bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct Cardiac Actions of Sodium-Glucose Cotransporter 2 Inhibition Improve Mitochondrial Function and Attenuate Oxidative Stress in Pressure Overload-Induced Heart Failure
Authors: Li Xuan , Flynn Elizabeth R. , do Carmo Jussara M. , Wang Zhen , da Silva Alexandre A. , Mouton Alan J. , Omoto Ana C. M. , Hall Michael E. , Hall John E.
Published: May 2022

Clinical trials showed that sodium-glucose cotransporter 2 (SGLT2) inhibitors, a class of drugs developed for treating diabetes mellitus, improve prognosis of patients with heart failure (HF). However, the mechanisms for cardioprotection by SGLT2 inhibitors are still unclear. Mitochondrial dysfunction and oxidative stress play important roles in progression of HF. This study tested the hypothesis that empagliflozin (EMPA), a highly selective SGLT2 inhibitor, improves mitochondrial function and reduces reactive oxygen species (ROS) while enhancing cardiac performance through direct effects on the heart in a non-diabetic mouse model of HF induced by transverse aortic constriction (TAC). EMPA or vehicle was administered orally for 4 weeks starting 2 weeks post-TAC. EMPA treatment did not alter blood glucose or body weight but significantly attenuated TAC-induced cardiac dysfunction and ventricular remodeling. Impaired mitochondrial oxidative phosphorylation (OXPHOS) in failing hearts was significantly improved by EMPA. EMPA treatment also enhanced mitochondrial biogenesis and restored normal mitochondria morphology. Although TAC increased mitochondrial ROS and decreased endogenous antioxidants, EMPA markedly inhibited cardiac ROS production and upregulated expression of endogenous antioxidants. In addition, EMPA enhanced autophagy and decreased cardiac apoptosis in TAC-induced HF. Importantly, mitochondrial respiration significantly increased in ex vivo cardiac fibers after direct treatment with EMPA. Our results indicate that EMPA has direct effects on the heart, independently of reductions in blood glucose, to enhance mitochondrial function by upregulating mitochondrial biogenesis, enhancing OXPHOS, reducing ROS production, attenuating apoptosis, and increasing autophagy to improve overall cardiac function in a non-diabetic model of pressure overload-induced HF.
Association of QTc Interval and V4-S Wave With Appropriate ICD Therapy in Hypertrophic Cardiomyopathy
Authors: Zhang Nixiao , Cheng Sijing , Niu Hongxia , Gu Min , Peng Hui , Sun Zhijun , Liu Xi , Deng Yu , Chen Xuhua , Hua Wei
Published: May 2022

Background

Ventricular arrhythmias in patients with hypertrophic cardiomyopathy (HCM) may lead to sudden cardiac death (SCD). We aimed to investigate the relationship between electrocardiogram (ECG) indicators and the risk of appropriate implantable cardioverter-defibrillator (ICD) therapy in HCM.

Methods

The HCM patients receiving ICD implantation were enrolled consecutively. QT interval correction (QTc) was calculated using Bazett's formula. Long or deep S wave in V4 lead was defined as duration time >50 ms and/or voltage amplitude >0.6 mV. The endpoint in our study was at least one ICD appropriate therapy triggered by ventricular tachyarrhythmia (VT) or ventricular fibrillation (VF), including anti-tachyarrhythmia pacing (ATP) and electrical shock.

Results

A total of 149 patients with HCM (mean age 53 ± 14 years, male 69.8%) were studied. Appropriate ICD therapies occurred in 47 patients (31.5%) during a median follow-up of 2.9 years. Cox regression analysis showed that long or deep S wave in V4 lead [hazard ratio (HR) 1.955, 95% confidence interval (CI) 1.017–3.759, P = 0.045] and QTc interval (HR 1.014, 95% CI 1.008–1.021, P < 0.001) were independent risk factors for appropriate ICD therapy. The ROC showed that the optimal cut-off point value for the QTc interval to predict the appropriate ICD therapy was 464 ms, and the AUC was 0.658 (95% CI 0.544–0.762, P = 0.002). The AUC for S wave anomalies in V4 lead was 0.608 (95% CI 0.511–0.706, P = 0.034). We developed a new model that combined the QTc interval and S wave anomalies in V4 lead based on four patient groups. Patients with QTc ≥464 ms and long or deep V4-S wave had the highest risk of developing appropriate ICD therapy (log-rank P < 0.0001). After adding QTc interval and V4-S wave anomalies into the HCM-risk-SCD model, the prediction effect of the new model was significantly improved, and the NRI was 0.302.

