bluuebunny/crossref_metadata_2025 huggingface dataset:
A Substrate-Mimicking Basement Membrane Drives the Organization of Human Mesenchymal Stromal Cells and Endothelial Cells Into Perivascular Niche-Like Structures
Authors: Perugini Valeria , Santin Matteo
Published: September 2021

Extracellular matrix-derived products (e.g. Matrigel) are widely used for in vitro cell cultures both as two-dimensional (2D) substrates and as three-dimensional (3D) encapsulation gels because of their ability to control cell phenotypes through biospecific cues. However, batch-to-batch variations, poor stability, cumbersome handling, and the relatively high costs strictly limit their use. Recently, a new substrate known as PhenoDrive-Y has been used as 2D coating of tissue culture plastic showing to direct the bone marrow mesenchymal stromal cells (MSCs) toward the formation of 3D spheroids. When organized into 3D spheroids, the MSCs expressed levels of pluripotency markers and of paracrine angiogenic activity higher than those of the MSCs adhering as fibroblast-like colonies on tissue culture plastic. The formation of the spheroids was attributed to the properties of this biomaterial that resemble the main features of the basement membrane by mimicking the mesh structure of collagen IV and by presenting the cells with orderly spaced laminin bioligands. In this study, PhenoDrive-Y was compared to Matrigel for its ability to drive the formation of perivascular stem cell niche-like structures in 2D co-culture conditions of human endothelial cells and adult bone marrow MSCs. Morphological analyses demonstrated that, when compared to Matrigel, PhenoDrive-Y led endothelial cells to sprout into a more consolidated tubular network and that the MSCs nestled as compact spheroids above the anastomotic areas of this network resemble more closely the histological features of the perivascular stem cell niche. A study of the expressions of relevant markers led to the identification of the pathways linking the PhenoDrive-Y biomimicking properties to the acquired histological features, demonstrating the enhanced levels of stemness, renewal potential, predisposition to migration, and paracrine activities of the MSCs.
Tumor-Derived Exosomal Protein Tyrosine Phosphatase Receptor Type O Polarizes Macrophage to Suppress Breast Tumor Cell Invasion and Migration
Authors: Dong Hongmei , Xie Chaoyu , Jiang Yuchen , Li Kai , Lin Yusheng , Pang Xijiao , Xiong Xiao , Zheng Jiehua , Ke Xiurong , Chen Yexi , Li Yong , Zhang Hao
Published: September 2021

Tumor-derived exosomes, containing multiple nucleic acids and proteins, have been implicated to participate in the interaction between tumor cells and microenvironment. However, the functional involvement of phosphatases in tumor-derived exosomes is not fully understood. We and others previously demonstrated that protein tyrosine phosphatase receptor type O (PTPRO) acts as a tumor suppressor in multiple cancer types. In addition, its role in tumor immune microenvironment remains elusive. Bioinformatical analyses revealed that PTPRO was closely associated with immune infiltration, and positively correlated to M1-like macrophages, but negatively correlated to M2-like macrophages in breast cancer tissues. Co-cultured with PTPRO-overexpressing breast cancer cells increased the proportion of M1-like tumor-associated macrophages (TAMs) while decreased that of M2-like TAMs. Further, we observed that tumor-derived exosomal PTPRO induced M1-like macrophage polarization, and regulated the corresponding functional phenotypes. Moreover, tumor cell-derived exosomal PTPRO inhibited breast cancer cell invasion and migration, and inactivated STAT signaling in macrophages. Our data suggested that exosomal PTPRO inhibited breast cancer invasion and migration by modulating macrophage polarization. Anti-tumoral effect of exosomal PTPRO was mediated by inactivating STAT family in macrophages. These findings highlight a novel mechanism of tumor invasion regulated by tumor-derived exosomal tyrosine phosphatase, which is of translational potential for the therapeutic strategy against breast cancer.
Single Cell RNA-Sequencing Reveals a Murine Gallbladder Cell Transcriptome Atlas During the Process of Cholesterol Gallstone Formation
Authors: Liang Jingjia , Shao Wentao , Liu Qian , Lu Qifan , Gu Aihua , Jiang Zhaoyan
Published: September 2021

Gallstone disease is a worldwide common disease. However, the knowledge concerning the gallbladder in the pathogenesis of cholesterol gallstone formation remains limited. In this study, using single-cell RNA sequencing (scRNA-seq) to obtain the transcriptome of gallbladder cells, we showed cellular heterogeneity and transcriptomic dynamics in murine gallbladder cells during the process of lithogenesis. Our results indicated gallbladder walls were subjected to remodeling during the process of lithogenesis. The major molecular events that happened included proliferation of epithelial cells, infiltration of immune-cells, activation of angiogenesis, and extracellular matrix modulation. Furthermore, we observed partial reversal of gallbladder cell transcriptomes by ursodeoxycholic acid treatment. This work thus provides novel and integral knowledges on the cellular changes during lithogenesis, which is of great significance to the understanding of pathogenesis and treatment of cholesterol gallstone.
Notch Signaling Regulates Muscle Stem Cell Homeostasis and Regeneration in a Teleost Fish
Authors: Sultan Sami H. A. , Dyer Carlene , Knight Robert D.
Published: September 2021

