bluuebunny/crossref_metadata_2025 huggingface dataset:
Human Wharton’s Jelly Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles Drive Oligodendroglial Maturation by Restraining MAPK/ERK and Notch Signaling Pathways
Authors: Joerger-Messerli Marianne S. , Thomi Gierin , Haesler Valérie , Keller Irene , Renz Patricia , Surbek Daniel V. , Schoeberlein Andreina
Published: March 2021

Peripartum cerebral hypoxia and ischemia, and intrauterine infection and inflammation, are detrimental for the precursor cells of the myelin-forming oligodendrocytes in the prematurely newborn, potentially leading to white matter injury (WMI) with long-term neurodevelopmental sequelae. Previous data show that hypomyelination observed in WMI is caused by arrested oligodendroglial maturation rather than oligodendrocyte-specific cell death. In a rat model of premature WMI, we have recently shown that small extracellular vesicles (sEV) derived from Wharton’s jelly mesenchymal stromal cells (WJ-MSC) protect from myelination deficits. Thus, we hypothesized that sEV derived from WJ-MSC directly promote oligodendroglial maturation in oligodendrocyte precursor cells. To test this assumption, sEV were isolated from culture supernatants of human WJ-MSC by ultracentrifugation and co-cultured with the human immortalized oligodendrocyte precursor cell line MO3.13. As many regulatory functions in WMI have been ascribed to microRNA (miR) and as sEV are carriers of functional miR which can be delivered to target cells, we characterized and quantified the miR content of WJ-MSC-derived sEV by next-generation sequencing. We found that WJ-MSC-derived sEV co-localized with MO3.13 cells within 4 h. After 5 days of co-culture, the expression of myelin basic protein (MBP), a marker for mature oligodendrocytes, was significantly increased, while the oligodendrocyte precursor marker platelet-derived growth factor alpha (PDGFRα) was decreased. Notch and MAPK/ERK pathways known to inhibit oligodendrocyte maturation and differentiation were significantly reduced. The pathway enrichment analysis showed that the miR present in WJ-MSC-derived sEV target genes having key roles in the MAPK pathway. Our data strongly suggest that sEV from WJ-MSC directly drive the maturation of oligodendrocyte precursor cells by repressing Notch and MAPK/ERK signaling.
Bisphenol A Exposure Disrupts Organelle Distribution and Functions During Mouse Oocyte Maturation
Authors: Pan Meng-Hao , Wu Yu-Ke , Liao Bi-Yun , Zhang Hui , Li Chan , Wang Jun-Li , Hu Lin-Lin , Ma Baohua
Published: March 2021

Bisphenol A (BPA) is one of the ubiquitous environmental endocrine disruptors (EEDs). Previous studies have shown that the reproduction toxicity of BPA could cause severe effects on the mammal oocytes and disturb the quality of mature oocytes. However, the toxic effects of BPA on the organelles of mouse oocytes have not been reported. In this study, to investigate whether BPA can be toxic to the organelles, we used different concentrations of BPA (50, 100, and 200 μM) to culture mouse oocytes in vitro. The results showed that 100 μM BPA exposure could significantly decrease the developmental capacity of oocytes. Then, we used the immunofluorescence staining, confocal microscopy, and western blotting to investigate the toxic effects of BPA on the organelles. The results revealed that mitochondrial dysfunction is manifested by abnormal distribution and decreased mitochondrial membrane potential. Moreover, the endoplasmic reticulum (ER) is abnormally distributed which is accompanied by ER stress showing increased expression of GRP78. For the Golgi apparatus, BPA-exposed dose not disorder the Golgi apparatus distribution but caused abnormal structure of Golgi apparatus, which is manifested by the decrease of GM130 protein expression. Moreover, we also found that BPA-exposed led to the damage of lysosome, which were shown by the increase of LAMP2 protein expression. Collectively, our findings demonstrated that the exposure of BPA could damage the normal function of the organelles, which may explain the reduced maturation quality of oocytes.
Vector Competence for DENV-2 Among Aedes albopictus (Diptera: Culicidae) Populations in China
Authors: Wei Yong , Wang Jiatian , Wei Yuan-Huan , Song Zhangyao , Hu Ke , Chen Yulan , Zhou Guofa , Zhong Daibin , Zheng Xueli
Published: March 2021

Aedes albopictus is a vector of over 20 arboviruses that has spread throughout the world, mainly in the second half of the twentieth century. Approximately 50–100 million people are infected with dengue virus (DENV) transmitted by Aedes mosquitoes each year, leading to heavy economic burdens for both governments and individuals, among countless other negative consequences. Understanding the vector competence of vector species is critical for effectively preventing and controlling vector-borne diseases. Accordingly, in this study, vector competence was evaluated by quantitative analysis of DENV-2 loads in mosquito tissues (midguts, heads, and salivary glands) and whole mosquitoes through real-time quantitative polymerase chain reaction (RT-qPCR) analysis. Wolbachia and the expression of immune-associated genes (Rel1, Rel2, Dicer2, and STAT) in mosquitoes were also detected by RT-qPCR to explore their impact on vector competence. The amount of DENV-2 in the mosquito midguts, heads, and salivary glands from southern-western China were found to be lower than those from eastern-central-northern China. The DENV-2 loads in whole mosquitoes showed a negative correlation with Rel1 gene (r = -0.285, P = 0.011) and STAT gene expression levels (r = -0.289, P = 0.009). In terms of Wolbachia strains, the density of the wAlbB strain was found to be significantly higher than that of the wAlbA strain in the eight Ae. albopictus populations, and the relative density of the wAlbB strain in mosquitoes from southern-western China was higher than those from eastern-central-northern China. The relative density of the wAlbB strain showed a negative correlation with the mean loads of DENV-2 in the heads (r = -0.729, P = 0.040), salivary glands (r = -0.785, P = 0.021), and whole mosquitoes (r = -0.909, P = 0.002). Thus, there are lower DENV-2 loads in the mosquitoes from southern-western China, which may be related to the innate immunity of mosquitoes as affected by Rel1 in the Toll pathway, STAT in the JAK-STAT pathway, and the relative density of the wAlbB strain.
Why Does Language Complexity Resist Measurement?
Authors: Joseph John E.
Published: March 2021

