bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diosmetin alleviates liver inflammation by improving liver sinusoidal endothelial cell dysfunction
Authors: Żurawek Dariusz , Pydyn Natalia , Major Piotr , Szade Krzysztof , Trzos Katarzyna , Kuś Edyta , Pośpiech Ewelina , Małczak Piotr , Radkowiak Dorota , Budzyński Andrzej , Chłopicki Stefan , Jura Jolanta , Kotlinowski Jerzy 
Published: October 2023

AbstractBackground & AimsTumor necrosis factor-alpha (TNFα) induces pro-inflammatory activation in liver sinusoidal endothelial cells (LSEC) and liver inflammation. However, knowledge about whether modulating LSEC activation can alleviate liver inflammation is scarce. This study aimed to establish and validate an animal model mimicking LSEC dysfunction observed in patients with elevated plasma levels of TNFα, and explore whether vasoactive flavonoid diosmetin could serve as a therapeutic agent for liver inflammation.Approach & ResultsGenetic deletion of Mcpip1 in myeloid leukocytes (Mcpip1fl/flLysMCre) resulted in the development of systemic and liver inflammation in mice. Symptoms were compared with those in liver samples from obese humans with elevated TNFα. Mice were treated with diosmetin, and its effectiveness in alleviating liver inflammation was evaluated. Elevated TNFα correlated with reduced Mcpip1 expression in peripheral blood mononuclear cells and LSEC dysfunction in obese patients. Mcpip1 knockout in myeloid cells in mice replicated molecular signs observed in human samples. Diosmetin efficiently reduced LSEC activation and liver inflammation in Mcpip1fl/flLysMCremice. Diosmetin’s effects may stem from inhibiting NF-κB-p50 subunit production in TNFα-activated endothelial cells.ConclusionsDiosmetin treatment efficiently restricted liver inflammation, despite ongoing systemic inflammation, by diminishing LSEC dysfunction. Mcpip1fl/flLysMCremice mimic symptoms of liver inflammation observed in humans and can be useful in studies on new anti-inflammatory therapies for the liver. We show that diosmetin, a vasoactive flavonoid that is successfully used in the clinic to treat chronic venous insufficiency, has also strong anti-inflammatory properties in the liver. This suggests that diosmetin treatment may be tested in humans as a supportive therapy for liver inflammation.Graphical abstract
Brief disruption of activity in a subset of dopaminergic neurons during consolidation impairs long-term memory by fragmenting sleep
Authors: Yan Lin , Wu Litao , Wiggin Timothy D. , Su Xiaojuan , Yan Wei , Li Hailiang , Li Lei , Lu Zhonghua , Li Yuantao , Meng Zhiqiang , Guo Fang , Li Fan , Griffith Leslie C. , Liu Chang 
Published: October 2023

AbstractSleep disturbances are associated with poor long-term memory (LTM) formation, yet the underlying cell types and neural circuits involved have not been fully decoded. Dopamine neurons (DANs) are involved in memory processing at multiple stages. Here, using both male and female flies,Drosophila melanogaster, we show that, during the first few hours of memory consolidation, disruption of basal activity of a small subset of protocerebral anterior medial DANs (PAM-DANs), by either brief activation or inhibition of the two dorsal posterior medial (DPM) neurons, impairs 24 h LTM. Interestingly, these brief changes in activity using female flies result in sleep loss and fragmentation, especially at night. Pharmacological rescue of sleep after manipulation restores LTM. A specific subset of PAM-DANs (PAM-α1) that synapse onto DPM neurons specify the microcircuit that links sleep and memory. PAM-DANs, including PAM-α1, form functional synapses onto DPM mainly via multiple dopamine receptor subtypes. This PAM-α1 to DPM microcircuit exhibits a synchronized, transient, post-training increase in activity during the critical memory consolidation window, suggesting an effect of this microcircuit on maintaining the sleep necessary for LTM consolidation. Our results provide a new cellular and circuit basis for the complex relationship between sleep and memory.
Piezo1 Mutant Zebrafish as a Model of Idiopathic Scoliosis
Authors: Ramli  , Aramaki Toshihiro , Watanabe Masakatsu , Kondo Shigeru 
Published: October 2023