Conclusions

In this HCM cohort, QTc and S wave anomalies in V4 lead were found to be significant and strong predictors of the risk of appropriate ICD therapy. Patients with QTc ≥464 ms and long or deep S wave had the highest risk. After QTc interval and V4-S wave anomalies adding to the HCM-risk-SCD model, the prediction effect is significantly improved.
ICA II Alleviates Testicular Torsion Injury by Dampening the Oxidative and Inflammatory Stress
Authors: Chi Ani , Yang Bicheng , Cao Xiaohui , Wang Zhenqing , Liu Hanchao , Dai Hao , Deng Chunhua , Zhang Min
Published: May 2022

Testicular torsion-detorsion is an ischaemia-reperfusion-induced male gonad injury that may lead to male infertility. Oxidative stress plays an important role in the ischaemia-reperfusion injury. Icariside II (ICA II) prevents oxidative stress and has obvious protective effects on spermatogenic function. The present study was aimed to investigate therapeutic potentials of ICA II on testicular torsion. 72 mice were randomly divided into three groups: sham-operated control group (n = 24), testicular ischemia-reperfusion + saline group (n = 24) and testicular ischemia-reperfusion + icariside II treated group (n = 24). Testicular ischemia-reperfusion was induced by the left testis rotated 360 degrees in a clockwise direction for 30 minutes followed by detorsion, the contralateral testis was removed. ICA II in saline (5 mg/kg/day) was administrated by gavage immediately after detorsion. The results demonstrated that ICA II alleviated testicular damage by mitigating spermatogenic cell injury and improving testosterone production in mouse models of testicular torsion. We revealed that ICA II alleviated oxidative stress and apoptosis in the testes, reduced inflammatory infiltration and accelerated angiogenesis. Briefly, ICA II administration ameliorated testicular damage by improving spermatogenic function and testosterone production, which supports its use as a pharmacological treatment of testicular torsion.
Discussion on the Reconstruction of Electrical Engineering Undergraduate Teaching Scheme Facing the New Generation Power System
Authors: Gong Wangyang , Deng Feng , Wang Xuhong , Chen Fangfang
Published: May 2022

With the construction of a new generation of electric power systems with new energy as the main body, there are major changes in the traditional electrical engineering undergraduate teaching system. On the one hand, the dynamic operating characteristics of the power system dominated by new energy sources and dominated by power electronic equipment will be significantly different from the traditional power system dominated by synchronous generators. Therefore, there is an urgent need to reform the curriculum system to train electrical engineering professionals who can adapt to the future development trend of the power system. On the other hand, with the rapid advancement of advanced information technology in recent years, the application of cutting-edge technologies such as cloud computing, big data, and artificial intelligence in the field of electrical engineering has become more and more in-depth. Therefore, there is an urgent need to cultivate advanced technical experts who possess more advanced information theory and cybernetics knowledge and master the application of cutting-edge information technology in the field of electrical engineering. From the perspective of student training and professional construction needs, this paper systematically analyzes the lag of the traditional electrical engineering curriculum system, and analyzes the knowledge needs of electrical engineering students adapting to the development of the new generation of power systems. From the perspective of teaching schemes, curriculum systems, and evaluation systems, a plan for restructuring the teaching system was proposed. The work in this article can provide a reference for the training of college students majoring in electrical engineering, and it can also provide a more feasible improvement idea for the training of college students in other majors.
A Temporal-Spatial Model Based Short-Term Power Load Forecasting Method in COVID-19 Context
Authors: Liu Bowen , Xu Da , Jiang Lin , Chen Shuangyin , He Yong
Published: May 2022