Muscle regeneration is mediated by the activity of resident muscle satellite cells (muSCs) that express Pax7. In mouse Notch signaling regulates muSCs during quiescence and promotes muSC proliferation in regeneration. It is unclear if these roles of Notch in regulating muSC biology are conserved across vertebrates or are a mammalian specific feature. We have therefore investigated the role of Notch in regulating muSC homeostasis and regeneration in a teleost fish, the zebrafish. We have also tested whether muSCs show differential sensitivity to Notch during myotome development. In an absence of injury Notch is important for preventing muSC proliferation at the vertical myoseptum. In contrast, Notch signaling promotes proliferation and prevents differentiation in the context of injury. Notch is required for the proliferative response to injury at early and later larval stages, suggesting it plays a similar role in regulating muSCs at developing and adult stages. Our results reveal a conserved role for Notch signaling in regulating muSCs under homeostasis and for promoting proliferation during regeneration in teleost fish.
Estrogen Attenuates Chronic Stress-Induced Cardiomyopathy by Adaptively Regulating Macrophage Polarizations via β2-Adrenergic Receptor Modulation
Authors: Hou Hongjian , Adzika Gabriel Komla , Wu Qi , Ma Tongtong , Ma Yanhong , Geng Juan , Shi Mingjin , Fu Lu , Rizvi Ruqayya , Gong Zheng , Sun Hong
Published: September 2021

Clinical demographics have demonstrated that postmenopausal women are predisposed to chronic stress-induced cardiomyopathy (CSC) and this has been associated with the decrease of estrogen. Meanwhile, recent studies have implicated unsolved myocardial proinflammatory responses, which are characterized by enormous CD86+ macrophage infiltrations as an underlying disease mechanism expediting the pathological remodeling of the heart during chronic stress. However, we had previously demonstrated that estrogen confers cardioprotection via the modulation of cardiomyocytes β2-adrenoceptors (β2AR)-Gs/Gi pathways during stress to lessen the incidence of stress-induced cardiovascular diseases in premenopausal women. Intriguingly, macrophages express β2AR profoundly as well; as such, we sought to elucidate the possibilities of estrogen modulating β2AR-Gs/Gi pathway to confer cardioprotection during stress via immunomodulation. To do this, ovariectomy (OVX) and sham operations (Sham) were performed on female Sprague-Dawley (SD) rats. Two weeks after OVX, the rats were injected with 40 μg/kg/day of estradiol (E2). Next, on day 36 after OVX, chronic stress was induced by a daily subcutaneous injection of 5 mg/kg/day of isoproterenol (ISO). The effect of E2 on relevant clinical cardiac function indexes (LVSP, LVEDP, + dp/dt and −dp/dt), myocardial architecture (cardiomyocyte diameter and fibrosis), β2AR alterations, and macrophage (CD86+ and CD206+) infiltrations were assessed. In vitro, peritoneal macrophages (PMΦ) were isolated from wild-type and β2AR-knockout female mice. The PMΦ were treated with ISO, E2, and β2AR blocker ICI 118,551 for 24 h, and flow cytometric evaluations were done to assess their phenotypic expression. E2 deficiency permitted the induction of CSC, which was characterized by cardiac dysfunctions, maladaptive myocardial hypertrophy, unresolved proinflammatory responses, and fibrosis. Nonetheless, E2 presence/supplementation during stress averted all the aforementioned adverse effects of chronic stress while preventing excessive depletion of β2AR. Also, we demonstrated that E2 facilitates timely resolution of myocardial proinflammation to permit reparative functions by enhancing the polarization of CD86+ to CD206+ macrophages. However, this adaptive immunomodulation is hampered when β2AR is inhibited. Taken together, the outcomes of this study show that E2 confers cardioprotection to prevent CSC via adaptive immunomodulation of macrophage phenotypes, and β2AR-mediated signaling is crucial for the polarizations of CD86+ to CD206+ macrophages.
Nicotinamide Riboside and Metformin Ameliorate Mitophagy Defect in Induced Pluripotent Stem Cell-Derived Astrocytes With POLG Mutations
Authors: Chen Anbin , Kristiansen Cecilie Katrin , Hong Yu , Kianian Atefeh , Fang Evandro Fei , Sullivan Gareth John , Wang Jian , Li Xingang , Bindoff Laurence A. , Liang Kristina Xiao
Published: September 2021

Mitophagy specifically recognizes and removes damaged or superfluous mitochondria to maintain mitochondrial homeostasis and proper neuronal function. Defective mitophagy and the resulting accumulation of damaged mitochondria occur in several neurodegenerative diseases. Previously, we showed mitochondrial dysfunction in astrocytes withPOLGmutations, and here, we examined howPOLGmutations affect mitophagy in astrocytes and how this can be ameliorated pharmacologically. Using induced pluripotent stem cell (iPSC)-derived astrocytes carryingPOLGmutations, we found downregulation of mitophagy/autophagy-related genes using RNA sequencing-based KEGG metabolic pathway analysis. We confirmed a deficit in mitochondrial autophagosome formation under exogenous stress conditions and downregulation of the mitophagy receptor p62, reduced lipidation of LC3B-II, and decreased expression of lysosome protein lysosomal-associated membrane protein 2A (LAMP2A). These changes were regulated by the PINK1/Parkin pathway and AKT/mTOR/AMPK/ULK1 signaling pathways. Importantly, we found that double treatment with nicotinamide riboside (NR) and metformin rescued mitophagy defects and mitochondrial dysfunction in POLG-mutant astrocytes. Our findings reveal that impaired mitophagy is involved in the observed mitochondrial dysfunction caused byPOLGmutations in astrocytes, potentially contributing to the phenotype in POLG-related diseases. This study also demonstrates the therapeutic potential of NR and metformin in these incurable mitochondrial diseases.
Breakage of CRISPR/Cas9-Induced Chromosome Bridges in Mitotic Cells
Authors: Rodriguez-Muñoz Marina , Serrat Martina , Soler David , Genescà Anna , Anglada Teresa
Published: September 2021