ABSTRACTScoliosis is a condition where the spine curves sideways, unique to humans due to their upright posture. However, the cause of this disease is not well understood because it’s challenging to find a model for experimentation. This study aimed to create a model for human idiopathic scoliosis by manipulating the function of mechanosensitive channels called Piezo channels in zebrafish. Zebrafish were chosen because they experience similar biomechanical forces to humans, particularly in relation to the role of mechanical force in scoliosis progression. Here we describepiezo1andpiezo2aare involved in bone formation, with a double knockout resulting in congenital systemic malformations. However, an in-frame mutation ofpiezo1led to fully penetrant juvenile-onset scoliosis, bone asymmetry, reduced tissue mineral density, and abnormal intervertebral discs-resembling non-congenital scoliosis symptoms in humans. These findings suggest that functional Piezo channels responding to mechanical forces are crucial for bone formation and maintaining spine integrity, providing insights into skeletal disorders.
Sex determination system turnovers play important roles in the willows speciation
Authors: Xue Zhi-Qing , Applequist Wendy L. , Hörandl Elvira , He Li 
Published: October 2023

AbstractAlmost all species in the genusSalix(willow) are dioecious, but some have male and some female heterogamety, and the chromosomal location of the sex-linked regions (termed SDSs) differs between different species. We first analyzed the SDSs of two species,Salix cardiophyllaandS. interior, whose positions in theSalixphylogeny make them important species for understanding a sex chromosome turnover that has been detected in their relatives, and that changed the system from male to female heterogamety. We show that both species have male heterogamety, with XY-linked regions on chromosome 15 (termed a 15XY system). The sex-linked regions occupy 21.3% and 22.8% of the entire reference chromosome, respectively. By constructing phylogenetic trees of species with known SDSs, we determined the phylogenetic positions of all the species. Reconstruction of SDSs revealed that 15XY system is likely the ancestral of willows. Finally, we tested for both current and ancestral gene flow between different species with the same or different sex-determining systems, as the sex chromosomes can play important roles in reproductive isolation between species. We inferred lower gene flow between species with XY on chromosome 7 (7XY) and ZW on chromosome 15 (15ZW) systems, compared with gene flow either between species with XY on chromosome 15 (15XY) and 15ZW systems or between species with 7XY and 15XY systems. We argue that, although sex chromosomes turnovers in willows may not create complete reproductive barriers, gene flow may be reduced between species with different SDSs.
Lysogeny destabilizes computationally simulated microbiomes
Authors: Gilman R. Tucker , Muldoon Mark R. , Megremis Spyridon , Robertson David L. , Chanishvili Nina , Papadopoulos Nikolaos G. 
Published: October 2023

AbstractBackgroundThe Anna Karenina Principle predicts that stability in host-associated microbiomes correlates with health in the host. Microbiomes are ecosystems, and classical ecological theory suggests that predators impact ecosystem stability. Phages can act as predators on bacterial species in microbiomes. However, our ability to extrapolate results from existing ecological theory to phages and microbiomes is limited because some phages can stage lysogenic infections, a process with no precise analog in classical ecology. In lysogenic infections, so-called “temperate” phages integrate into the cells of their hosts where they can remain dormant as prophages for many generations. Prophages can later be induced by environmental conditions, whereupon they lyse their host cells and phage progeny are released. It has been suggested that prophages can act as biological timebombs that destabilize microbial ecosystems, but formal theory to support this hypothesis is lacking.ResultsWe studied the effects of temperate and virulent phages on diversity and stability in computationally simulated microbiomes. The presence of either phage type in a microbiome increased bacterial diversity. Bacterial populations were more likely to fluctuate over time when there were more temperate phages in the system. When microbiomes were disturbed from their steady states, both phage types affected return times, but in different ways. Bacterial species returned to their pre-disturbance densities more slowly when there were more temperate phage species, but cycles engendered by disturbances dampened more slowly when there were more virulent phage species.ConclusionsPhages shape the diversity and stability of microbiomes, and temperate and virulent phages impact microbiomes in different ways. A clear understanding of the effects of phage life cycles on microbiome dynamics is needed to predict the role of microbiome composition in host health, and for applications including phage therapy and microbiome transplants. The results we present here provide a theoretical foundation for this body of work.
CSTA: A Biomarker Regulating Esophageal Stricture Epithelial Barrier, Potential Medication Target
Authors: Yang Fang , Hu Yiwei , Shi Zewen , Jin Haozhou , Hu Kefeng , Ye Guoliang , Pang Qian , Hou Ruixia , Tang Keqi , Zhu Yabin 
Published: October 2023

