023

ABSTRACTThe global double-fluorescent cre-dependent reporter mousemT/mGhas been a valuable tool for differential identification of tissues and cells. This line was previously shown to have EGFP expression in a cre-dependent fashion in single neurons. Here, we demonstrate very sparse labeling in aThCre:mT/mGcross. This is evident in sweat glands, thoracic spinal cord, sciatic nerve, and lumbar sympathetic ganglia. Therefore, this model may be suitable for imaging or electrophysiology studies of postganglionic sympathetic neuron cell bodies but ineffective for visualizing peripheral axons and tissue targets of the sympathetic nervous system.