Chromosomal instability, the most frequent form of plasticity in cancer cells, often proceeds through the formation of chromosome bridges. Despite the importance of these bridges in tumor initiation and progression, debate remains over how and when they are resolved. In this study, we investigated the behavior and properties of chromosome bridges to gain insight into the potential mechanisms underlying bridge-induced genome instability. We report that bridges may break during mitosis or may remain unbroken until the next interphase. During mitosis, we frequently observed discontinuities in the bridging chromatin, and our results strongly suggest that a substantial fraction of chromosome bridges are broken during this stage of the cell cycle. This notion is supported by the observation that the chromatin flanking mitotic bridge discontinuities is often decorated with the phosphorylated form of the histone H2AX, a marker of DNA breaks, and by MDC1, an early mediator of the cell response to DNA breaks. Also, free 3′OH DNA ends were detected in more than half of the bridges during the final stages of cell division. However, even if detected, the DNA ends of broken bridges are not repaired in mitosis. To investigate whether mitotic bridge breakage depends on mechanical stress, we used experimental models in which chromosome bridges with defined geometry are formed. Although there was no association between spindle pole separation or the distance among non-bridge kinetochores and bridge breakage, we found a direct correlation between the distance between bridge kinetochores and bridge breakage. Altogether, we conclude that the discontinuities observed in bridges during mitosis frequently reflect a real breakage of the chromatin and that the mechanisms responsible for chromosome bridge breakage during mitosis may depend on the separation between the bridge kinetochores. Considering that previous studies identified mechanical stress or biochemical digestion as possible causes of bridge breakage in interphase cells, a multifactorial model emerges for the breakage of chromosome bridges that, according to our results, can occur at different stages of the cell cycle and can obey different mechanisms.
Accurate Prediction of Band Structure of FeS2: A Hard Quest of Advanced First-Principles Approaches
Authors: Zhang Min-Ye , Jiang Hong
Published: September 2021

The pyrite and marcasite polymorphs of FeS2 have attracted considerable interests for their potential applications in optoelectronic devices because of their appropriate electronic and optical properties. Controversies regarding their fundamental band gaps remain in both experimental and theoretical materials research of FeS2. In this work, we present a systematic theoretical investigation into the electronic band structures of the two polymorphs by using many-body perturbation theory with the GW approximation implemented in the full-potential linearized augmented plane waves (FP-LAPW) framework. By comparing the quasi-particle (QP) band structures computed with the conventional LAPW basis and the one extended by high-energy local orbitals (HLOs), denoted as LAPW + HLOs, we find that one-shot or partially self-consistent GW (G0W0 and GW0, respectively) on top of the Perdew-Burke-Ernzerhof (PBE) generalized gradient approximation with a converged LAPW + HLOs basis is able to remedy the artifact reported in the previous GW calculations, and leads to overall good agreement with experiment for the fundamental band gaps of the two polymorphs. Density of states calculated from G0W0@PBE with the converged LAPW + HLOs basis agrees well with the energy distribution curves from photo-electron spectroscopy for pyrite. We have also investigated the performances of several hybrid functionals, which were previously shown to be able to predict band gaps of many insulating systems with accuracy close or comparable to GW. It is shown that the hybrid functionals considered in general fail badly to describe the band structures of FeS2 polymorphs. This work indicates that accurate prediction of electronic band structure of FeS2 poses a stringent test on state-of-the-art first-principles approaches, and the G0W0 method based on semi-local approximation performs well for this difficult system if it is practiced with well-converged numerical accuracy.
Using Molecular Diagnostics to Develop Therapeutic Strategies for Carbapenem-Resistant Gram-Negative Infections
Authors: Tenover Fred C.
Published: September 2021

Infections caused by multidrug-resistant Gram-negative organisms have become a global threat. Such infections can be very difficult to treat, especially when they are caused by carbapenemase-producing organisms (CPO). Since infections caused by CPO tend to have worse outcomes than non-CPO infections, it is important to identify the type of carbapenemase present in the isolate or at least the Ambler Class (i.e., A, B, or D), to optimize therapy. Many of the newer beta-lactam/beta-lactamase inhibitor combinations are not active against organisms carrying Class B metallo-enzymes, so differentiating organisms with Class A or D carbapenemases from those with Class B enzymes rapidly is critical. Using molecular tests to detect and differentiate carbapenem-resistance genes (CRG) in bacterial isolates provides fast and actionable results, but utilization of these tests globally appears to be low. Detecting CRG directly in positive blood culture bottles or in syndromic panels coupled with bacterial identification are helpful when results are positive, however, even negative results can provide guidance for anti-infective therapy for key organism-drug combinations when linked to local epidemiology. This perspective will focus on the reluctance of laboratories to use molecular tests as aids to developing therapeutic strategies for infections caused by carbapenem-resistant organisms and how to overcome that reluctance.
Coexistence for Whom?
Authors: Pooley Simon
Published: September 2021

