bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Plasma Extracellular Vesicles in Remote Ischemic Conditioning and Exercise-Induced Ischemic Tolerance
Authors: Gu Tingting , Just Jesper , Stenz Katrine Tang , Yan Yan , Sieljacks Peter , Wang Jakob , Groennebaek Thomas Skjaerlund , Jakobsgaard Jesper Emil , Rindom Emil , Herskind Jon , Gravholt Anders , Lassen Thomas Ravn , Jørgensen Mathias , Bæk Rikke , Gutiérrez-Jiménez Eugenio , Iversen Nina Kerting , Rasmussen Peter Mondrup , Nyengaard Jens Randel , Jørgensen Malene Møller , de Paoli Frank , Bøtker Hans Erik , Kjems Jørgen , Vissing Kristian , Drasbek Kim Ryun
Published: March 2022

Ischemic conditioning and exercise have been suggested for protecting against brain ischemia-reperfusion injury. However, the endogenous protective mechanisms stimulated by these interventions remain unclear. Here, in a comprehensive translational study, we investigated the protective role of extracellular vesicles (EVs) released after remote ischemic conditioning (RIC), blood flow restricted resistance exercise (BFRRE), or high-load resistance exercise (HLRE). Blood samples were collected from human participants before and at serial time points after intervention. RIC and BFRRE plasma EVs released early after stimulation improved viability of endothelial cells subjected to oxygen-glucose deprivation. Furthermore, post-RIC EVs accumulated in the ischemic area of a stroke mouse model, and a mean decrease in infarct volume was observed for post-RIC EVs, although not reaching statistical significance. Thus, circulating EVs induced by RIC and BFRRE can mediate protection, but the in vivo and translational effects of conditioned EVs require further experimental verification.
Cannabinoids: Therapeutic Use in Clinical Practice
Authors: Pagano Cristina , Navarra Giovanna , Coppola Laura , Avilia Giorgio , Bifulco Maurizio , Laezza Chiara
Published: March 2022

Medical case reports suggest that cannabinoids extracted from Cannabis sativa have therapeutic effects; however, the therapeutic employment is limited due to the psychotropic effect of its major component, Δ9-tetrahydrocannabinol (THC). The new scientific discoveries related to the endocannabinoid system, including new receptors, ligands, and mediators, allowed the development of new therapeutic targets for the treatment of several pathological disorders minimizing the undesirable psychotropic effects of some constituents of this plant. Today, FDA-approved drugs, such as nabiximols (a mixture of THC and non-psychoactive cannabidiol (CBD)), are employed in alleviating pain and spasticity in multiple sclerosis. Dronabinol and nabilone are used for the treatment of chemotherapy-induced nausea and vomiting in cancer patients. Dronabinol was approved for the treatment of anorexia in patients with AIDS (acquired immune deficiency syndrome). In this review, we highlighted the potential therapeutic efficacy of natural and synthetic cannabinoids and their clinical relevance in cancer, neurodegenerative and dermatological diseases, and viral infections.
Structural Plasticity of the Hippocampus in Neurodegenerative Diseases
Authors: Weerasinghe-Mudiyanselage Poornima D. E. , Ang Mary Jasmin , Kang Sohi , Kim Joong-Sun , Moon Changjong
Published: March 2022

Neuroplasticity is the capacity of neural networks in the brain to alter through development and rearrangement. It can be classified as structural and functional plasticity. The hippocampus is more susceptible to neuroplasticity as compared to other brain regions. Structural modifications in the hippocampus underpin several neurodegenerative diseases that exhibit cognitive and emotional dysregulation. This article reviews the findings of several preclinical and clinical studies about the role of structural plasticity in the hippocampus in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis. In this study, literature was surveyed using Google Scholar, PubMed, Web of Science, and Scopus, to review the mechanisms that underlie the alterations in the structural plasticity of the hippocampus in neurodegenerative diseases. This review summarizes the role of structural plasticity in the hippocampus for the etiopathogenesis of neurodegenerative diseases and identifies the current focus and gaps in knowledge about hippocampal dysfunctions. Ultimately, this information will be useful to propel future mechanistic and therapeutic research in neurodegenerative diseases.
Bone Healing Materials in the Treatment of Recalcitrant Nonunions and Bone Defects
Authors: Rodríguez-Merchán Emérito Carlos
Published: March 2022