The worldwide coronavirus disease 2019 (COVID-19) pandemic has greatly affected the power system operations as a result of the great changes of socio-economic behaviours. This paper proposes a short-term load forecasting method in COVID-19 context based on temporal-spatial model. In the spatial scale, the cross-domain couplings analysis of multi-factor in COVID-19 dataset is performed by means of copula theory, while COVID-19 time-series data is decomposed via variational mode decomposition algorithm into different intrinsic mode functions in the temporal scale. The forecasting values of load demand can then be acquired by combining forecasted IMFs from light Gradient Boosting Machine (LightGBM) algorithm. The performance and superiority of the proposed temporal-spatial forecasting model are evaluated and verified through a comprehensive cross-domain dataset.
Does Fiscal Decentralization Promote or Inhibit the Improvement of Carbon Productivity? Empirical Analysis Based on China’s Data
Authors: Feng Guo , Shulian Xue , Renjin Sun
Published: May 2022

Based on the panel data of 30 provinces in China from 2010 to 2019, this study empirically analyzes the relationship between fiscal decentralization and carbon productivity using a spatial econometric model and calculates the direct effect, spatial spillover effect, and total effect of fiscal revenue decentralization and fiscal expenditure decentralization on carbon productivity through effect decomposition. The empirical results show that 1) the spatial agglomeration effect of China’s provincial carbon productivity is obvious, which shows an upward trend. The heterogeneity of carbon productivity among different provinces is obvious. The overall performance is as follows: Eastern provinces > Central provinces > Western provinces. 2) Fiscal revenue decentralization and fiscal expenditure decentralization can significantly promote the improvement of carbon productivity. Fiscal expenditure decentralization plays a greater role in promoting carbon productivity than fiscal revenue decentralization. 3) Fiscal revenue decentralization and fiscal expenditure decentralization have significant positive direct effects and negative spatial spillover effects on the improvement of carbon productivity. Increasing fiscal decentralization is conducive to improving the carbon productivity of the province, but it will inhibit the carbon productivity of neighboring provinces. Finally, it puts forward policy suggestions to promote the improvement of carbon productivity from the perspective of fiscal decentralization.
Financial Risk, Renewable Energy Technology Budgets, and Environmental Sustainability: Is Going Green Possible?
Authors: Ahmad Mahmood , Ahmed Zahoor , Gavurova Beata , Oláh Judit
Published: May 2022

Since the industrial revolution, countries have been facing the issue of climate change and environmental degradation. It is widely believed that the investment in research and development of renewable energy can play a pivotal role in fighting against climate change. However, the financial risk also increases, which can influence renewable energy technology R&D budgets and environmental sustainability. Nevertheless, the current literature is silent on the linkage between financial risk, renewable energy technology budgets, and environmental quality. Against this backdrop, this article attempts to explore the dynamic linkage between financial risk, renewable energy technology budgets, and ecological footprint under the Environment Kuznets Curve (EKC) framework in Organization for Economic Cooperation and Development (OECD) countries. For this purpose, yearly data from 1984 to 2018 is employed using the advanced panel data estimation methods that address the slope heterogeneity and cross-sectional dependence issues. The results indicate that improvement in the financial risk index significantly decreases footprints, and renewable energy technology budgets also promote environmental sustainability. Economic globalization poses a significant negative effect on the ecological footprint, while energy consumption adds to the footprint. Moreover, the findings validated the EKC hypothesis in OECD countries. In addition, a unidirectional causality is detected from financial risk to renewable technology energy budgets, while bidirectional causality exists between financial risk and ecological footprint, and between financial risk, and economic growth. Based on the empirical findings, policy suggestions are presented to promote environmental sustainability.
Effect of Altitude on Volatile Organic and Phenolic Compounds of Artemisia brevifolia Wall ex Dc. From the Western Himalayas
Authors: Nataraj Nandita , Hussain Manzoor , Ibrahim Mohd , Hausmann Alexander E. , Rao Srinivas , Kaur Satwinderjeet , Khazir Jabeena , Mir Bilal Ahmad , Olsson Shannon B.
Published: May 2022