This perspective essay considers ethical and conceptual questions around who coexistence is for, who it affects, and who is to make it happen. The introduction considers some approaches to thinking about human-wildlife coexistence, debates on the utility of the concept and reasons for its current emergence into the mainstream. It next outlines the preliminary conception of coexistence informing this essay. The discussion considers challenges for a narrow conservation-oriented framing of human-wildlife coexistence, and offers insights from the literatures on stewardship and relational values for tackling these.
Notch Intracellular Domain Plasmid Delivery via Poly(Lactic-Co-Glycolic Acid) Nanoparticles to Upregulate Notch Pathway Molecules
Authors: Messerschmidt Victoria L. , Chintapula Uday , Kuriakose Aneetta E. , Laboy Samantha , Truong Thuy Thi Dang , Kydd LeNaiya A. , Jaworski Justyn , Pan Zui , Sadek Hesham , Nguyen Kytai T. , Lee Juhyun
Published: September 2021

Notch signaling is a highly conserved signaling system that is required for embryonic development and regeneration of organs. When the signal is lost, maldevelopment occurs and leads to a lethal state. Delivering exogenous genetic materials encoding Notch into cells can reestablish downstream signaling and rescue cellular functions. In this study, we utilized the negatively charged and FDA approved polymer poly(lactic-co-glycolic acid) to encapsulate Notch Intracellular Domain-containing plasmid in nanoparticles. We show that primary human umbilical vein endothelial cells (HUVECs) readily uptake the nanoparticles with and without specific antibody targets. We demonstrated that our nanoparticles are non-toxic, stable over time, and compatible with blood. We further demonstrated that HUVECs could be successfully transfected with these nanoparticles in static and dynamic environments. Lastly, we elucidated that these nanoparticles could upregulate the downstream genes of Notch signaling, indicating that the payload was viable and successfully altered the genetic downstream effects.
Plaque Erosion: A Distinctive Pathological Mechanism of Acute Coronary Syndrome
Authors: Luo Xing , Lv Ying , Bai Xiaoxuan , Qi Jinyu , Weng Xiuzhu , Liu Shaoyu , Bao Xiaoyi , Jia Haibo , Yu Bo
Published: September 2021

Plaque erosion (PE) is one of the most important pathological mechanisms underlying acute coronary syndrome (ACS). The incidence of PE is being increasingly recognized owing to the development and popularization of intracavitary imaging. Unlike traditional vulnerable plaques, eroded plaques have unique pathological characteristics. Moreover, recent studies have revealed that there are differences in the physiopathological mechanisms, biomarkers, and clinical outcomes between PE and plaque rupture (PR). Accurate diagnosis and treatment of eroded plaques require an understanding of the pathogenesis of PE. In this review, we summarize recent scientific discoveries of the pathological characteristics, mechanisms, biomarkers, clinical strategies, and prognosis in patients with PE.
Bioimpedance Vector Analysis for Heart Failure: Should We Put It on the Agenda?
Authors: Liang Bo , Li Rui , Bai Jia-Yue , Gu Ning
Published: September 2021

Heart failure is a clinical syndrome, resulting in increased intracardiac pressure and/or decreased cardiac output under rest or stress. In acute decompensated heart failure, volume assessment is essential for clinical diagnosis and management. More and more evidence shows the advantages of bioimpedance vector analysis in this issue. Here, we critically present a brief review of bioimpedance vector analysis in the prediction and management of heart failure to give a reference to clinical physicians and guideline makers.
Role of the Mitochondrial Protein Import Machinery and Protein Processing in Heart Disease
Authors: Zhao Fujie , Zou Ming-Hui
Published: September 2021

Mitochondria are essential organelles for cellular energy production, metabolic homeostasis, calcium homeostasis, cell proliferation, and apoptosis. About 99% of mammalian mitochondrial proteins are encoded by the nuclear genome, synthesized as precursors in the cytosol, and imported into mitochondria by mitochondrial protein import machinery. Mitochondrial protein import systems function not only as independent units for protein translocation, but also are deeply integrated into a functional network of mitochondrial bioenergetics, protein quality control, mitochondrial dynamics and morphology, and interaction with other organelles. Mitochondrial protein import deficiency is linked to various diseases, including cardiovascular disease. In this review, we describe an emerging class of protein or genetic variations of components of the mitochondrial import machinery involved in heart disease. The major protein import pathways, including the presequence pathway (TIM23 pathway), the carrier pathway (TIM22 pathway), and the mitochondrial intermembrane space import and assembly machinery, related translocases, proteinases, and chaperones, are discussed here. This review highlights the importance of mitochondrial import machinery in heart disease, which deserves considerable attention, and further studies are urgently needed. Ultimately, this knowledge may be critical for the development of therapeutic strategies in heart disease.
The Rise of Populism and the Reconfiguration of the German Political Space
Authors: Olbrich Eckehard , Banisch Sven
Published: September 2021