The usual treatment for bone defects and recalcitrant nonunions is an autogenous bone graft. However, due to the limitations in obtaining autogenous bone grafts and the morbidity associated with their procurement, various bone healing materials have been developed in recent years. The three main treatment strategies for bone defects and recalcitrant nonunions are synthetic bone graft substitutes (BGS), BGS combined with bioactive molecules, and BGS and stem cells (cell-based constructs). Regarding BGS, numerous biomaterials have been developed to prepare bone tissue engineering scaffolds, including biometals (titanium, iron, magnesium, zinc), bioceramics (hydroxyapatite (HA)), tricalcium phosphate (TCP), biopolymers (collagen, polylactic acid (PLA), polycaprolactone (PCL)), and biocomposites (HA/MONs@miR-34a composite coating, Bioglass (BG)-based ABVF-BG (antibiotic-releasing bone void filling) putty). Bone tissue engineering scaffolds are temporary implants that promote tissue ingrowth and new bone regeneration. They have been developed to improve bone healing through appropriate designs in terms of geometric, mechanical, and biological performance. Concerning BGS combined with bioactive molecules, one of the most potent osteoinductive growth factors is bone morphogenetic proteins (BMPs). In recent years, several natural (collagen, fibrin, chitosan, hyaluronic acid, gelatin, and alginate) and synthetic polymers (polylactic acid, polyglycolic acid, polylactic-coglycolide, poly(e-caprolactone) (PCL), poly-p-dioxanone, and copolymers consisting of glycolide/trimethylene carbonate) have been investigated as potential support materials for bone tissue engineering. Regarding BGS and stem cells (cell-based constructs), the main strategies are bone marrow stromal cells, adipose-derived mesenchymal cells, periosteum-derived stem cells, and 3D bioprinting of hydrogels and cells or bioactive molecules. Currently, significant research is being performed on the biological treatment of recalcitrant nonunions and bone defects, although its use is still far from being generalized. Further research is needed to investigate the efficacy of biological treatments to solve recalcitrant nonunions and bone defects.
Histone Extraction from Human Articular Cartilage for the Study of Epigenetic Regulation in Osteoarthritis
Authors: Núñez-Carro Carmen , Blanco-Blanco Margarita , Montoya Tatiana , Villagrán-Andrade Karla M. , Hermida-Gómez Tamara , Blanco Francisco J. , de Andrés María C.
Published: March 2022

Osteoarthritis (OA) is a chronic disease that affects articular cartilage, causing its degeneration. Although OA is one of the most prevalent pathologies globally, there are no definitive treatments available. Recently, research has focused on elucidating the complex interplay that takes place between inflammatory processes and epigenetic regulation, showing that histone post-translational modifications (PTMs) can exert a pronounced effect on the expression of OA-related genes. OA chondrocytes enhance the production of interleukin 1β (IL-1β) and interleukin 8 (IL-8), which are epigenetically regulated. These cytokines upregulate the synthesis of matrix metalloproteinases (MMPs) and aggrecanases, which promote the extracellular matrix (ECM) destruction. This motivates the study of histone PTMs to investigate the epigenetic regulation of proinflammatory molecules, but the absence of specific protocols to extract histones from human articular cartilage has complicated this task. The lack of effective methods can be explained by the structural complexity and low cellularity of this tissue, which are responsible for the biomechanical properties that allow the movement of the joint but also complicate histone isolation. Here, we provide a histone extraction procedure specifically adapted for cryopreserved human articular cartilage that can be useful to understand epigenetic regulation in OA and accelerate the search for novel strategies.
Versatile Oral Insulin Delivery Nanosystems: From Materials to Nanostructures
Authors: Wang Mengjie , Wang Chunxin , Ren Shuaikai , Pan Junqian , Wang Yan , Shen Yue , Zeng Zhanghua , Cui Haixin , Zhao Xiang
Published: March 2022

Diabetes is a chronic metabolic disease characterized by lack of insulin in the body leading to failure of blood glucose regulation. Diabetes patients usually need frequent insulin injections to maintain normal blood glucose levels, which is a painful administration manner. Long-term drug injection brings great physical and psychological burden to diabetic patients. In order to improve the adaptability of patients to use insulin and reduce the pain caused by injection, the development of oral insulin formulations is currently a hot and difficult topic in the field of medicine and pharmacy. Thus, oral insulin delivery is a promising and convenient administration method to relieve the patients. However, insulin as a peptide drug is prone to be degraded by digestive enzymes. In addition, insulin has strong hydrophilicity and large molecular weight and extremely low oral bioavailability. To solve these problems in clinical practice, the oral insulin delivery nanosystems were designed and constructed by rational combination of various nanomaterials and nanotechnology. Such oral nanosystems have the advantages of strong adaptability, small size, convenient processing, long-lasting pharmaceutical activity, and drug controlled-release, so it can effectively improve the oral bioavailability and efficacy of insulin. This review summarizes the basic principles and recent progress in oral delivery nanosystems for insulin, including physiological absorption barrier of oral insulin and the development of materials to nanostructures for oral insulin delivery nanosystems.
The Expression of Active CD11b Monocytes in Blood and Disease Progression in Amyotrophic Lateral Sclerosis
Authors: Yildiz Ozlem , Schroth Johannes , Lombardi Vittoria , Pucino Valentina , Bobeva Yoana , Yip Ping , Schmierer Klaus , Mauro Claudio , Tree Timothy , Henson Sian , Malaspina Andrea
Published: March 2022

Monocytes expressing the inflammation suppressing active CD11b, a beta2 integrin, may regulate neuroinflammation and modify clinical outcomes in amyotrophic lateral sclerosis (ALS). In this single site, retrospective study, peripheral blood mononuclear cells from 38 individuals living with ALS and 20 non-neurological controls (NNC) were investigated using flow cytometry to study active CD11b integrin classical (CM), intermediate (IM) and non-classical (NCM) monocytes during ALS progression. Seventeen ALS participants were sampled at the baseline (V1) and at two additional time points (V2 and V3) for longitudinal analysis. Active CD11b+ CM frequencies increased steeply between the baseline and V3 (ANOVA repeated measurement, p < 0.001), and the V2/V1 ratio negatively correlated with the disease progression rate, similar to higher frequencies of active CD11b+ NCM at the baseline (R = −0.6567; p = 0.0031 and R = 0.3862; p = 0.0168, respectively). CD11b NCM, clinical covariates and neurofilament light-chain plasma concentration at the baseline predicted shorter survival in a multivariable and univariate analysis (CD11b NCM—HR: 1.05, CI: 1.01–1.11, p = 0.013. Log rank: above median: 43 months and below median: 21.22 months; p = 0.0022). Blood samples with the highest frequencies of active CD11b+ IM and NCM contained the lowest concentrations of soluble CD11b. Our preliminary data suggest that the levels of active CD11b+ monocytes and NCM in the blood predict different clinical outcomes in ALS.
CD8+ T Cell Senescence: Lights and Shadows in Viral Infections, Autoimmune Disorders and Cancer
Authors: Tedeschi Valentina , Paldino Giorgia , Kunkl Martina , Paroli Marino , Sorrentino Rosa , Tuosto Loretta , Fiorillo Maria Teresa
Published: March 2022