Adaptation to changing environmental conditions is a driver of plant diversification. Elevational gradients offer a unique opportunity for investigating adaptation to a range of climatic conditions. The use of specialized metabolites as volatile and phenolic compounds is a major adaptation in plants, affecting their reproductive success and survival by attracting pollinators and protecting themselves from herbivores and other stressors. The wormseed Artemisia brevifolia can be found across multiple elevations in the Western Himalayas, a region that is considered a biodiversity hotspot and is highly impacted by climate change. This study aims at understanding the volatile and phenolic compounds produced by A. brevifolia in the high elevation cold deserts of the Western Himalayas with the view to understanding the survival strategies employed by plants under harsh conditions. Across four sampling sites with different elevations, polydimethylsiloxane (PDMS) sampling and subsequent GCMS analyses showed that the total number of volatile compounds in the plant headspace increased with elevation and that this trend was largely driven by an increase in compounds with low volatility, which might improve the plant’s resilience to abiotic stress. HPLC analyses showed no effect of elevation on the total number of phenolic compounds detected in both young and mature leaves. However, the concentration of the majority of phenolic compounds decreased with elevation. As the production of phenolic defense compounds is a costly trait, plants at higher elevations might face a trade-off between energy expenditure and protecting themselves from herbivores. This study can therefore help us understand how plants adjust secondary metabolite production to cope with harsh environments and reveal the climate adaptability of such species in highly threatened regions of our planet such as the Himalayas.
Base Editing in Peanut Using CRISPR/nCas9
Authors: Neelakandan Anjanasree K. , Subedi Binita , Traore Sy M. , Binagwa Papias , Wright David A. , He Guohao
Published: May 2022

Peanut (Arachis hypogaea L.), an allotetraploid legume of the Fabaceae family, is able to thrive in tropical and subtropical regions and is considered as a promising oil seed crop worldwide. Increasing the content of oleic acid has become one of the major goals in peanut breeding because of health benefits such as reduced blood cholesterol level, antioxidant properties and industrial benefits such as longer shelf life. Genomic sequencing of peanut has provided evidence of homeologous AhFAD2A and AhFAD2B genes encoding Fatty Acid Desaturase2 (FAD2), which are responsible for catalyzing the conversion of monounsaturated oleic acid into polyunsaturated linoleic acid. Research studies demonstrate that mutations resulting in a frameshift or stop codon in an FAD2 gene leads to higher oleic acid content in oil. In this study, two expression vectors, pDW3873 and pDW3876, were constructed using Cas9 fused to different deaminases, which were tested as tools to induce point mutations in the promoter and the coding sequences of peanut AhFAD2 genes. Both constructs harbor the single nuclease null variant, nCas9 D10A, to which the PmCDA1 cytosine deaminase was fused to the C-terminal (pDW3873) while rAPOBEC1 deaminase and an uracil glycosylase inhibitor (UGI) were fused to the N-terminal and the C-terminal respectively (pDW3876). Three gRNAs were cloned independently into both constructs and the functionality and efficiency were tested at three target sites in the AhFAD2 genes. Both constructs displayed base editing activity in which cytosine was replaced by thymine or other bases in the targeted editing window. pDW3873 showed higher efficiency compared to pDW3876 suggesting that the former is a better base editor in peanut. This is an important step forward considering introgression of existing mutations into elite varieties can take up to 15 years making this tool a benefit for peanut breeders, farmers, industry and ultimately for consumers.
An Integrated Systematic Analysis and the Clinical Significance of Hepcidin in Common Malignancies of the Male Genitourinary System
Authors: Wang Xiaogang , Shi Qianqian , Gong Pengfeng , Zhou Cuixing , Cao Yunjie
Published: May 2022

Tumors of the male genitourinary system are of great concern to the health of men worldwide. Although emerging experiment-based evidence indicates an association between hepcidin and such cancers, an integrated analysis is still lacking. For this reason, in this study, we determined the underlying oncogenic functions of hepcidin in common male genitourinary system tumors, including bladder urothelial carcinoma (BLCA), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), prostate adenocarcinoma (PRAD), and testicular germ cell tumors (TGCT) according to the data from The Cancer Genome Atlas. We found that hepcidin was highly expressed in kidney and testicular cancers. Meanwhile, the expression level of hepcidin was distinctly associated with the prognosis and immune cell infiltration in male patients with certain genitourinary system cancers, especially in KIRC. Elevated hepcidin levels also present as a risk factor in male genitourinary system tumors. Moreover, enrichment analyses revealed that some of the principal associated signaling pathways involving hepcidin and its related genes are identified as tumorigenesis-related. Immunofluorescence staining confirmed the conclusion of our immune infiltration analysis in KIRC tissue. In this study, for the first time, we provided evidence for the oncogenic function of hepcidin in different types of male genitourinary system tumors.
Comprehensive Analysis of the Expression and Prognosis for the DREAM Complex in Human Cancers
Authors: Wang Lulu , Liu Xiaowei
Published: May 2022