Insofar as linguists operate with a conception of languages as closed and self-contained systems, there should be no obstacle to comparing those systems in terms of simplicity and complexity. Even if complexity ‘trade-offs’ between sub-systems of phonology, morphology and syntax are considered, it ought to be relatively straightforward to quantify constitutive elements and rules, and assign each language system its place on a complexity scale. In practice, however, such attempts have turned up a series of problems and paradoxes, which can be seen in work by Peter Trudgill and Johanna Nichols; the latter has proposed an alternative means of measuring complexity which presents new problems of its own. This paper makes the case that overcoming the difficulty of measuring simplicity and complexity requires confronting the normative and interpretative judgments that enter into how language systems are conceived, identified and analysed.
PCSK9 Functions in Atherosclerosis Are Not Limited to Plasmatic LDL-Cholesterol Regulation
Authors: Luquero Aureli , Badimon Lina , Borrell-Pages Maria
Published: March 2021

The relevance of PCSK9 in atherosclerosis progression is demonstrated by the benefits observed in patients that have followed PCSK9-targeted therapies. The impact of these therapies is attributed to the plasma lipid-lowering effect induced when LDLR hepatic expression levels are recovered after the suppression of soluble PCSK9. Different studies show that PCSK9 is involved in other mechanisms that take place at different stages during atherosclerosis development. Indeed, PCSK9 regulates the expression of key receptors expressed in macrophages that contribute to lipid-loading, foam cell formation and atherosclerotic plaque formation. PCSK9 is also a regulator of vascular inflammation and its expression correlates with pro-inflammatory cytokines release, inflammatory cell recruitment and plaque destabilization. Furthermore, anti-PCSK9 approaches have demonstrated that by inhibiting PCSK9 activity, the progression of atherosclerotic disease is diminished. PCSK9 also modulates thrombosis by modifying platelets steady-state, leukocyte recruitment and clot formation. In this review we evaluate recent findings on PCSK9 functions in cardiovascular diseases beyond LDL-cholesterol plasma levels regulation.
Hypertension and Atrial Fibrillation: A Study on Epidemiology and Mendelian Randomization Causality
Authors: Liao Li-Zhen , Wen Xiu-Yun , Zhang Shao-Zhao , Li Wei-Dong , Zhuang Xiao-Dong
Published: March 2021

Introduction: Hypertension (HT) and atrial fibrillation (AF) often coexist. However, the causality between these two conditions remains to be determined.

Methods: We used individual participant data from the Atherosclerosis Risk in Communities (ARIC) prospective cohort with 9,474 participants. HT was ascertained at visit 1 (1987–1989), and incident AF was identified by ECGs conducted during study examinations at each visit, hospital discharge codes, and death certificates. We used the Kaplan–Meier estimate to compute the cumulative incidence of AF by the HT subgroup. Then we used Cox hazard regression model to assess the association between HT and incident AF. The causality between genetically determined HT and AF was analyzed by the two-sample Mendelian randomization (MR) based on publicly summarized genome-wide association studies (GWASs) data.

Results: A total of 1,414 cases (14.9%) of AF were identified during the follow-up period (median 24.1 years). After adjusting for all covariates, the hazard ratio between the participants with HT and incident AF was 1.50 [95% confidence interval (CI) 1.29–1.73]. In the HT → AF MR analysis, we detected a causal correlation between HT and AF (OR: 1.90, 95% CI 1.18–3.04, P = 0.01) with no evidence of heterogeneity from single-nucleotide polymorphisms. Besides, the genetically determined SBP and DBP (10 mmHg) were consistently associated with a higher risk of AF.

Conclusions: In the ARIC study, the incident AF increased by 50% in patients with HT. In the MR analysis, our results supported causal inference between HT and AF.
FALKE: Experiences From Transdisciplinary Educational Research by Fourteen Disciplines
Authors: Schilcher Anita , Krauss Stefan , Kirchhoff Petra , Lindl Alfred , Hilbert Sven , Asen-Molz Katharina , Ehras Christina , Elmer Michael , Frei Mario , Gaier Lisa , Gastl-Pischetsrieder Maria , Gunga Eileen , Murmann Renate , Röhrl Simone , Ruck Anna-Maria , Weich Matthias , Dittmer Arne , Fricke Michael , Hofmann Bernhard , Memminger Josef , Rank Astrid , Tepner Oliver , Thim-Mabrey Christiane
Published: March 2021