AbstractEsophageal strictures resulting from ESD/EMR in the esophagus are distressing, with uncertain causes and treatments due to epithelial barrier dysfunction. We explored cystatin A (CSTA) as a novel biomarker for the esophageal epithelial barrier. CSTA regulates the barrier and is influenced by tacrolimus (FK506). Analyzing biopsy samples by proteomics, we identified CSTA as an esophageal epithelial biomarker. Knocking down CSTA reduced responsiveness to triamcinolone acetonide (TA) and lowered expression of proteins related to cell-cell junctions and barrier function during inflammation. These findings suggest that down-regulate CSTA weakens tight junctions and the esophageal barrier, leading to strictures. Notably, FK506 showed promise in rescuing CSTA-knockdown cells by increasing the expression of proteins related to cell-cell junctions and barrier function. This highlights FK506 as a potential therapy for esophageal strictures in patients with CSTA mutations.
Inference and design of antibody specificity: from experiments to models and back
Authors: Fernandez-de-Cossio-Diaz Jorge , Uguzzoni Guido , Ricard Kévin , Anselmi Francesca , Nizak Clément , Pagnani Andrea , Rivoire Olivier 
Published: October 2023

AbstractExquisite binding specificity is essential for many protein functions but is difficult to engineer. Many biotechnological or biomedical applications require the discrimination of very similar ligands, which poses the challenge of designing protein sequences with highly specific binding profiles. Current methods for generating specific binders rely onin vitroselection experiments, but these have limitations in terms of library size and control over specificity profiles. We present a multi-stage approach that overcomes these limitations by combining high-throughput sequencing of phage display experiments with machine learning and biophysical modeling. Our models predict the binding profiles of antibodies against multiple ligands and generate antibody sequences with desired specificity profiles. The approach involves the identification of different binding modes, each associated with a particular ligand against which the antibodies are either selected or not. We demonstrate that the model successfully disentangles these modes, even when they are associated with chemically very similar ligands. Additionally, we demonstrate and validate experimentally the computational design of antibodies with customized specificity profiles, either with specific high affinity for a particular target ligand, or with cross-specificity for multiple target ligands. Overall, our results showcase the potential of leveraging a biophysical model learned from selections against multiple ligands to design proteins with tailored specificity, with applications to protein engineering extending beyond the design of antibodies.
Quantifying fluorescence lifetime responsiveness of environment sensitive probes for membrane fluidity measurements
Authors: Ragaller Franziska , Sjule Ellen , Urem Yagmur Balim , Schlegel Jan , El Rojbin , Urbancic Dunja , Urbancic Iztok , Blom Hans , Sezgin Erdinc 
Published: October 2023

AbstractThe structural diversity of different lipid species within the membrane defines its biophysical properties such as membrane fluidity, phase transition, curvature, charge distribution and tension. Environment-sensitive probes, which change their spectral properties in response to their surrounding milieu, have greatly contributed to our understanding of such biophysical properties. To realize the full potential of these probes and to avoid misinterpretation of their spectral responses, a detailed investigation of their fluorescence characteristics in different environments is necessary. Here, we examined fluorescence lifetime of two newly developed membrane order probes, NR12S and NR12A, in response to alterations in their environments such as degree of lipid saturation, cholesterol content, double bond position and configuration and phospholipid headgroup. As comparison, we investigated lifetime sensitivity of the membrane tension probe Flipper in these environments. Applying fluorescence lifetime imaging microscopy (FLIM) in both model membranes and biological membranes, all probes distinguished membrane phases by lifetime, but exhibited different lifetime sensitivities to varying membrane biophysical properties (e.g. cholesterol). While the lifetime of Flipper is particularly sensitive to membrane cholesterol content, NR12S and NR12A lifetime is moderately sensitive to both cholesterol content and lipid acyl chains. Moreover, all probes exhibit longer lifetimes at longer emission wavelengths in membranes of any complexity. This emission-wavelength dependency results in varying lifetime resolution at different spectral regions, highly relevant for FLIM data acquisition. Our data provides valuable insights on how to perform FLIM with these probes and highlights both their potential and limitations.
Synthetic Biodegradable Void-forming Hydrogels forIn Vitro3D Culture of Functional Human Bone Cell Networks
Authors: Zauchner Doris , Müller Monica Zippora , Horrer Marion , Bissig Leana , Zhao Feihu , Lee Sung Sik , Müller Ralph , Qin Xiao-Hua 
Published: October 2023