The DREAM complex is an evolutionarily conserved cell cycle regulating multi-protein complex. In addition to playing an essential function in the cell cycle, it also plays a vital role in various survival activities. Accumulating evidence suggests that the DREAM complex plays a crucial role in oncogenesis. However, the regulatory mechanism of the DREAM complex in cancer remains unclear. This study used multi-omics data from Cancer Genome Atlas and Cancer Cell Line Encyclopedia to comprehensively identify the DREAM complex in tumor samples from 33 cancer types. In the genomic landscape, we identified the missense mutation as the dominant alteration events. Expression analysis showed that the expression of methylation-mediated the DREAM complex was downregulated. In addition, we found that the expression of the DREAM complex can be performed to predict the survival of various cancer patients. Pathway activation analysis showed that the DREAM complex is related to apoptosis inhibition, cell cycle, DNA damage response, RAS/MAPK, and RTK signaling pathway activation. Importantly, through a comprehensive analysis of drug sensitivity genomics in cancer databases, we identified a number of potential drugs that may target the DREAM complex. In summary, this study revealed the genomic changes and clinical features of the DREAM complex in 33 cancers, which may also provide new insights for cancer treatment and may offer alternative options for the treatment of clinically refractory cancers.
Whole-Genome/Exome Sequencing Uncovers Mutations and Copy Number Variations in Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System
Authors: Zhu Qiong , Wang Jianchao , Zhang Wenfang , Zhu Weifeng , Wu Zaizeng , Chen Yanping , Chen Musheng , Zheng Limei , Tang Jianqing , Zhang Sheng , Wang Di , Wang Xingfu , Chen Gang
Published: May 2022

Background/objective: Identification of key genetic alterations is of importance in the targeted therapies of primary central nervous system lymphoma (PCNSL). However, only a small number of studies have been carried out in PCNSL. In this study, we further described the genetic mutations and copy number variations (CNVs) in PCNSL patients using whole-genome/exome sequencing (WGS/WES), as well as revealed their associations with patients’ clinicopathological features and prognosis.

Methods: Tumor specimens from 38 patients with primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL) were enrolled to WGS (n = 24) or WES (n = 14). The CNVs and mutations of 24 samples (WGS) and 38 samples (WGS/WES) were characterized, respectively. The associations between CNVs and mutations with the overall survival rates of PCNSL patients were also evaluated.

Results: The most common mutations were identified in IGLL5 (68%), PIM1 (63%), MYD88 (55%), CD79B (42%), BTG2 (39%), PCLO (39%), KMT2D (34%), and BTG1 (29%) genes. Among the mutated genes, EP300, ETV6, and HIST1H1E mutations were exclusively detected in the elderly, while DUSP2 mutations were associated with the immune microenvironment indicators. In addition, KMT2D mutation was associated with a poor prognosis. In addition, 488 CNVs including 91 gains and 397 deletions were observed across 24 samples from WGS results. Notably, 1q31.3 amplification was closely associated with the poor prognosis of PCNSL patients.

Conclusion: This study further characterizes the genomic landscape of primary CNS DLBCL using WGS/WES, which provides insight into understanding the pathogenesis of PCNSL and fosters new ideas for the targeted treatment of PCNSL.
Alcohol Impairs Immunometabolism and Promotes Naïve T Cell Differentiation to Pro-Inflammatory Th1 CD4+ T Cells
Authors: McTernan Patrick M. , Levitt Danielle E. , Welsh David A. , Simon Liz , Siggins Robert W. , Molina Patricia E.
Published: May 2022