This article details how the FALKE research project (Fachspezifische Lehrerkompetenzen im Erklären; Engl.: subject-specific teacher competency in explaining) integrates 14 heterogeneous disciplines in order to empirically examine the didactic quality of teacher explanations in eleven school subjects by bringing together trans-, multi-, and interdisciplinary perspectives. In order to illustrate the academic landscape of the FALKE project we briefly outline the nature of the transdisciplinary German “Fachdidaktiken” (Engl.: subject-matter didactics, i.e., special academic disciplines of teaching and learning specific school subjects). The FALKE project required the willingness of all researchers from eleven participating subject-matter didactics to rely on both the concepts and the methods of educational sciences as an overarching research framework (transdisciplinary aspect). All researchers of subject-matter didactics had to develop a shared conceptual, methodological, and administrative framework in order to empirically investigate commonalities in and differences between “good explanations” across the range of school subjects represented (multidisciplinary aspect). The additional perspectives of researchers in speech science and linguistics proved fruitful in recognizing rhetorical and linguistic aspects of teacher explanations (interdisciplinary aspect). Data management and statistical analysis were provided by the discipline methods of educational sciences. Rather than reporting empirical results, we here discuss opportunities and challenges as well as the lessons learned from the FALKE project regarding cognitive-epistemic reasoning, communication, and organization.
Solid Waste Management in Indian Himalayan Region: Current Scenario, Resource Recovery, and Way Forward for Sustainable Development
Authors: Thakur Aman , Kumari Sareeka , Sinai Borker Shruti , Prashant Swami Pragya , Kumar Aman , Kumar Rakshak
Published: March 2021

With the growing population, solid waste management (SWM) is becoming a significant environmental challenge and an emerging issue, especially in the eco-sensitive Indian Himalayan region (IHR). Though IHR does not host high local inhabitants, growing tourist footfall in the IHR increases solid wastes significantly. The lack of appropriate SWM facilities has posed a serious threat to the mountain-dwelling communities. SWM is challenging in the highlands due to the remoteness, topographical configuration, increasing urbanization, and harsh climate compared to plain areas. Difficulty in managing SWM has led to improper disposal methods, like open dumping and open burning of waste, that are adversely affecting the fragile IHR ecosystem. Open dumping of unsegregated waste pollutes the freshwater streams, and burning releases major pollutants often linked to the glacier melt. Processes like composting, vermicomposting, and anaerobic digestion to treat biodegradable wastes are inefficient due to the regions' extreme cold conditions. IHR specific SWM rules were revised in 2016 to deal with the rising problem of SWM, providing detailed criteria for setting up solid waste treatment facilities and promoting waste-to-energy (WtE). Despite governments' effort to revise SWM; measures like proper collection, segregation, treatment, and solid waste disposal needs more attention in the IHR. Door-to-door collection, segregation at source, covered transportation, proper treatment, and disposal are the primary steps to resource recovery across the IHR. Approaches such as waste recycling, composting, anaerobic digestion, refuse-derived fuel (RDF), and gas recovery from landfills are essential for waste alteration into valuable products initiatives like 'ban on single-use plastic' and 'polluters to pay' have a potential role in proper SWM in the IHR. Research and technology, capacity building, mass awareness programs, and initiatives like ‘ban on single-use plastic’ and ‘polluters to pay’ have a potential role in proper SWM in the IHR. This review highlights the current status of waste generation, the current SWM practices, and SWM challenges in the IHR. The review also discusses the possible resource recovery from waste in the IHR, corrective measures introduced by the government specific to IHR and, the way forward for improved SWM for achieving sustainable development of the IHR.
CCN Family Proteins in Cancer: Insight Into Their Structures and Coordination Role in Tumor Microenvironment
Authors: Jia Qingan , Xu Binghui , Zhang Yaoyao , Ali Arshad , Liao Xia
Published: March 2021

The crosstalk between tumor cells and the tumor microenvironment (TME), triggers a variety of critical signaling pathways and promotes the malignant progression of cancer. The success rate of cancer therapy through targeting single molecule of this crosstalk may be extremely low, whereas co-targeting multiple components could be complicated design and likely to have more side effects. The six members of cellular communication network (CCN) family proteins are scaffolding proteins that may govern the TME, and several studies have shown targeted therapy of CCN family proteins may be effective for the treatment of cancer. CCN protein family shares similar structures, and they mutually reinforce and neutralize each other to serve various roles that are tightly regulated in a spatiotemporal manner by the TME. Here, we review the current knowledge on the structures and roles of CCN proteins in different types of cancer. We also analyze CCN mRNA expression, and reasons for its diverse relationship to prognosis in different cancers. In this review, we conclude that the discrepant functions of CCN proteins in different types of cancer are attributed to diverse TME and CCN truncated isoforms, and speculate that targeting CCN proteins to rebalance the TME could be a potent anti-cancer strategy.
Circular RNA Foxo3: A Promising Cancer-Associated Biomarker
Authors: Yang Tianli , Li Yang , Zhao Feng , Zhou Liuhua , Jia Ruipeng
Published: March 2021

Circular RNAs (circRNAs) are a class of novel non-coding RNAs (ncRNAs). Emerging evidence demonstrates that circRNAs play crucial roles in many biological processes by regulating linear RNA transcription, downstream gene expression and protein or peptide translation. Meanwhile, recent studies have suggested that circRNAs have the potential to be oncogenic or anti-oncogenic and play vital regulatory roles in the initiation and progression of tumors. Circular RNA Forkhead box O3 (circ-Foxo3, hsa_circ_0006404) is encoded by the human FOXO3 gene and is one of the most studied circular RNAs acting as a sponge for potential microRNAs (miRNAs) (Du et al., 2016). Previous studies have reported that circ-Foxo3 is involved in the development and tumorigenesis of a variety of cancers (bladder, gastric, acute lymphocytic leukemia, glioma, etc.). In this review, we summarize the current studies concerning circ-Foxo3 deregulation and the correlative mechanism in various human cancers. We also point out the potential clinical applications of this circRNA as a biomarker for cancer diagnosis and prognosis.
Intestinal Dysbiosis and Autoimmune Pancreatitis
Authors: Yoshikawa Tomoe , Watanabe Tomohiro , Kamata Ken , Hara Akane , Minaga Kosuke , Kudo Masatoshi
Published: March 2021