CD8+ T lymphocytes are a heterogeneous class of cells that play a crucial role in the adaptive immune response against pathogens and cancer. During their lifetime, they acquire cytotoxic functions to ensure the clearance of infected or transformed cells and, in addition, they turn into memory lymphocytes, thus providing a long-term protection. During ageing, the thymic involution causes a reduction of circulating T cells and an enrichment of memory cells, partially explaining the lowering of the response towards novel antigens with implications in vaccine efficacy. Moreover, the persistent stimulation by several antigens throughout life favors the switching of CD8+ T cells towards a senescent phenotype contributing to a low-grade inflammation that is a major component of several ageing-related diseases. In genetically predisposed young people, an immunological stress caused by viral infections (e.g., HIV, CMV, SARS-CoV-2), autoimmune disorders or tumor microenvironment (TME) could mimic the ageing status with the consequent acceleration of T cell senescence. This, in turn, exacerbates the inflamed conditions with dramatic effects on the clinical progression of the disease. A better characterization of the phenotype as well as the functions of senescent CD8+ T cells can be pivotal to prevent age-related diseases, to improve vaccine strategies and, possibly, immunotherapies in autoimmune diseases and cancer.
The Pathogen-Induced MATE Gene TaPIMA1 Is Required for Defense Responses to Rhizoctonia cerealis in Wheat
Authors: Su Qiang , Rong Wei , Zhang Zengyan
Published: March 2022

The sharp eyespot, mainly caused by the soil-borne fungus Rhizoctonia cerealis, is a devastating disease endangering production of wheat (Triticum aestivum). Multi-Antimicrobial Extrusion (MATE) family genes are widely distributed in plant species, but little is known about MATE functions in wheat disease resistance. In this study, we identified TaPIMA1, a pathogen-induced MATE gene in wheat, from RNA-seq data. TaPIMA1 expression was induced by Rhizoctonia cerealis and was higher in sharp eyespot-resistant wheat genotypes than in susceptible wheat genotypes. Molecular biology assays showed that TaPIMA1 belonged to the MATE family, and the expressed protein could distribute in the cytoplasm and plasma membrane. Virus-Induced Gene Silencing plus disease assessment indicated that knock-down of TaPIMA1 impaired resistance of wheat to sharp eyespot and down-regulated the expression of defense genes (Defensin, PR10, PR1.2, and Chitinase3). Furthermore, TaPIMA1 was rapidly induced by exogenous H2O2 and jasmonate (JA) treatments, which also promoted the expression of pathogenesis-related genes. These results suggested that TaPIMA1 might positively regulate the defense against R. cerealis by up-regulating the expression of defense-associated genes in H2O2 and JA signal pathways. This study sheds light on the role of MATE transporter in wheat defense to Rhizoctonia cerealis and provides a potential gene for improving wheat resistance against sharp eyespot.
Effects of Cryopreservation on Sperm with Cryodiluent in Viviparous Black Rockfish (Sebastes schlegelii)
Authors: Niu Jingjing , Wang Xuliang , Liu Pingping , Liu Huaxiang , Li Rui , Li Ziyi , He Yan , Qi Jie
Published: March 2022

Black rockfish is an economically important fish in East Asia. Little mention has been paid to the sperm cryopreservation in black rockfish. In this study, the optimal cryodiluent was selected from 48 combinations by detecting various sperm parameters. Transcriptome and methylome analysis were further performed to explore the molecular mechanism of inevitable cryoinjuries. The results showed that cryopreservation had negative effects on the viability, DNA integrity, mitochondrial activity, total ATPase and LDH of sperm even with optimal cryodiluent (FBS + 15% Gly). Transcriptome and methylome analysis revealed that the expression of 179 genes and methylation of 1266 genes were affected by cryopreservation. These genes were enriched in GO terms of death, G-protein coupled receptor signaling pathway, response to external stimulus and KEGG pathways of phospholipase D signaling pathway and xenobiotic and carbohydrate metabolism pathways. The role of PIK3CA and CCNA2 were highlighted in the protein-protein interaction network, and the sperm quality-related imprinted gene mest was identified among the 7 overlapping genes between transcriptome and methylome. Overall, the cryodiluent for black rockfish sperm was optimized, providing a feasible method for cryopreservation. The transcriptome and methylome data further demonstrated the underlying molecular mechanisms of cryoinjuries, proving clues for improvement of cryopreservation method of black rockfish.
The Molecular Bases of the Interaction between a Saponin from the Roots of Gypsophila paniculata L. and Model Lipid Membranes
Authors: Korchowiec Beata , Korchowiec Jacek , Kwiecińska Klaudia , Gevrenova Reneta , Bouguet-Bonnet Sabine , Deng Cheng , Henry Max , Rogalska Ewa
Published: March 2022