AbstractGenerating 3D bone cell networksin vitrothat accurately mimic the dynamic process of osteoblast embedding during early bone formation poses a significant challenge. Herein, we report a synthetic biodegradable macroporous hydrogel for efficient formation of 3D networks from human primary cells, analysis of cell-secreted extracellular matrix (ECM) and microfluidic integration. Using polymerization-induced phase separation, matrix metalloproteinase-sensitive polyethylene glycol hydrogels are formed with interconnected porosity in the presence of living cells. The pore size (5-20 μm) and permeability can be fine-tuned by adjusting the concentration and molecular weight of dextran. After encapsulation in these hydrogels, human mesenchymal stem cells and osteoblasts form a 3D cell network within 24 hours. The synthetic nature of this hydrogel enables histological analysis of cell-secreted collagen, a task previously challenging using collagen-derived hydrogels. Moreover, this hydrogel is integrated with a commercial chip, showcasing the potential for microfluidic perfusion cultures. Time-lapsed imaging of fluid flow and fast formation of 3D cell networks is demonstrated on chip. Altogether, this work introduces a versatile synthetic macroporous hydrogel, which can be integrated with microfluidic chip to enable 3D culture of human bone cell networks and analysis of cell-secreted ECM. This hydrogel may facilitate future mechanistic studies on bone development.
Genetic drift and purifying selection shape within-host influenza A virus populations during natural swine infections
Authors: VanInsberghe David , McBride Dillon S. , DaSilva Juliana , Stark Thomas J. , Lau Max S.Y. , Shepard Samuel S. , Barnes John R. , Bowman Andrew S. , Lowen Anice C. , Koelle Katia 
Published: October 2023

AbstractPatterns of within-host influenza A virus (IAV) diversity and evolution have been described in natural human infections, but these patterns remain poorly characterized in non-human hosts. Elucidating these dynamics is important to better understand IAV biology and the evolutionary processes that govern spillover into humans. Here, we sampled an IAV outbreak in pigs during a week-long county fair to characterize viral diversity and evolution in this important reservoir host. Nasal wipes were collected on a daily basis from all pigs present at the fair, yielding up to 421 samples per day. Subtyping of PCR-positive samples revealed the co-circulation of H1N1 and H3N2 subtype IAVs. PCR-positive samples with robust Ct values were deep-sequenced, yielding 506 sequenced samples from a total of 253 pigs. Based on higher-depth re-sequenced data from a subset of these initially sequenced samples (260 samples from 168 pigs), we characterized patterns of within-host IAV genetic diversity and evolution. We find that IAV genetic diversity in single-subtype infected pigs is low, with the majority of intra-host single nucleotide variants (iSNVs) present at frequencies of <10%. The ratio of the number of nonsynonymous to the number of synonymous iSNVs is significantly lower than under the neutral expectation, indicating that purifying selection shapes patterns of within-host viral diversity in swine. The dynamic turnover of iSNVs and their pronounced frequency changes further indicate that genetic drift also plays an important role in shaping IAV populations within pigs. Taken together, our results highlight similarities in patterns of IAV genetic diversity and evolution between humans and swine, including the role of stochastic processes in shaping within-host IAV dynamics.
Lipin-1 restrains macrophage lipid synthesis to promote inflammation resolution
Authors: Bamgbose Temitayo T. , Schilke Robert M. , Igiehon Oluwakemi O. , Nkadi Ebubechukwu H. , Custis David , Bharrhan Sushma , Schwarz Benjamin , Bohrnsen Eric , Bosio Catharine M. , Scott Rona S. , Yurdagul Arif , Finck Brian N. , Woolard Matthew D. 
Published: October 2023