Autoimmune pancreatitis (AIP) is a chronic fibro-inflammatory disorder of the pancreas. Recent clinicopathological analysis revealed that most cases of AIP are pancreatic manifestations of systemic IgG4-related disease (IgG4-RD), a newly established disease characterized by enhanced IgG4 antibody responses and the involvement of multiple organs. Although the immuno-pathogenesis of AIP and IgG4-RD has been poorly defined, we recently showed that activation of plasmacytoid dendritic cells (pDCs) with the ability to produce large amounts of IFN-α and IL-33 mediates chronic fibro-inflammatory responses in experimental and human AIP. Moreover, M2 macrophages producing a large amount of IL-33 play pathogenic roles in the development of human IgG4-RD. Interestingly, recent studies including ours provide evidence that compositional alterations of gut microbiota are associated with the development of human AIP and IgG4-RD. In addition, intestinal dysbiosis plays pathological roles in the development of chronic pancreatic inflammation as dysbiosis mediates the activation of pDCs producing IFN-α and IL-33, thereby causing experimental AIP. In this Mini Review, we focus on compositional alterations of gut microbiota in AIP and IgG4-RD to clarify the mechanisms by which intestinal dysbiosis contributes to the development of these disorders.
Effects of Nutrient Management Scenarios on Marine Food Webs: A Pan-European Assessment in Support of the Marine Strategy Framework Directive
Authors: Piroddi Chiara , Akoglu Ekin , Andonegi Eider , Bentley Jacob W. , Celić Igor , Coll Marta , Dimarchopoulou Donna , Friedland René , de Mutsert Kim , Girardin Raphael , Garcia-Gorriz Elisa , Grizzetti Bruna , Hernvann P.-Y. , Heymans Johanna J. , Müller-Karulis Bärbel , Libralato Simone , Lynam Christopher P. , Macias Diego , Miladinova Svetla , Moullec Fabien , Palialexis Andreas , Parn Ove , Serpetti Natalia , Solidoro Cosimo , Steenbeek Jeroen , Stips Adolf , Tomczak Maciej T. , Travers-Trolet Morgane , Tsikliras Athanassios C.
Published: March 2021

Eutrophication is one of the most important anthropogenic pressures impacting coastal seas. In Europe, several legislations and management measures have been implemented to halt nutrient overloading in marine ecosystems. This study evaluates the impact of freshwater nutrient control measures on higher trophic levels (HTL) in European marine ecosystems following descriptors and criteria as defined by the Marine Strategy Framework Directive (MSFD). We used a novel pan-European marine modeling ensemble of fourteen HTL models, covering almost all the EU seas, under two nutrient management scenarios. Results from our projections suggest that the proposed nutrient reduction measures may not have a significant impact on the structure and function of European marine ecosystems. Among the assessed criteria, the spawning stock biomass of commercially important fish stocks and the biomass of small pelagic fishes would be the most impacted, albeit with values lower than 2.5%. For the other criteria/indicators, such as species diversity and trophic level indicators, the impact was lower. The Black Sea and the North-East Atlantic were the most negatively impacted regions, while the Baltic Sea was the only region showing signs of improvement. Coastal and shelf areas were more sensitive to environmental changes than large regional and sub-regional ecosystems that also include open seas. This is the first pan-European multi-model comparison study used to assess the impacts of land-based measures on marine and coastal European ecosystems through a set of selected ecological indicators. Since anthropogenic pressures are expanding apace in the marine environment and policy makers need to use rapid and effective policy measures for fast-changing environments, this modeling framework is an essential asset in supporting and guiding EU policy needs and decisions.
Antibiotic Modulation of Capsular Exopolysaccharide in Pelagicoccus enzymogenes sp. nov. Isolated From Marine Sediment
Authors: Feng Xi , Gong Ya , Ye Meng-Qi , Du Zong-Jun
Published: March 2021

Although Verrucomicrobia is widely distributed in the marine environment, their physiological or cellular properties are poorly characterized because of the lack of cultured representatives. Under the selective pressure of two antibiotics, ofloxacin and norfloxacin, a Gram-stain-negative, aerobic coccus with exopolysaccharide (EPS) production ability was isolated from the coastal sediment of Xiaoshi Island, Weihai, China. These antibiotics inhibited bacterial growth, giving rise to the relatively slow-growing Verrucomicrobia that formed colonies on the isolation plates. It may be an effective method for the isolation of Puniceicoccaceae. From the taxonomic data obtained in this study, the new marine isolate NFK12T (=KCTC 72940T = MCCC 1H00424T) is proposed to be placed into a novel species within the genus Pelagicoccus for which the name Pelagicoccus enzymogenes sp. nov. is proposed. The EPS production of the strain NFK12T and the related strains were investigated and the effect of EPS produced by the strain NFK12T on the growth of other strains was examined. Besides, the effect of EPS on tolerance to ofloxacin and norfloxacin of the strain NFK12T was studied by measuring the biomass of the strain NFK12T. It was deduced that those strains that produced EPS tentatively protected themselves against the inhibitory effects of ofloxacin and norfloxacin.
CD107a+ (LAMP-1) Cytotoxic CD8+ T-Cells in Lupus Nephritis Patients
Authors: Wiechmann Anika , Wilde Benjamin , Tyczynski Bartosz , Amann Kerstin , Abdulahad Wayel H. , Kribben Andreas , Lang Karl Sebastian , Witzke Oliver , Dolff Sebastian
Published: March 2021