In view of the possible medical applications of saponins, the molecular structure of a GOTCAB saponin from the roots of Gypsophila paniculata L. was determined by NMR. The biological activity of saponins may depend on the interaction with cell membranes. To obtain more insight in the mechanism of membrane-related saponin function, an experimental and theoretical study was conducted. Ternary lipid systems composed of sphingomyelin, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, and cholesterol were used as models of mammalian cell membranes. The membrane–saponin interaction was studied experimentally by monitoring surface pressure in the monomolecular films formed at the air–aqueous subphase interface. The behavior of GOTCAB saponin in a water box and model monolayer systems was characterized by molecular dynamics simulations. The results obtained showed that, in the systems used, cholesterol had a decisive effect on the interaction between GOTCAB and phosphocholine or sphingomyelin as well as on its location within the lipid film.
Therapeutic Treatment of Superoxide Dismutase 1 (G93A) Amyotrophic Lateral Sclerosis Model Mice with Medical Ozone Decelerates Trigeminal Motor Neuron Degeneration, Attenuates Microglial Proliferation, and Preserves Monocyte Levels in Mesenteric Lymph Nodes
Authors: Bette Michael , Cors Eileen , Kresse Carolin , Schütz Burkhard
Published: March 2022

Amyotrophic lateral sclerosis (ALS) is an incurable and lethal neurodegenerative disease in which progressive motor neuron loss and associated inflammation represent major pathology hallmarks. Both the prevention of neuronal loss and neuro-destructive inflammation are still unmet challenges. Medical ozone, an ozonized oxygen mixture (O3/O2), has been shown to elicit profound immunomodulatory effects in peripheral organs, and beneficial effects in the aging brain. We investigated, in a preclinical drug testing approach, the therapeutic potential of a five-day O3/O2i.p. treatment regime at the beginning of the symptomatic disease phase in the superoxide dismutase (SOD1G93A) ALS mouse model. Clinical assessment of SOD1G93A mice revealed no benefit of medical ozone treatment over sham with respect to gross body weight, motor performance, disease duration, or survival. In the brainstem of end stage SOD1G93A mice, however, neurodegeneration was found decelerated, and SOD1-related vacuolization was reduced in the motor trigeminal nucleus in the O3/O2 treatment group when compared to sham-treated mice. In addition, microglia proliferation was less pronounced in the brainstem, while the hypertrophy of astroglia remained largely unaffected. Finally, monocyte numbers were reduced in the blood, spleen, and mesenteric lymph nodes at postnatal day 60 in SOD1G93A mice. A further decrease in monocyte numbers seen in mesenteric lymph nodes from sham-treated SOD1G93A mice at an advanced disease stage, however, was prevented by medical ozone treatment. Collectively, our study revealed a select neuroprotective and possibly anti-inflammatory capacity for medical ozone when applied as a therapeutic agent in SOD1G93A ALS mice.
Integration of Light and Auxin Signaling in Shade Plants: From Mechanisms to Opportunities in Urban Agriculture
Authors: Xie Xiulan , Cheng Hao , Hou Chenyang , Ren Maozhi
Published: March 2022

With intensification of urbanization throughout the world, food security is being threatened by the population surge, frequent occurrence of extreme climate events, limited area of available cultivated land, insufficient utilization of urban space, and other factors. Determining the means by which high-yielding and high-quality crops can be produced in a limited space is an urgent priority for plant scientists. Dense planting, vertical production, and indoor cultivation are effective ways to make full use of space and improve the crop yield. The results of physiological and molecular analyses of the model plant species Arabidopsis thaliana have shown that the plant response to shade is the key to regulating the plant response to changes in light intensity and quality by integrating light and auxin signals. In this study, we have summarized the major molecular mechanisms of shade avoidance and shade tolerance in plants. In addition, the biotechnological strategies of enhancing plant shade tolerance are discussed. More importantly, cultivating crop varieties with strong shade tolerance could provide effective strategies for dense planting, vertical production, and indoor cultivation in urban agriculture in the future.
Combination Effect of Cilengitide with Erlotinib on TGF-β1-Induced Epithelial-to-Mesenchymal Transition in Human Non-Small Cell Lung Cancer Cells
Authors: Jeong Jisu , Kim Jiyeon
Published: March 2022

The epithelial-to-mesenchymal transition (EMT) is important for morphogenesis during development and is mainly induced by transforming growth factor (TGF)-β. In lung cancer, EMT is characterized by the transformation of cancer cells into a mobile, invasive form that can transit to other organs. Here, using a non–small cell lung cancer (NSCLC) cell line, we evaluated the EMT-related effects of the epidermal growth factor receptor inhibitor erlotinib alone and in combination with cilengitide, a cyclic RGD-based integrin antagonist. Erlotinib showed anti-proliferative and inhibitory effects against the TGF-β1–induced EMT phenotype in NSCLC cells. Compared with erlotinib alone, combination treatment with cilengitide led to an enhanced inhibitory effect on TGF-β1–induced expression of mesenchymal markers and invasion in non–small cell lung cancer A549 cells. These results suggest that cilengitide could improve anticancer drug efficacy and contribute to improved treatment strategies to inhibit and prevent EMT-based cancer progression.
Recycling and Reshaping—E3 Ligases and DUBs in the Initiation of T Cell Receptor-Mediated Signaling and Response
Authors: Cammann Clemens , Israel Nicole , Slevogt Hortense , Seifert Ulrike
Published: March 2022