CD4+ T cell differentiation to pro-inflammatory and immunosuppressive subsets depends on immunometabolism. Pro-inflammatory CD4+ subsets rely on glycolysis, while immunosuppressive Treg cells require functional mitochondria for their differentiation and function. Previous pre-clinical studies have shown that ethanol (EtOH) administration increases pro-inflammatory CD4+ T cell subsets; whether this shift in immunophenotype is linked to alterations in CD4+ T cell metabolism had not been previously examined. The objective of this study was to determine whether ethanol alters CD4+ immunometabolism, and whether this affects CD4+ T cell differentiation. Naïve human CD4+ T cells were plated on anti-CD3 coated plates with soluble anti-CD28, and differentiated with IL-12 in the presence of ethanol (0 and 50 mM) for 3 days. Both Tbet-expressing (Th1) and FOXP3-expressing (Treg) CD4+ T cells increased after differentiation. Ethanol dysregulated CD4+ T cell differentiation by increasing Th1 and decreasing Treg CD4+ T cell subsets. Ethanol increased glycolysis and impaired oxidative phosphorylation in differentiated CD4+ T cells. Moreover, the glycolytic inhibitor 2-deoxyglucose (2-DG) prevented the ethanol-mediated increase in Tbet-expressing CD4+ T cells but did not attenuate the decrease in FOXP3 expression in differentiated CD4+ T cells. Ethanol increased Treg mitochondrial volume and altered expression of genes implicated in mitophagy and autophagosome formation (PINK1 and ATG7). These results suggest that ethanol impairs CD4+ T cell immunometabolism and disrupts mitochondrial repair processes as it promotes CD4+ T cell differentiation to a pro-inflammatory phenotype.
Soluble SIRP-Alpha Promotes Murine Acute Lung Injury Through Suppressing Macrophage Phagocytosis
Authors: Shen Qinjun , Zhao Li , Pan Linyue , Li Dandan , Chen Gang , Chen Zhihong , Jiang Zhilong
Published: May 2022

Soluble signal regulatory protein-alpha (SIRP-alpha) is elevated in bronchoalveolar lavage (BAL) of mice with lipopolysaccharides (LPS)-induced acute lung injury (ALI). To define the role of soluble SIRP-alpha in the pathogenesis of ALI, we established murine ALI in wild-type (WT) and SIRP-alpha knock-out (KO) mice by intratracheal administration of LPS. The results indicated that lack of SIRP-alpha significantly reduced the pathogenesis of ALI, in association with attenuated lung inflammation, infiltration of neutrophils and expression of pro-inflammatory cytokines in mice. In addition, lack of SIRP-alpha reduced the expression of pro-inflammatory cytokines in LPS-treated bone marrow-derived macrophages (BMDMs) from KO mice, accompanied with improved macrophage phagocytosis. Blockade of soluble SIRP-alpha activity in ALI BAL by anti-SIRP-alpha antibody (aSIRP) effectively reduced the expression of TNF-alpha and IL-6 mRNA transcripts and proteins, improved macrophage phagocytosis in vitro. In addition, lack of SIRP-alpha reduced activation of Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) and improved activation of signal transducer and activator of transcription-3 (STAT3) and STAT6. Suppression of SHP-1 activity by tyrosine phosphatase inhibitor 1 (TPI-1) increased activation of STAT3 and STAT6, and improved macrophage phagocytosis, that was effectively reversed by STAT3 and STAT6 inhibitors. Thereby, SIRP-alpha suppressed macrophage phagocytosis through activation of SHP-1, subsequently inhibiting downstream STAT3 and STAT6 signaling. Lack of SIRP-alpha attenuated murine ALI possibly through increasing phagocytosis, and improving STAT3 and STAT6 signaling in macrophages. SIRP-alpha would be promising biomarker and molecular target in the treatment of murine ALI and patients with acute respiratory distress syndrome (ARDS).
Modulation of Gut Microbiota by Magnesium Isoglycyrrhizinate Mediates Enhancement of Intestinal Barrier Function and Amelioration of Methotrexate-Induced Liver Injury
Authors: Xia Yawen , Shi Hang , Qian Cheng , Han Hongkuan , Lu Keqin , Tao Ruizhi , Gu Renjun , Zhao Yang , Wei Zhonghong , Lu Yin
Published: May 2022

Background

The gut–liver axis plays a crucial role in various liver diseases. Therefore, targeting this crosstalk may provide a new treatment strategy for liver diseases. However, the exact mechanism underlying this crosstalk and its impact on drug-induced liver injury (DILI) requires clarification.