Cytotoxic CD8+ T-cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to investigate the role of CD107a (LAMP-1) on cytotoxic CD8+ T-cells in SLE-patients in particular with lupus nephritis. Peripheral blood of SLE-patients (n = 31) and healthy controls (n = 21) was analyzed for the expression of CD314 and CD107a by flow cytometry. Kidney biopsies of lupus nephritis patients were investigated for the presence of CD8+ and C107a+ cells by immunohistochemistry and immunofluorescence staining. The percentages of CD107a+ on CD8+ T-cells were significantly decreased in SLE-patients as compared to healthy controls (40.2 ± 18.5% vs. 47.9 ± 15.0%, p = 0.02). This was even more significant in SLE-patients with inactive disease. There was a significant correlation between the percentages of CD107a+CD8+ T-cells and SLEDAI. The evaluation of lupus nephritis biopsies showed a significant number of CD107a+CD8+ T-cells mainly located in the peritubular infiltrates. The intrarenal expression of CD107a+ was significantly correlated with proteinuria. These results demonstrate that CD8+ T-cells of patients with systemic lupus erythematosus have an altered expression of CD107a which seems to be associated with disease activity. The proof of intrarenal CD107a+CD8+ suggests a role in the pathogenesis of lupus nephritis.
Intestinal Mucosal Wound Healing and Barrier Integrity in IBD–Crosstalk and Trafficking of Cellular Players
Authors: Sommer Katrin , Wiendl Maximilian , Müller Tanja M. , Heidbreder Karin , Voskens Caroline , Neurath Markus F. , Zundler Sebastian
Published: March 2021

The intestinal epithelial barrier is carrying out two major functions: restricting the entry of potentially harmful substances while on the other hand allowing the selective passage of nutrients. Thus, an intact epithelial barrier is vital to preserve the integrity of the host and to prevent development of disease. Vice versa, an impaired intestinal epithelial barrier function is a hallmark in the development and perpetuation of inflammatory bowel disease (IBD). Besides a multitude of genetic, molecular and cellular alterations predisposing for or driving barrier dysintegrity in IBD, the appearance of intestinal mucosal wounds is a characteristic event of intestinal inflammation apparently inducing breakdown of the intestinal epithelial barrier. Upon injury, the intestinal mucosa undergoes a wound healing process counteracting this breakdown, which is controlled by complex mechanisms such as epithelial restitution, proliferation and differentiation, but also immune cells like macrophages, granulocytes and lymphocytes. Consequently, the repair of mucosal wounds is dependent on a series of events including coordinated trafficking of immune cells to dedicated sites and complex interactions among the cellular players and other mediators involved. Therefore, a better understanding of the crosstalk between epithelial and immune cells as well as cell trafficking during intestinal wound repair is necessary for the development of improved future therapies. In this review, we summarize current concepts on intestinal mucosal wound healing introducing the main cellular mediators and their interplay as well as their trafficking characteristics, before finally discussing the clinical relevance and translational approaches to therapeutically target this process in a clinical setting.
Immune-Inhibitory Gene Expression is Positively Correlated with Overall Immune Activity and Predicts Increased Survival Probability of Cervical and Head and Neck Cancer Patients
Authors: Budhwani Megha , Turrell Gavin , Yu Meihua , Frazer Ian H. , Mehdi Ahmed M. , Chandra Janin
Published: March 2021

Background: Limited immunotherapy options are approved for the treatment of cervical cancer and only 10–25% of patients respond effectively to checkpoint inhibition monotherapy. To aid the development of novel therapeutic immune targets, we aimed to explore survival-associated immune biomarkers and co-expressed immune networks in cervical cancer.

Methods: Using The Cancer Genome Atlas (TCGA) Cervical Squamous Cell Carcinoma (CESC) data (n = 304), we performed weighted gene co-expression network analysis (WGCNA), and determined which co-expressed immune-related genes and networks are associated with survival probability in CESC patients under conventional therapy. A “Pan-Immune Score” and “Immune Suppression Score” was generated based on expression of survival-associated co-expressed immune networks and immune suppressive genes, which were subsequently tested for association with survival probablity using the TCGA Head Neck Squamous Cell Carcinoma (HNSCC) data (n = 528), representing a second SCC cancer type.

Results: In CESC, WGCNA identified a co-expression module enriched in immune response related genes, including 462 genes where high expression was associated with increased survival probability, and enriched for genes associated with T cell receptor, cytokine and chemokine signaling. However, a high level of expression of 43 of the genes in this module was associated with decreased survival probability but were not enriched in particular pathways. Separately, we identified 20 genes associated with immune suppression including inhibitory immune checkpoint and regulatory T cell-related genes, where high expression was associated with increased survival probability. Expression of these 20 immune suppressive genes (represented as “Immune Suppression Score”) was highly correlated with expression of overall survival-associated immune genes (represented as “Pan-Immune Score”). However, high expression of seven immune suppression genes, including TWEAK-R, CD73, IL1 family and TGFb family genes, was significantly associated with decreased survival probability. Both scores also significantly associated with survival probability in HNSCC, and correlated with the previously established “Immunophenoscore.”