T cell activation plays a central role in supporting and shaping the immune response. The induction of a functional adaptive immune response requires the control of signaling processes downstream of the T cell receptor (TCR). In this regard, protein phosphorylation and dephosphorylation have been extensively studied. In the past decades, further checkpoints of activation have been identified. These are E3 ligases catalyzing the transfer of ubiquitin or ubiquitin-like proteins to protein substrates, as well as specific peptidases to counteract this reaction, such as deubiquitinating enzymes (DUBs). These posttranslational modifications can critically influence protein interactions by targeting proteins for degradation by proteasomes or mediating the complex formation required for active TCR signaling. Thus, the basic aspects of T cell development and differentiation are controlled by defining, e.g., the threshold of activation in positive and negative selection in the thymus. Furthermore, an emerging role of ubiquitination in peripheral T cell tolerance has been described. Changes in the function and abundance of certain E3 ligases or DUBs involved in T cell homeostasis are associated with the development of autoimmune diseases. This review summarizes the current knowledge of E3 enzymes and their target proteins regulating T cell signaling processes and discusses new approaches for therapeutic intervention.
Modification of Ischemia/Reperfusion-Induced Alterations in Subcellular Organelles by Ischemic Preconditioning
Authors: Tappia Paramjit S. , Shah Anureet K. , Ramjiawan Bram , Dhalla Naranjan S.
Published: March 2022

It is now well established that ischemia/reperfusion (I/R) injury is associated with the compromised recovery of cardiac contractile function. Such an adverse effect of I/R injury in the heart is attributed to the development of oxidative stress and intracellular Ca2+-overload, which are known to induce remodeling of subcellular organelles such as sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils. However, repeated episodes of brief periods of ischemia followed by reperfusion or ischemic preconditioning (IP) have been shown to improve cardiac function and exert cardioprotective actions against the adverse effects of prolonged I/R injury. This protective action of IP in attenuating myocardial damage and subcellular remodeling is likely to be due to marked reductions in the occurrence of oxidative stress and intracellular Ca2+-overload in cardiomyocytes. In addition, the beneficial actions of IP have been attributed to the depression of proteolytic activities and inflammatory levels of cytokines as well as the activation of the nuclear factor erythroid factor 2-mediated signal transduction pathway. Accordingly, this review is intended to describe some of the changes in subcellular organelles, which are induced in cardiomyocytes by I/R for the occurrence of oxidative stress and intracellular Ca2+-overload and highlight some of the mechanisms for explaining the cardioprotective effects of IP.
Clozapine Increases Nestin Concentration in the Adult Male Rat Hippocampus: A Preliminary Study
Authors: Kayir Hakan , Jenkins Bryan W. , Alural Begüm , Khokhar Jibran Y.
Published: March 2022

Patients with schizophrenia, and rodent models of the disease, both exhibit suppressed neurogenesis, with antipsychotics possibly enhancing neurogenesis in pre-clinical models. Nestin, a cytoskeletal protein, is implicated in neuronal differentiation and adult neurogenesis. We hypothesized that schizophrenia pathogenesis involves nestin downregulation; however, few studies have related nestin to schizophrenia. We assessed nestin protein concentration, prepulse inhibition (PPI), and social interaction in the MK-801 model of schizophrenia, with or without antipsychotic (clozapine) treatment. Adult male Sprague–Dawley rats were intraperitoneally administered saline or MK-801 (0.1 mg/kg) to produce a schizophrenia-like phenotype, with concomitant subcutaneous injections of vehicle or clozapine (5 mg/kg). PPI was assessed on days 1, 8, and 15, and social interaction was assessed on day 4. Hippocampus tissue samples were dissected for Western blotting of nestin concentration. MK-801 alone did not alter nestin concentration, while clozapine alone enhanced hippocampal nestin concentration; this effect was not apparent in animals with MK-801 and clozapine co-administration. MK-801 also produced schizophrenia-like PPI disruptions, some of which were reversed by clozapine. Social interaction deficits were not detected in this model. This is the first report of clozapine-induced enhancements of hippocampal nestin concentration that might be mediated by NMDA receptors. Future studies will explore the impact of neurodevelopmental nestin concentration on symptom onset and antipsychotic treatment.
Transcriptional and Distributional Profiling of Microglia in Retinal Angiomatous Proliferation
Authors: Schlecht Anja , Wolf Julian , Boneva Stefaniya , Prinz Gabriele , Braunger Barbara M. , Wieghofer Peter , Agostini Hansjürgen , Schlunck Günther , Lange Clemens
Published: March 2022