AbstractMacrophages are critical to maintaining and restoring tissue homeostasis during inflammation. The lipid metabolic state of macrophages influences their function, but a deeper understanding of how lipid metabolism is regulated in pro-resolving macrophage responses is needed. Lipin-1 is a phosphatidic acid phosphatase with a transcriptional coregulatory activity (TC) that regulates lipid metabolism. We previously demonstrated that lipin-1 supports pro-resolving macrophage responses, and here, myeloid-associated lipin-1 is required for inflammation resolution, yet how lipin-1-regulated cellular mechanisms promote macrophage pro-resolution responses is unknown. We demonstrated that the loss of lipin-1 in macrophages led to increased free fatty acid, neutral lipid, and ceramide content and increased phosphorylation of acetyl-CoA carboxylase. The inhibition of the first step of lipid synthesis and transport of citrate from the mitochondria in macrophages reduced lipid content and restored efferocytosis and inflammation resolution in lipin-1mKO macrophages and mice. Our findings suggest macrophage-associated lipin-1 restrains lipid synthesis, promoting pro-resolving macrophage function in response to pro-resolving stimuli.TeaserLipin 1 blockade of lipid biosynthesis inducing mitochondrial citrate export promotes efferocytosis and inflammation resolution.
Multilayer network associations between the exposome and childhood brain development
Authors: Simpson-Kent Ivan L. , Gataviņš Mārtiņš M. , Tooley Ursula A. , Boroshok Austin L. , McDermott Cassidy L. , Park Anne T. , Reyes Lourdes Delgado , Bathelt Joe , Tisdall M. Dylan , Mackey Allyson P. 
Published: October 2023

AbstractGrowing up in a high poverty neighborhood is associated with elevated risk for academic challenges and health problems. Here, we take a data-driven approach to exploring how measures of children’s environments relate to the development of their brain structure and function in a community sample of children between the ages of 4 and 10 years. We constructed exposomes including measures of family socioeconomic status, children’s exposure to adversity, and geocoded measures of neighborhood socioeconomic status, crime, and environmental toxins. We connected the exposome to two structural measures (cortical thickness and surface area,n= 170) and two functional measures (participation coefficient and clustering coefficient,n= 130). We found dense connectionswithinexposome and brain layers and sparse connectionsbetweenexposome and brain layers. Lower family income was associated with thinner visual cortex, consistent with the theory that accelerated development is detectable in early-developing regions. Greater neighborhood incidence of high blood lead levels was associated with greater segregation of the default mode network, consistent with evidence that toxins are deposited into the brain along the midline. Our study demonstrates the utility of multilayer network analysis to bridge environmental and neural explanatory levels to better understand the complexity of child development.
Functional effects of TBC1 domain containing kinase deletion in immortalized B cells and plasma cells
Authors: von Beck Troy , Jacob Joshy 
Published: October 2023

AbstractTBC1 domain containing kinase (TBCK) is a ubiquitous protein pseudokinase highly expressed in neurons and glial cells. Mutations in TBCK disrupt nervous system function and cause a characteristic syndrome of intellectual disability and hypotonia with various other comorbidities occurring in non-nervous tissues. Previous studies have shown a vacuolation defect present in B cells from individuals with TBCK mutations, but it is unclear if this affects plasma cell differentiation or humoral immunity. Recent research has revealed that TBCK is part of the FERRY complex involved in mRNA transport and is implicated in regulating mTORC1 signaling, autophagy, and cellular processes like cell proliferation and migration. Yet, the exact role of TBCK in these processes is still not fully understood. In this study, TBCK knockout cell lines were generated to investigate its impact on B cells and plasma cells. TBCK knockout plasma cells showed reduced immunoglobulin secretion after one week in culture, suggesting a possible defect in recycling cell components or energy usage. However, more experiments are needed to confirm this observation.