The paper explores the notion of a reconfiguration of political space in the context of the rise of populism and its effects on the political system. We focus on Germany and the appearance of the new right wing party “Alternative for Germany” (AfD). The idea of a political space is closely connected to the ubiquitous use of spatial metaphors in political talk. In particular the idea of a “distance” between “political positions” would suggest that political actors are situated in a metric space. Using the electoral manifestos from the Manifesto project database we investigate to which extent the spatial metaphors so common in political talk can be brought to mathematical rigor. Many scholars of politics discuss the rise of the new populism in Western Europe and the United States with respect to a new political cleavage related to globalization, which is assumed to mainly affect the cultural dimension of the political space. As such, it might replace the older economic cleavage based on class divisions in defining the dominant dimension of political conflict. An explanation along these lines suggests a reconfiguration of the political space in the sense that 1) the main cleavage within the political space changes its direction from the economic axis towards the cultural axis, but 2) also the semantics of the cultural axis itself is changing towards globalization related topics. In this paper, we empirically address this reconfiguration of the political space by comparing political spaces for Germany built using topic modeling with the spaces based on the content analysis of the Manifesto project and the corresponding categories of political goals. We find that both spaces have a similar structure and that the AfD appears on a new dimension. In order to characterize this new dimension we employ a novel technique, inter-issue consistency networks (IICN) that allow to analyze the evolution of the correlations between the political positions on different issues over several elections. We find that the new dimension introduced by the AfD can be related to the split off of a new “cultural right” issue bundle from the previously existing center-right bundle.
Challenges and Pitfalls for Implementing Digital Health Solutions in Clinical Studies in Europe
Authors: Meyerheim Marcel , Burns-Gebhart Anna , Mirzaie Kasra , Garani-Papadatos Tina , Braun Yvonne , Graf Norbert
Published: September 2021

The increasing number of digital solutions developed for use in clinical health care settings is accompanied by new challenges to develop and conduct clinical studies that include eHealth technologies. Clinical study implementation plans often disregard or underestimate the necessity of additional administrative and logistic tasks required at clinical sites as well as ethical aspects to test digital solutions. Experiences made in the run-up of an observational clinical feasibility study at three international clinical sites in the framework of the MyPal project (https://mypal-project.eu/) result in recommendations to avoid delays and barriers in the planning of such prospective studies in clinical and also palliative care for increased efficiency.
Spatio-Temporal Evolution Model of the Hydraulic Transport Characteristics of Particulate Solids
Authors: Zhang Zhi , Sun Baojiang , Wang Zhiyuan , Pan Shaowei , Lou Wenqiang , Tong Shikun
Published: September 2021

The hydraulic transport of solid materials is widely used in various industrial fields owing to its high efficiency, low cost, and environmental friendliness, and it has received extensive attention. However, the violent interaction between the liquid and solid phases during transportation makes the slurry flow strongly unsteady and heterogeneous, and it is difficult to use the existing mathematical models describing the motion characteristics in the hydraulic transport of slurry because of the limitations of a single theory or experimental data basis. In this study, considering the randomness and uncertainty in the transportation of solids, a spatio-temporal evolution model of the hydraulic transport characteristics of particulate solids was established. This model is suitable for hydraulic transport in pressure pipelines and open channels, and it can be used to analyze the influence of changes in the motion and property parameters of the liquid–solid phase on the characteristics of the temporal-spatial evolution of the slurry velocity and concentration distributions. The rationality of the model was verified through laboratory experiments. Through an interaction analysis of slurry components, this work explores the influence of the transport of solids on the slurry motion and property parameters, fills the gap in the evolution mechanism of the slurry velocity and concentration distributions in existing models, and overcomes the limitation that layer-based models can only be used in pressure pipelines. Therefore, it has important guiding significance for the engineering design of particulate solid hydraulic transport.
Peripheral Hybrid CB1R and iNOS Antagonist MRI-1867 Displays Anti-Fibrotic Efficacy in Bleomycin-Induced Skin Fibrosis
Authors: Zawatsky Charles N. , Park Joshua K. , Abdalla Jasmina , Kunos George , Iyer Malliga R. , Cinar Resat
Published: September 2021

Scleroderma, or systemic sclerosis, is a multi-organ connective tissue disease resulting in fibrosis of the skin, heart, and lungs with no effective treatment. Endocannabinoids acting via cannabinoid-1 receptors (CB1R) and increased activity of inducible NO synthase (iNOS) promote tissue fibrosis including skin fibrosis, and joint targeting of these pathways may improve therapeutic efficacy. Recently, we showed that in mouse models of liver, lung and kidney fibrosis, treatment with a peripherally restricted hybrid CB1R/iNOS inhibitor (MRI-1867) yields greater anti-fibrotic efficacy than inhibiting either target alone. Here, we evaluated the therapeutic efficacy of MRI-1867 in bleomycin-induced skin fibrosis. Skin fibrosis was induced in C57BL/6J (B6) and Mdr1a/b-Bcrp triple knock-out (KO) mice by daily subcutaneous injections of bleomycin (2 IU/100 µL) for 28 days. Starting on day 15, mice were treated for 2 weeks with daily oral gavage of vehicle or MRI-1867. Skin levels of MRI-1867 and endocannabinoids were measured by mass spectrometry to assess target exposure and engagement by MRI-1867. Fibrosis was characterized histologically by dermal thickening and biochemically by hydroxyproline content. We also evaluated the potential increase of drug-efflux associated ABC transporters by bleomycin in skin fibrosis, which could affect target exposure to test compounds, as reported in bleomycin-induced lung fibrosis. Bleomycin-induced skin fibrosis was comparable in B6 and Mdr1a/b-Bcrp KO mice. However, the skin level of MRI-1867, an MDR1 substrate, was dramatically lower in B6 mice (0.023 µM) than in Mdr1a/b-Bcrp KO mice (8.8 µM) due to a bleomycin-induced increase in efflux activity of MDR1 in fibrotic skin. Furthermore, the endocannabinoids anandamide and 2-arachidonylglycerol were elevated 2-4-fold in the fibrotic vs. control skin in both mouse strains. MRI-1867 treatment attenuated bleomycin-induced established skin fibrosis and the associated increase in endocannabinoids in Mdr1a/b-Bcrp KO mice but not in B6 mice. We conclude that combined inhibition of CB1R and iNOS is an effective anti-fibrotic strategy for scleroderma. As bleomycin induces an artifact in testing antifibrotic drug candidates that are substrates of drug-efflux transporters, using Mdr1a/b-Bcrp KO mice for preclinical testing of such compounds avoids this pitfall.
Torrefaction and Pelleting of Wheat and Barley Straw for Biofuel and Energy Applications
Authors: Agu Obiora S. , Tabil Lope G. , Mupondwa Edmund , Emadi Bagher
Published: September 2021