Conclusion: CESC and HNSCC tumors expressing genes predictive of T cell infiltrates (hot tumors) have a better prognosis, despite simultaneous expression of many immune inhibitory genes, than tumors lacking expression of genes associated with T cell infiltrates (cold tumors) whether or not these tumor express immune inhibitory genes.
Differentiating Dynamic Cerebral Autoregulation Across Vascular Territories
Authors: Reehal Navpreet , Cummings Stephanie , Mullen Michael T. , Baker Wesley B. , Kung David , Tackett William , Favilla Christopher G.
Published: March 2021

Objective: Transcranial Doppler is commonly used to calculate cerebral autoregulation, but measurements are typically restricted to a single cerebral artery. In exploring topographic heterogeneity, this study reports the first thorough comparison of autoregulation in all major cerebral vessels.

Methods: In forty healthy adults, flow velocity was monitored in the anterior, middle, and posterior cerebral arteries, and synchronized with arterial blood pressure. A transfer function analysis provided characteristics of autoregulation by quantifying the relationship between blood pressure and cerebral blood flow velocity.

Results: Phase, which quantifies the time course of autoregulation, was similar in all vessels. Gain, which quantifies the magnitude of hemodynamic regulation, was lower in posterior cerebral artery, indicative of tighter regulation. However, after adjusting for baseline flow differences in each vascular territory, normalized gain was similar in all vessels.

Conclusions: Discriminating dynamic cerebral autoregulation between cerebrovascular territories is feasible with a transcranial doppler based approach. In the posterior cerebral artery of healthy volunteers, absolute flow is more tightly regulated, but relative flow regulation is consistent across cerebrovascular territories.

Significance: The methodology can be applied to focal disease states such as stroke or posterior reversible encephalopathy syndrome, in which the topographic distribution of autoregulation may be particularly critical.
Astragaloside IV Protects 6-Hydroxydopamine-Induced SH-SY5Y Cell Model of Parkinson’s Disease via Activating the JAK2/STAT3 Pathway
Authors: Xu ZhengHu , Yang Dongfeng , Huang Xiaojing , Huang Huai
Published: March 2021

Objectives

Astragaloside IV (AS-IV), the main active component of Astragalus membranaceus, bears anti-inflammatory, antioxidant, and neuroprotective activity. Parkinson’s disease (PD) is a common neurodegenerative disease. This study explored the protective effect of AS-IV on the cell model of PD.

Materials and Methods

SH-SY5Y cells were incubated with different concentrations (10, 50, 100, 150, and 200 μM) of 6-hydroxydopamine (6-OHDA) for 0, 3, 6, 12, 24, and 48 h to establish the PD cell model. Different concentrations (0, 25, 50, 100, 150, and 200 μM) of AS-IV or 15 mM JAK2/STAT3 pathway inhibitor SC99 was added for intervention 2 h before 6-OHDA treatment. The viability and morphological damage of 6-OHDA-treated SH-SY5Y cells were measured using MTT assay and Hoechst 33258 staining. The expression of microtubule associated protein 2 (MAP2) was detected by immunofluorescence staining. The levels of inflammation and oxidative stress were measured using ELISA. Apoptosis of 6-OHDA-treated SH-SY5Y cells was detected using flow cytometry, and phosphorylation level of JAK2 and STAT3 were detected using Western blot analysis.

Results

The survival rate of SH-SY5Y cells treated with 100 μM 6-OHDA for 24 h was about 50%. AS-IV (25–100 μM) significantly improved the viability (all p < 0.01), increased MAP2 expression, and repaired the morphological damage induced by 6-OHDA. AS-IV inhibited IL-1β, IL-6, and TNF-α level (all p < 0.05), reduced MDA and ROS content and increased SOD concentration, thereby reducing inflammation and oxidative stress (all p < 0.01) in 6-OHDA-treated SH-SY5Y cells. Moreover, AS-IV decreased apoptosis rate and Bax/Bcl-2 ratio induced by 6-OHDA (all p < 0.05). Mechanically, AS-IV significantly increased the phosphorylation of JAK2 and STAT3 (p < 0.01); the addition of SC99 decreased the cell viability, increased the apoptosis rate, enhanced the levels of inflammatory factors and oxidative stress.

Conclusion

AS-IV enhanced the cell viability, and inhibited apoptosis, inflammation and oxidative stress of 6-OHDA-treated SH-SY5Y cells via activating the JAK2/STAT3 signaling pathway. This study may confer novel insights for the management of PD.
Using lncRNA Sequencing to Reveal a Putative lncRNA-mRNA Correlation Network and the Potential Role of PCBP1-AS1 in the Pathogenesis of Cervical Cancer
Authors: Li Linhan , Peng Qisong , Gong Min , Ling Ling , Xu Yingxue , Liu Qiaoling
Published: March 2021

Background/Aims

Long non-coding RNAs (lncRNAs) play important roles in many diseases and participate in posttranscriptional regulatory networks in tumors. However, the functions of major lncRNAs in cervical cancer are unclear. Therefore, the aim of this study was to construct a lncRNA-mRNA coexpression functional network and analyze lncRNAs that might contribute to the pathogenesis of cervical cancer.

Methods

Differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) between three pairs of cervical cancer tissues and adjacent mucosa were identified by lncRNA microarray analysis. LncRNA-mRNA correlation analysis and functional enrichment were performed on the DEGs. From the correlation network, PCBP1-AS1 was selected as a candidate for further analysis. PCBP1-AS1 expression was examined by qPCR, and Kaplan–Meier survival, clinicopathology, GSEA, and immune infiltration analysis of PCBP1-AS1 were performed. The immune responses of PCBP1-AS1 expression in cervical cancer were analyzed using TIMER and western blot. PCBP1-AS1 was knocked down and overexpressed to evaluate its role in cell proliferation, migration, and invasion.