Macular neovascularization type 3, formerly known as retinal angiomatous proliferation (RAP), is a hallmark of age-related macular degeneration and is associated with an accumulation of myeloid cells, such as microglia (MG) and infiltrating blood-derived macrophages (MAC). However, the contribution of MG and MAC to the myeloid cell pool at RAP sites and their exact functions remain unknown. In this study, we combined a microglia-specific reporter mouse line with a mouse model for RAP to identify the contribution of MG and MAC to myeloid cell accumulation at RAP and determined the transcriptional profile of MG using RNA sequencing. We found that MG are the most abundant myeloid cell population around RAP, whereas MAC are rarely, if ever, associated with late stages of RAP. RNA sequencing of RAP-associated MG showed that differentially expressed genes mainly contribute to immune-associated processes, including chemotaxis and migration in early RAP and proliferative capacity in late RAP, which was confirmed by immunohistochemistry. Interestingly, MG upregulated only a few angiomodulatory factors, suggesting a rather low angiogenic potential. In summary, we showed that MG are the dominant myeloid cell population at RAP sites. Moreover, MG significantly altered their transcriptional profile during RAP formation, activating immune-associated processes and exhibiting enhanced proliferation, however, without showing substantial upregulation of angiomodulatory factors.
Glucagon-like Peptide-1 Receptor Agonists in the Management of Type 2 Diabetes Mellitus and Obesity: The Impact of Pharmacological Properties and Genetic Factors
Authors: Klen Jasna , Dolžan Vita
Published: March 2022

Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of antihyperglycemic drugs that enhance appropriate pancreatic β-cell secretion, pancreatic α-cell (glucagon) suppression, decrease liver glucose production, increase satiety through their action on the central nervous system, slow gastric emptying time, and increase insulin action on peripheral tissue. They are effective in the management of type 2 diabetes mellitus and have a favorable effect on weight loss. Their cardiovascular and renal safety has been extensively investigated and confirmed in many clinical trials. Recently, evidence has shown that in addition to the existing approaches for the treatment of obesity, semaglutide in higher doses promotes weight loss and can be used as a drug to treat obesity. However, some T2DM and obese patients do not achieve a desired therapeutic effect of GLP-1 receptor agonists. This could be due to the multifactorial etiologies of T2DM and obesity, but genetic variability in the GLP-1 receptor or signaling pathways also needs to be considered in non-responders to GLP-1 receptor agonists. This review focuses on the pharmacological, clinical, and genetic factors that may influence the response to GLP-1 receptor agonists in the treatment of type 2 diabetes mellitus and obesity.
Pharmacologic Ascorbic Acid as Early Therapy for Hospitalized Patients with COVID-19: A Randomized Clinical Trial
Authors: Coppock Dagan , Violet Pierre-Christian , Vasquez Gustavo , Belden Katherine , Foster Michael , Mullin Bret , Magee Devon , Mikell Isabelle , Shah Lokesh , Powers Victoria , Curcio Brian , Monti Daniel , Levine Mark
Published: March 2022

Despite the widespread availability of effective vaccines, new cases of infection with severe acute respiratory syndrome coronavirus-2, the cause of coronavirus disease 2019 (COVID-19), remain a concern in the settings of vaccine hesitancy and vaccine breakthrough. In this randomized, controlled, phase 2 trial, we hypothesized that high-dose ascorbic acid delivered intravenously to achieve pharmacologic concentrations may target the high viral phase of COVID-19 and thus improve early clinical outcomes. Sixty-six patients admitted with COVID-19 and requiring supplemental oxygen were randomized to receive either escalating doses of intravenous ascorbic acid plus standard of care or standard of care alone. The demographic and clinical characteristics were well-balanced between the two study arms. The primary outcome evaluated in this study was clinical improvement at 72 h after randomization. While the primary outcome was not achieved, point estimates for the composite outcome and its individual components of decreased use of supplemental oxygen, decreased use of bronchodilators, and the time to discharge were all favorable for the treatment arm. Possible favorable effects of ascorbic acid were most apparent during the first 72 h of hospitalization, although these effects disappeared over the course of the entire hospitalization. Future larger trials of intravenous ascorbic acid should be based on our current understanding of COVID-19 with a focus on the potential early benefits of ascorbic in hospitalized patients.
On the Transient Effects at the Beginning of 3D Elastic-Plastic Rolling Contacts for a Circular Point Contact Considering Isotropic Hardening
Authors: Juettner Michael , Bartz Marcel , Tremmel Stephan , Wartzack Sandro
Published: March 2022

In a three-dimensional transient simulation of the elastic–plastic rolling contact, transient effects can be observed at the beginning of the rolling until a stationary state is reached after rolling for a length of several times the contact radius. In most cases, the steady-state regime is in focus of scientific investigations, whereas the transient effects are hardly considered. In the present work, those transient effects at the beginning of a frictionless rolling contact of a rigid sphere on an elastic–plastic plane are studied in detail. The analysis is limited to isotropic strain hardening. In particular, the changes of the contact pressure during rolling, as well as the plastic strain state and plastic deformations remaining after rolling are investigated. This is intended to get to the bottom of existing explanatory approaches from literature, which are based on the change in conformity. Beyond that, a more profound explanation of the transient effects is developed by identifying existing correlations.
Numerical Simulation of Tailings Flow from Dam Failure over Complex Terrain
Authors: Yang Yi , Zhou Xiaowen , Chen Xiaoyu , Xie Chao
Published: March 2022