Microwave (MW)-assisted torrefaction and pelleting could enhance biomass fuel properties and energy applications. Plastic wastes are considered as a replacement source binder in pellets to minimize their effect on the environment as pollutants. High-density polyethylene (HDPE), an extractable plastic from recycling waste, was investigated as a binder for torrefied wheat and barley straw pellets. Fuel pellet characteristics, such as durability, density, tensile strength, and water absorption, were used to evaluate the pellets produced from a single pelleting test. The results showed that the addition of HDPE as a binder significantly increased the pellet quality in terms of density (686.12–982.93 kg/m3), tensile strength (3.68 and 4.53 MPa) for wheat and barley straw, and reduced ash content of the pellet from 10.34 to 4.59% for barley straw pellet and 10.66 to 3.88% for wheat straw pellets. The higher heating value (HHV) increased with increasing biochar mix and HDPE binder blend. The highest HHV value observed for barley straw was 28.34 MJ/kg, while wheat straw was 29.78 MJ/kg. The study further indicated that MW torrefaction of biomass-biochar mix with HDPE binder reduced the moisture adsorption of wheat and barley straw pellets, which can significantly improve their storage capability in humid locations. The moisture uptake ratio for MW-torrefied barley straw pellets was 0.10–0.25 and wheat straw pellets 0.11–0.25 against a moisture uptake ratio of 1.0 for untreated biomass. MW torrefaction of wheat and barley straw with biochar and HDPE binder addition during pelleting is a promising technique to improve biomass fuel pellet properties.
Control of the Distributed Hybrid Energy Storage System Considering the Equivalent SOC
Authors: Jiang Wei , Xu Zhiqi , Yu Bin , Sun Ke , Ren Kai , Deng Yifan , Rahman Saifur
Published: September 2021

A hybrid energy storage system (HESS) consists of two or more types of energy storage components and the power electronics circuit to connect them. Therefore, the real-time capacity of this system highly depends on the state of the system and cannot be simply evaluated with traditional battery models. To tackle this challenge, an equivalent state of charge (ESOC) which reflects the remaining capacity of a HESS unit in a specific operation mode, is proposed in this paper. Furthermore, the proposed ESOC is applied to the control of the distributed HESS which contains several units with their own local targets. To optimally distribute the overall power target among these units, a sparse communication network-based hierarchical control framework is proposed. This framework considers the distributed control and optimal power distribution in the HESS from two aspects - the power output capability and the ESOC balance. Based on the primary droop control, the total power is allocated according to the maximum output capacity of each unit, and the secondary control is used to adjust the power from the perspective of ESOC balance. Therefore, each energy storage unit can be controlled to meet the local power demand of the microgrid. Simulation results based on MATLAB/Simulink verify the effectiveness of the application of the proposed equivalent SOC.
Viable Disposal of Post-Consumer Polymers in Mexico: A Review
Authors: Ángeles-Hurtado L.A. , Rodríguez-Reséndiz Juvenal , Salazar-Colores Sebastián , Torres-Salinas Hugo , Sevilla-Camacho P. Y.
Published: September 2021

Post-consumer polymers require viable actions to transfer value to the final consumer to reduce environmental impact. Worldwide, initiatives are being developed to promote the culture of recycling and thus reduce waste generation. These initiatives seek to make the work of thousands of people visible, encourage job creation, and promote businesses through incentive schemes for effective separation, collection, classification, reuse, and recycling, in the hands of consumers, collectors, and scavenges. It is necessary to emphasize that Mexico needs to develop techniques to increase the productivity of collection centers for recyclable materials and to face the challenges that recycling implies. For these reasons, the Mexican government has spoken of waste management as a national priority due to the COVID-19 pandemic, which increased urban solid waste between 3.3 % and 16.5 % in addition to what was generated under normal conditions. Also, the recycling chain provides economic income to more than 35 thousand Mexicans. Polyethylene terephthalate (PET) is an example of the most notable circular economy in Mexico because 60 % of PET bottles are recycled. Therefore, this article addresses the methods and systems in the management of urban solid waste. It focuses on post-consumer recycled plastic bottles to provide an overview of cost-effective strategies for designing and developing an affordable sorting system in Mexico from the academic field. In addition, to simplify the solution that we propose, it is recommended to combine optical techniques such as infrared spectroscopy and Raman spectroscopy with others methods that work together, such as computer vision, to develop affordable systems that address the limitations of mechanical systems.
The Evolution of Alternative Buoyancy Mechanisms in Freshwater Fish Eggs
Authors: Chen Feng , Smith Carl , Wang Yeke , He Jun , Xia Wulai , Xue Ge , Chen Jun , Xie Ping
Published: September 2021