Results

A total of 130 lncRNAs were significantly differentially expressed in cervical cancer patient samples compared with control samples. Differentially expressed mRNAs in the lncRNA-mRNA interaction network were involved in the EMT process. Combined with the Kaplan–Meier survival analyses, the coexpression network revealed that PCBP1-AS1 was significantly associated with OS and clinicopathological parameters in cervical cancer patients. Moreover, PCBP1-AS1 expression was not only significantly increased in cervical cancer specimens but also associated with tumor stage, TNM, and invasion. GSEA revealed that PCBP1-AS1 is closely correlated with cell biological function via the p53 and notch signaling pathways. TIMER analysis revealed that the numbers of NK cells and M2 macrophages decreased when PCBP1-AS1 expression was high, which was consistent with the western blot results in clinical samples. Furthermore, in vitro experiments showed that high expression of PCBP1-AS1 promoted cell proliferation, migration, and invasion.

Conclusions

Transcriptomic and lncRNA-mRNA correlation analyses revealed that PCBP1-AS1 plays a key role as an independent prognostic factor in patients with cervical cancer. The identification of PCBP1-AS1 as a new biomarker for cervical cancer could help explain how changes in the immune environment promote cervical cancer development.
Effect of Applying Leakage Correction on rCBV Measurement Derived From DSC-MRI in Enhancing and Nonenhancing Glioma
Authors: Arzanforoosh Fatemeh , Croal Paula L. , van Garderen Karin A. , Smits Marion , Chappell Michael A. , Warnert Esther A. H.
Published: March 2021

Purpose

Relative cerebral blood volume (rCBV) is the most widely used parameter derived from DSC perfusion MR imaging for predicting brain tumor aggressiveness. However, accurate rCBV estimation is challenging in enhancing glioma, because of contrast agent extravasation through a disrupted blood-brain barrier (BBB), and even for nonenhancing glioma with an intact BBB, due to an elevated steady-state contrast agent concentration in the vasculature after first passage. In this study a thorough investigation of the effects of two different leakage correction algorithms on rCBV estimation for enhancing and nonenhancing tumors was conducted.

Methods

Two datasets were used retrospectively in this study: 1. A publicly available TCIA dataset (49 patients with 35 enhancing and 14 nonenhancing glioma); 2. A dataset acquired clinically at Erasmus MC (EMC, Rotterdam, NL) (47 patients with 20 enhancing and 27 nonenhancing glial brain lesions). The leakage correction algorithms investigated in this study were: a unidirectional model-based algorithm with flux of contrast agent from the intra- to the extravascular extracellular space (EES); and a bidirectional model-based algorithm additionally including flow from EES to the intravascular space.

Results

In enhancing glioma, the estimated average contrast-enhanced tumor rCBV significantly (Bonferroni corrected Wilcoxon Signed Rank Test, p < 0.05) decreased across the patients when applying unidirectional and bidirectional correction: 4.00 ± 2.11 (uncorrected), 3.19 ± 1.65 (unidirectional), and 2.91 ± 1.55 (bidirectional) in TCIA dataset and 2.51 ± 1.3 (uncorrected), 1.72 ± 0.84 (unidirectional), and 1.59 ± 0.9 (bidirectional) in EMC dataset. In nonenhancing glioma, a significant but smaller difference in observed rCBV was found after application of both correction methods used in this study: 1.42 ± 0.60 (uncorrected), 1.28 ± 0.46 (unidirectional), and 1.24 ± 0.37 (bidirectional) in TCIA dataset and 0.91 ± 0.49 (uncorrected), 0.77 ± 0.37 (unidirectional), and 0.67 ± 0.34 (bidirectional) in EMC dataset.

Conclusion

Both leakage correction algorithms were found to change rCBV estimation with BBB disruption in enhancing glioma, and to a lesser degree in nonenhancing glioma. Stronger effects were found for bidirectional leakage correction than for unidirectional leakage correction.
A Patient With Focal Myositis and Primary Cutaneous Diffuse Large B-Cell Lymphoma: A Case Report
Authors: Wu Quanxin , Xu Cheng , Wang Li
Published: March 2021

We report a rare case of a 92-year-old male, with a history of statin/ezetimibe intake, complained of pain and swelling of left forearm. The patient was diagnosed with focal myositis at first. Symptoms aggravated after 2 months of immunomodulatory therapy, and accompanied with protrusion lesion at left elbow. Biopsy of the protrusion lesion turned out to be primary cutaneous diffuse large B-cell lymphoma.
Arginine Therapy for Lung Diseases
Authors: Scott Jeremy A. , Maarsingh Harm , Holguin Fernando , Grasemann Hartmut
Published: March 2021

Nitric oxide (NO) is produced by a family of isoenzymes, nitric oxide synthases (NOSs), which all utilize L-arginine as substrate. The production of NO in the lung and airways can play a number of roles during lung development, regulates airway and vascular smooth muscle tone, and is involved in inflammatory processes and host defense. Altered L-arginine/NO homeostasis, due to the accumulation of endogenous NOS inhibitors and competition for substrate with the arginase enzymes, has been found to play a role in various conditions affecting the lung and in pulmonary diseases, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pulmonary hypertension, and bronchopulmonary dysplasia. Different therapeutic strategies to increase L-arginine levels or bioavailability are currently being explored in pre-clinical and clinical studies. These include supplementation of L-arginine or L-citrulline and inhibition of arginase.
Modeling the Epidemic Growth of Preprints on COVID-19 and SARS-CoV-2
Authors: Vasconcelos Giovani L. , Cordeiro Luan P. , Duarte-Filho Gerson C. , Brum Arthur A.
Published: March 2021