A tailings dam failure can lead to disastrous impacts on people’s livelihood and the surrounding ecological environment. Due to interactions among water, tailings and ground, the mechanism of a tailings flow is more complicated than that of a flood flow. In this paper, the tailings flow is regarded as a homogeneous and incompressible non-Newtonian fluid. Its rheological properties were studied through rheological tests conforming to the Bingham model. The rheological parameters were further used in a Computational Fluid Dynamics (CFD) simulation over complex terrain to explore the tailings flow characteristics. The method was validated with experimental results of a non-Newtonian dam-break flow from literature. The flow characteristics, including flow velocity, runout distance, inundation area and depth, were analyzed in the case of the Dagangding tailings dam. The results showed that the downstream railway and village would not be affected in a conservative scenario. Finally, the effects of two measures for preventing tailings flow hazards were discussed. Setting the check dam and planting grasses and trees can effectively mitigate the damage of tailings flow.
Radiation-Induced Sharpening in Cr-Coated Zirconium Alloy
Authors: Ribis Joël , Wu Alexia , Guillou Raphaëlle , Brachet Jean-Christophe , Baumier Cédric , Gentils Aurélie , Loyer-Prost Marie
Published: March 2022

To improve the safety of nuclear power plants, a Cr protective layer is deposited on zirconium alloys to enhance oxidation resistance of the nuclear fuel cladding during both in-service and hypothetical accidental transients at High Temperature (HT) in Light Water Reactors. The formation of the Cr2O3 film on the coating surface considerably helps in reducing the oxidation kinetics of the zirconium alloy, especially during hypothetic Loss of Coolant Accident (LOCA). However, if the Cr coating is successful to increase the oxidation resistance at HT of the zirconium substrate, for in-service conditions, under neutron irradiation, Cr desquamation has to be avoided to guarantee a safe use of the Cr-coated zirconium alloys. Therefore, the adhesion properties have to be maintained despite the structural defects created by sustained neutron irradiation in the reactor environment. This paper proposes to study the behavior of the Zircaloy-Cr interface of a first generation Cr-coated material during a specific in situ ion irradiation. As deposited, the Cr-coated sample presents a f.c.c. C15 Laves-type intermetallic phase at the interface with off-stoichiometric composition. After irradiation and for the specific conditions applied, this interfacial phase has significantly dissolved. Energy Dispersion Spectroscopy revealed that the dissolution was accompanied by a counterintuitive “sharpening” effect.
Preparation and Properties of Pea Starch/ε-Polylysine Composite Films
Authors: Yu Zuolong , Gong Deping , Han Chao , Wei Yunxiao , Fu Changchun , Xu Xuejiao , Lu Youri
Published: March 2022

The composite films comprising pea starch (St) and ε-polylysine (PL) as the matrix and glycerol and sodium alginate as the plasticizers were investigated. The rheological properties, mechanical properties, Fourier transformed infrared spectroscopy, water vapor permeability (WVP), oil permeability, microstructure, thermogravimetry (TGA), and antimicrobial properties of the composite films were analyzed. The properties of the composite films with different mass ratios of St/PL varied significantly. First, the five film solutions were different pseudoplastic fluids. Additionally, as the mass ratio of PL increased, the tensile strength of the blends decreased from 9.49 to 0.14 MPa, the fracture elongation increased from 38.41 to 174.03%, the WVP increased, and the oil resistance decreased substantially. The films with a broad range of St/PL ratios were highly soluble; however, the solubility of the film with a St/PL ratio of 2:8 was reduced. Lastly, the inhibition of E. coli, B.subtilis, and yeast by the films increased with increasing mass ratios of PL, and the inhibition of B.subtilis was the strongest.
Mortar Bond Strength: A Brief Literature Review, Tests for Analysis, New Research Needs and Initial Experiments
Authors: Salustio Janaina , Torres Sandro M. , Melo Anne C. , Silva Ângelo J. Costa e , Azevedo António C. , Tavares Jennef C. , Leal Matheus S. , Delgado João M. P. Q.
Published: March 2022

Despite technological advances in the production processes of the materials for ceramic façade coatings, the problems of detachments are still frequent. Therefore, this work aims to investigate, through a literature review, the existing gaps related to the adhesion ability of adhesive mortars, identifying new research needs that can better explain the behavior of the material. In addition, an experimental procedure was developed to evaluate the mechanical capacity of adhesive mortars when subjected to cyclic stresses. Dynamic stress measurements are presented for several blocks of mortar and on similar blocks but with a slot drilled prior to measurements (intended to represent failure). From these data we calculated values of stress energy, elastic energy, and dissipated energy. The experimental results showed that the energy involved in the test process accompanied the load values and current stress values. The mortar samples with the previous failure absorbed and dissipated less energy than mortars without failure, showing that materials that have less energy to dissipate, are materials that have developed less capacity to adhere, that is, to keep their parts together.
Design, Fabrication, and Mechanical Properties of T-700TM Multiaxial-Warp-Knitting–Needled–C/SiC Composite and Pin
Authors: Luo Xiao , He Jiangyi , Liu Xiaochong , Xu Youliang , Li Jian , Guo Xiaojun , Wang Qianru , Li Longbiao
Published: March 2022