Alternative reproductive tactics (ARTs) are behavioural, morphological, and physiological traits associated with alternative reproductive phenotypes within a population or species. ARTs are widespread in nature, and are a particular feature of teleost fishes. However, few studies have examined egg buoyancy mechanisms in the context of the evolution of ARTs in freshwater fishes. In marine fishes, egg buoyancy is achieved chiefly through hydration. While the buoyancy of freshwater fish eggs has been suggested to be determined primarily through the presence of oil droplets, the majority (60%) of freshwater pelagic eggs do not possess an oil droplet. We applied a physical model of buoyancy to understand the contributions of oil droplets and hydration to the buoyancy of pelagic freshwater fish eggs. We further used phylogenetic regression to estimate the effect of the relative size of the perivitelline space, habitat and parental care on the occurrence of oil droplets, while controlling for non-independence among species due to phylogenetic relatedness. Our analysis demonstrates that the probability of oil droplets in freshwater pelagic eggs exhibits a significant negative relationship with the size of perivitelline space, which may reflect a trade-off relating to energy allocation in contrasting habitats. We also demonstrate a positive association between the probability of oil droplets and the provision of parental care and occupancy of lentic habitats. These findings indicates the evolution of contrasting buoyancy mechanisms as novel ARTs in freshwater fishes. A theoretical model in combination with empirical analysis indicate the evolution of novel ARTs in freshwater fishes as adaptive responses to flow conditions.
Identification and Validation of Hypoxia-Related lncRNA Signature as a Prognostic Model for Hepatocellular Carcinoma
Authors: Zhou Chenghui , Zhang Huajun , Lu Liqing
Published: September 2021

Hepatocellular carcinoma (HCC) is one of the most general malignant tumors. Hypoxia is a critical clinical characteristic and acts as a significant part in the development and cancers’ prognosis. The prognostic value and biological functions of hypoxia-related lncRNAs in hepatocellular carcinoma is little known. Thus, we aim to establish a hypoxia-related lncRNA signature to predict the HCC patients’ survival. First, we extracted the hypoxia-related genes and expression of lncRNAs from the MSigDB and TCGA database, respectively. The co-expression analysis among hypoxia-related mRNAs and lncRNAs was employed to identify hypoxia-related lncRNAs. Then, comprehensive analyses of lncRNAs expression level and survival data were applied to establish the signature. We built a prognostic signature on the foundation of the three differently expressed hypoxia-related lncRNAs. Kaplan-Meier curves indicated the low-risk group is associated with better survival. The 1−, 3−, and 5 years AUC values of the signature were 0.805, 0.672 and 0.63 respectively. The test set performed consistent outcomes. A nomogram was built grounded on the risk score and clinicopathological features. GSEA showed the immune-related pathways in high-risk group, while metabolism-related pathways in low-risk group. Besides, we found this model was correlated with the clinical features, tumor immune cell infiltration, immune checkpoints, and m6A-related genes. Finally, a novel signature based on hypoxia-related lncRNAs was established and validated for predicting HCC patients’ survival and may offer some useful information for immunotherapies.
Oral Immunotherapy for Food-Allergic Children: A Pro-Con Debate
Authors: Mori Francesca , Giovannini Mattia , Barni Simona , Jiménez-Saiz Rodrigo , Munblit Daniel , Biagioni Benedetta , Liccioli Giulia , Sarti Lucrezia , Liotti Lucia , Ricci Silvia , Novembre Elio , Sahiner Umit , Baldo Ermanno , Caimmi Davide
Published: September 2021

The prevalence of food allergy has increased in recent years, especially in children. Allergen avoidance, and drugs in case of an allergic reaction, remains the standard of care in food allergy. Nevertheless, increasing attention has been given to the possibility to treat food allergy, through immunotherapy, particularly oral immunotherapy (OIT). Several OIT protocols and clinical trials have been published. Most of them focus on children allergic to milk, egg, or peanut, although recent studies developed protocols for other foods, such as wheat and different nuts. OIT efficacy in randomized controlled trials is usually evaluated as the possibility for patients to achieve desensitization through the consumption of an increasing amount of a food allergen, while the issue of a possible long-term sustained unresponsiveness has not been completely addressed. Here, we evaluated current pediatric OIT knowledge, focusing on the results of clinical trials and current guidelines. Specifically, we wanted to highlight what is known in terms of OIT efficacy and effectiveness, safety, and impact on quality of life. For each aspect, we reported the pros and the cons, inferable from published literature. In conclusion, even though many protocols, reviews and meta-analysis have been published on this topic, pediatric OIT remains a controversial therapy and no definitive generalized conclusion may be drawn so far. It should be an option provided by specialized teams, when both patients and their families are prone to adhere to the proposed protocol. Efficacy, long-term effectiveness, possible role of adjuvant therapies, risk of severe reactions including anaphylaxis or eosinophilic esophagitis, and impact on the quality of life of both children and caregivers are all aspects that should be discussed before starting OIT. Future studies are needed to provide firm clinical and scientific evidence, which should also consider patient reported outcomes.
Comprehensive Analysis of Clinical Significance, Immune Infiltration and Biological Role of m6A Regulators in Early-Stage Lung Adenocarcinoma
Authors: Zhou Bolun , Gao Shugeng
Published: September 2021