The response of the scientific community to the global health emergency caused by the COVID-19 pandemic has produced an unprecedented number of manuscripts in a short period of time, the vast majority of which have been shared in the form of preprints posted on online preprint repositories before peer review. This surge in preprint publications has in itself attracted considerable attention, although mostly in the bibliometrics literature. In the present study we apply a mathematical growth model, known as the generalized Richards model, to describe the time evolution of the cumulative number of COVID-19 related preprints. This mathematical approach allows us to infer several important aspects concerning the underlying growth dynamics, such as its current stage and its possible evolution in the near future. We also analyze the rank-frequency distribution of preprints servers, ordered by the number of COVID-19 preprints they host, and find that it follows a power law in the low rank (high frequency) region, with the high rank (low frequency) tail being better described by a q-exponential function. The Zipf-like law in the high frequency regime indicates the presence of a cumulative advantage effect, whereby servers that already have more preprints receive more submissions.
Assessing Different Temporal Scales of Calcium Dynamics in Networks of Beta Cell Populations
Authors: Zmazek Jan , Klemen Maša Skelin , Markovič Rene , Dolenšek Jurij , Marhl Marko , Stožer Andraž , Gosak Marko
Published: March 2021

Beta cells within the pancreatic islets of Langerhans respond to stimulation with coherent oscillations of membrane potential and intracellular calcium concentration that presumably drive the pulsatile exocytosis of insulin. Their rhythmic activity is multimodal, resulting from networked feedback interactions of various oscillatory subsystems, such as the glycolytic, mitochondrial, and electrical/calcium components. How these oscillatory modules interact and affect the collective cellular activity, which is a prerequisite for proper hormone release, is incompletely understood. In the present work, we combined advanced confocal Ca2+ imaging in fresh mouse pancreas tissue slices with time series analysis and network science approaches to unveil the glucose-dependent characteristics of different oscillatory components on both the intra- and inter-cellular level. Our results reveal an interrelationship between the metabolically driven low-frequency component and the electrically driven high-frequency component, with the latter exhibiting the highest bursting rates around the peaks of the slow component and the lowest around the nadirs. Moreover, the activity, as well as the average synchronicity of the fast component, considerably increased with increasing stimulatory glucose concentration, whereas the stimulation level did not affect any of these parameters in the slow component domain. Remarkably, in both dynamical components, the average correlation decreased similarly with intercellular distance, which implies that intercellular communication affects the synchronicity of both types of oscillations. To explore the intra-islet synchronization patterns in more detail, we constructed functional connectivity maps. The subsequent comparison of network characteristics of different oscillatory components showed more locally clustered and segregated networks of fast oscillatory activity, while the slow oscillations were more global, resulting in several long-range connections and a more cohesive structure. Besides the structural differences, we found a relatively weak relationship between the fast and slow network layer, which suggests that different synchronization mechanisms shape the collective cellular activity in islets, a finding which has to be kept in mind in future studies employing different oscillations for constructing networks.
Doppler Flow Response Following Running Exercise Differs Between Healthy and Tendinopathic Achilles Tendons
Authors: Risch Lucie , Mayer Frank , Cassel Michael
Published: March 2021

Background

The relationship between exercise-induced intratendinous blood flow (IBF) and tendon pathology or training exposure is unclear.

Objective

This study investigates the acute effect of running exercise on sonographic detectable IBF in healthy and tendinopathic Achilles tendons (ATs) of runners and recreational participants.

Methods

48 participants (43 ± 13 years, 176 ± 9 cm, 75 ± 11 kg) performed a standardized submaximal 30-min constant load treadmill run with Doppler ultrasound “Advanced dynamic flow” examinations before (Upre) and 5, 30, 60, and 120 min (U5-U120) afterward. Included were runners (>30 km/week) and recreational participants (<10 km/week) with healthy (Hrun, n = 10; Hrec, n = 15) or tendinopathic (Trun, n = 13; Trec, n = 10) ATs. IBF was assessed by counting number [n] of intratendinous vessels. IBF data are presented descriptively (%, median [minimum to maximum range] for baseline-IBF and IBF-difference post-exercise). Statistical differences for group and time point IBF and IBF changes were analyzed with Friedman and Kruskal-Wallis ANOVA (α = 0.05).

Results

At baseline, IBF was detected in 40% (3 [1–6]) of Hrun, in 53% (4 [1–5]) of Hrec, in 85% (3 [1–25]) of Trun, and 70% (10 [2–30]) of Trec. At U5 IBF responded to exercise in 30% (3 [−1–9]) of Hrun, in 53% (4 [−2–6]) of Hrec, in 70% (4 [−10–10]) of Trun, and in 80% (5 [1–10]) of Trec. While IBF in 80% of healthy responding ATs returned to baseline at U30, IBF remained elevated until U120 in 60% of tendinopathic ATs. Within groups, IBF changes from Upre-U120 were significant for Hrec (p < 0.01), Trun (p = 0.05), and Trec (p < 0.01). Between groups, IBF changes in consecutive examinations were not significantly different (p > 0.05) but IBF-level was significantly higher at all measurement time points in tendinopathic versus healthy ATs (p < 0.05).

Conclusion

Irrespective of training status and tendon pathology, running leads to an immediate increase of IBF in responding tendons. This increase occurs shortly in healthy and prolonged in tendinopathic ATs. Training exposure does not alter IBF occurrence, but IBF level is elevated in tendon pathology. While an immediate exercise-induced IBF increase is a physiological response, prolonged IBF is considered a pathological finding associated with Achilles tendinopathy.