In this paper, the 12k T-700TM Multiaxial-Warp-Knitting–Needle (MWK–N) C/SiC composite and pin were designed and fabricated using the isothermal chemical vapor infiltration (ICVI) method. The composite’s microstructure and mechanical properties were examined by subjection to tensile and interlaminar shear tests. Three types of double-shear tests were conducted for C/SiC pins, including shear loading perpendicularly, along, and at 45° off-axial to the lamination. The fracture surface of the tensile and shear failure specimens was observed under scanning electronic microscope (SEM). The relationships between the composite’s microstructure, mechanical properties, and damage mechanisms were established. The composite’s average tensile strength was σuts = 68.3 MPa and the average interlaminar shear strength was τu = 38.7 MPa. For MWK–N–C/SiC pins, the double-shear strength was τu = 76.5 MPa, 99.7 MPa, and 79.6 MPa for test types I, II, and III, respectively. Compared with MWK–C/SiC pins, the double-shear strength of MWK–N–C/SiC pins all decreased, i.e., 26.7%, 50.8%, and 8% for test types I, II, and III, respectively. The MWK–N–C/SiC composite and pins possessed high interlaminar shear strength and double-shear strength, due to the needled fiber in the thickness direction, low porosity (10–15%), and high composite density (2.0 g/cm3).
Continuous Dependence for the Boussinesq Equations under Reaction Boundary Conditions in R2
Authors: Shi Jincheng , Liu Yan
Published: March 2022

In this paper, we studied the continuous dependence result for the Boussinesq equations. We considered the case where Ω was a bounded domain in R2. Temperatures T and C satisfied reaction boundary conditions. A first-order inequality for the differences of energy could be derived. An integration of this inequality produced a continuous dependence result. The result told us that the continuous dependence type stability was also valid for the Boussinesq coefficient λ of the Boussinesq equations with reaction boundary conditions.
In Silico Evaluation of Antifungal Compounds from Marine Sponges against COVID-19-Associated Mucormycosis
Authors: Pokharkar Omkar , Lakshmanan Hariharan , Zyryanov Grigory , Tsurkan Mikhail
Published: March 2022

The world is already facing the devastating effects of the SARS-CoV-2 pandemic. A disseminated mucormycosis epidemic emerged to worsen this situation, causing havoc, especially in India. This research aimed to perform a multitargeted docking study of marine-sponge-origin bioactive compounds against mucormycosis. Information on proven drug targets and marine sponge compounds was obtained via a literature search. A total of seven different targets were selected. Thirty-five compounds were chosen using the PASS online program. For homology modeling and molecular docking, FASTA sequences and 3D structures for protein targets were retrieved from NCBI and PDB databases. Autodock Vina in PyRx 0.8 was used for docking studies. Further, molecular dynamics simulations were performed using the IMODS server for top-ranked docked complexes. Moreover, the drug-like properties and toxicity analyses were performed using Lipinski parameters in Swiss-ADME, OSIRIS, ProTox-II, pkCSM, and StopTox servers. The results indicated that naamine D, latrunculin A and S, (+)-curcudiol, (+)-curcuphenol, aurantoside I, and hyrtimomine A had the highest binding affinity values of −8.8, −8.6, −9.8, −11.4, −8.0, −11.4, and −9.0 kcal/mol, respectively. In sum, all MNPs included in this study are good candidates against mucormycosis. (+)-curcudiol and (+)-curcuphenol are promising compounds due to their broad-spectrum target inhibition potential.
Comparison of the Efficacies of Direct-Acting Antiviral Treatment for HCV Infection in People Who Inject Drugs and Non-Drug Users
Authors: Hsu Jui-Ting , Hsu Ping-I , Shie Chang-Bih , Chuah Seng-Kee , Wu I-Ting , Huang Wen-Wei , Tang Sheng-Yeh , Tsai Kun-Feng , Kuo Li-Fu , Ghose Supratip , Hsu Jui-Che , Shih Chih-An
Published: March 2022

Background and Objectives: Hepatitis C virus (HCV) is a major cause of liver disease worldwide. People who inject drugs (PWIDs) constitute the majority of patients with HCV infection in the United States and Central Asia. There are several obstacles to treating HCV infection in PWIDs because PWIDs are often accompanied by concurrent infection, low compliance, substance abuse, and risky behavior. The aim of the study is to compare the efficacies of direct-acting antiviral (DAA) therapy for HCV infection in PWIDs and those without opioid injection. Materials and Methods: In this retrospective cohort study, we included 53 PWIDs with HCV infections treated on site in a methadone program and 106 age- and sex-matched patients with HCV infections who had no history of opioid injection (ratio of 1:2). All eligible subjects received anti-HCV treatment by DAA agents in our hospital from March 2018 to December 2020. The charts of these patients were carefully reviewed for demographic data, types of DAA agents, and treatment outcomes. The primary outcome measure was sustained virological response (SVR). Results: PWIDs and non-drug users had different HCV genotype profiles (p = 0.013). The former had higher proportions of genotype 3 (18.9% vs. 7.5%) and genotype 6 (24.5% vs. 14.2%) than the latter. The two patient groups had comparable rates of complete drug refilling (100.0% vs. 91.1%) and frequency of loss to follow-up (3.8% vs. 0.9%). However, PWIDs had a lower SVR rate of DAA treatment than non-drug users (92.2% vs. 99.0%; p = 0.04). Further analysis showed that both human immunodeficiency virus (HIV) coinfection and history of PWID were risk factors associated with treatment failure. The subjects with coinfection with HIV had lower SVR rates than those without HIV infection (50.0% vs. 96.5%; p = 0.021). Conclusions: PWIDs with HCV infections have higher proportions of HCV genotype 3 and genotype 6 than non-drug users with infections. DAA therapy can achieve a high cure rate (>90%) for HCV infection in PWID, but its efficacy in PWID is lower than that in non-drug users.