Recent publications have revealed that N6-methyladenosine (m6A) modification is critically involved in tumorigenesis and metastasis. However, the correlation of m6A modification and immune infiltration in early-stage lung adenocarcinoma (LUAD) is still uncertain. We performed NMF clustering based on 23 m6A regulators and identify three distinct m6A clusters and three m6A related genes clusters (m6A cluster-R) in early-stage LUAD. The immune infiltrating levels were calculated using CIBERSORT, MCPcounter and ssGSEA algorithms. And we established the m6A-predictive score to quantify m6A modified phenotypes and predict immunotherapeutic responses. Based on the TME characteristics, different immune profiles were also identified among three m6A gene-related clusters. And the m6A-R-C2 was related to a favorable overall survival (OS), whereas m6A-R-C3 had unfavorable overall survival. The m6A-predictive score was built according to the expression levels of m6A-related genes, and patients could be stratified into subgroups with low/high scores. Patients with high scores had poor overall survival, enhanced immune infiltration, high tumor mutation burden and increased level of somatic mutation. Besides, patients with high scores had unfavorable overall survival in the anti-PD-1 cohort, whereas the overall survival of high-score patients was better in the adoptive T cell therapy cohort. Our work highlights that m6A modification is closely related to immune infiltration in early-stage LUAD, which also contributes to the development of more effective immunotherapy strategies.
Abnormal Airway Mucus Secretion Induced by Virus Infection
Authors: Li Yao , Tang Xiao Xiao
Published: September 2021

The airway mucus barrier is a primary defensive layer at the airway surface. Mucins are the major structural components of airway mucus that protect the respiratory tract. Respiratory viruses invade human airways and often induce abnormal mucin overproduction and airway mucus secretion, leading to airway obstruction and disease. The mechanism underlying the virus-induced abnormal airway mucus secretion has not been fully studied so far. Understanding the mechanisms by which viruses induce airway mucus hypersecretion may open new avenues to treatment. In this article, we elaborate the clinical and experimental evidence that respiratory viruses cause abnormal airway mucus secretion, review the underlying mechanisms, and also discuss the current research advance as well as potential strategies to treat the abnormal airway mucus secretion caused by SARS-CoV-2.
Probiotic Interventions Alleviate Food Allergy Symptoms Correlated With Cesarean Section: A Murine Model
Authors: Jin Bi-Ying , Li Zhen , Xia Ya-Nan , Li Li-Xiang , Zhao Zi-Xiao , Li Xiao-Yu , Li Yan , Li Bing , Zhou Ru-Chen , Fu Shi-Chen , Li Shi-Yang , Li Yan-Qing
Published: September 2021

Delivery by cesarean section (CS) is linked to an increased incidence of food allergies in children and affects early gut microbiota colonization. Furthermore, emerging evidence has connected disordered intestinal microbiota to food allergies. Here, we investigated the impact of CS on a rat model for food allergy to ovalbumin (OVA). Rats delivered by CS were found to be more responsive to OVA sensitization than vaginally born ones, displaying a greater reduction in rectal temperature upon challenge, worse diarrhea, and higher levels of OVA-specific antibodies and histamine. 16S rRNA sequencing of feces revealed reduced levels of Lactobacillus and Bifidobacterium in the CS rats. Preventative supplementation with a probiotic combination containing Lactobacillus and Bifidobacterium could protect CS rats against an allergic response to OVA, indicating that the microbiota dysbiosis contributes to CS-related response. Additionally, probiotic intervention early in life might help to rebuild aberrant Th2 responses and tight junction proteins, both of which have been linked to CS-related high allergic reactions. Taken together, this study shows that disordered intestinal microbiota plays an essential role in the pathogenesis of food allergy mediated by CS. More importantly, interventions that modulate the microbiota composition in early life are therapeutically relevant for CS-related food allergies.
Beyond Immunity: Underappreciated Functions of Intestinal Macrophages
Authors: Chiaranunt Pailin , Tai Siu Ling , Ngai Louis , Mortha Arthur
Published: September 2021

The gastrointestinal tract hosts the largest compartment of macrophages in the body, where they serve as mediators of host defense and immunity. Seeded in the complex tissue-environment of the gut, an array of both hematopoietic and non-hematopoietic cells forms their immediate neighborhood. Emerging data demonstrate that the functional diversity of intestinal macrophages reaches beyond classical immunity and includes underappreciated non-immune functions. In this review, we discuss recent advances in research on intestinal macrophage heterogeneity, with a particular focus on how non-immune functions of macrophages impact tissue homeostasis and function. We delve into the strategic localization of distinct gut macrophage populations, describe the potential factors that regulate their identity and functional heterogeneity within these locations, and provide open questions that we hope will inspire research dedicated to elucidating a holistic view on macrophage-tissue cell interactions in the body’s largest mucosal organ.