Aim

This study aimed to investigate the potential mechanism and therapeutic effect of MgIG on MTX-induced liver injury, which is associated with the gut–liver axis and gut microbiota.

Methods

An MTX-induced liver injury model was generated after 20-mg/kg/3d MTX application for 30 days. Meanwhile, the treatment group was treated with 40-mg/kg MgIG daily. Histological examination, aminotransferase, and aspartate aminotransferase enzyme levels were estimated to evaluate liver function. Immune cells infiltration and inflammatory cytokines were detected to indicate inflammation levels. Colon histological score, intestinal barrier leakage, and expression of tight junctions were employed to assess the intestinal injury. Bacterial translocation was observed using fluorescent in situ hybridisation, colony-forming unit counting, and lipopolysaccharide detection. Alterations in gut microbial composition were analysed using 16s rDNA sequencing and relative quantitative polymerase chain reaction. Short-chain-fatty-acids and lactic acid concentrations were then utilized to validate changes in metabolites of specific bacteria. Lactobacillus sp. supplement and fecal microbiota transplantation were used to evaluate gut microbiota contribution.

Results

MTX-induced intestinal and liver injuries were significantly alleviated using MgIG treatment. Bacterial translocation resulting from the intestinal barrier disruption was considered a crucial cause of MTX-induced liver injury and the therapeutic target of MgIG. Moreover, MgIG was speculated to have changed the gut microbial composition by up-regulating probiotic Lactobacillus and down-regulating Muribaculaceae, thereby remodelling the intestinal barrier and inhibiting bacterial translocation.

Conclusion

The MTX-induced intestinal barrier was protected owing to MgIG administration, which reshaped the gut microbial composition and inhibited bacterial translocation into the liver, thus attenuating MTX-related DILI.
CCR4 and CCR5 Involvement in Monocyte-Derived Macrophage Migration in Neuroinflammation
Authors: Kim Jong Youl , Kim Jiwon , Huang Meiying , Kosonen Renée , Lee Jong Eun
Published: May 2022

Microglia, resident macrophages in the brain, play major roles in neuroinflammation after an acute many neurological diseases, including stroke. Our recent animal stroke model showed that interleukin (IL)-4 and IL-13 released by microglia are converted into monocyte-derived macrophages. However, the correlation with the migration mechanism of these cells is still unclear. This study aimed to clarify the effect of these cells on their migration and to identify potential targets that influence neuroinflammatory conditions. Inflammatory conditions were induced by lipopolysaccharide (LPS) treatment in in vitro and in vivo models. Cell migration was observed using transwell assay, and target chemokines were screened using the proteome profiler array in the in vitro model. Intravital, IVIS, and CLARITY imaging were used in the in vivo model. After LPS (1 ng/ml) treatment in BV2 (microglia cell line) and J774 (monocyte/macrophage cell line) cells, BV2 migration was approximately two-fold more enhanced compared to J774 migration. Overall, six types of chemokine C-C motif ligands (CCLs) were detected from the BV2 conditioned medium with LPS. These CCLs were related to C-C motif receptor (CCR)4 and CCR5. In the in vivo model, CCR4 and CCR5 antagonist significantly inhibited the migration of monocyte-derived macrophages to brain tissue following LPS (5 µg) treatment. In conclusion, the chemokines released by microglia may influence migration of monocyte-derived macrophages in necroinflammation conditions inducted by microglial activation. CCR4 and CCR5 expressed on monocyte-derived macrophages interacted with these chemokines and induced migration. Therefore, CCR4 and CCR5 may be explored as new therapeutic targets for neuroinflammation.
Pemphigus Foliaceus Autoantibodies Induce Redistribution Primarily of Extradesmosomal Desmoglein 1 in the Cell Membrane
Authors: Hiermaier Matthias , Kugelmann Daniela , Radeva Mariya Y. , Didona Dario , Ghoreschi Kamran , Farzan Solimani , Hertl Michael , Waschke Jens
Published: May 2022

The autoimmune dermatosis pemphigus foliaceus (PF) is predominantly caused by IgG autoantibodies against the desmosomal cadherin desmoglein (Dsg) 1. The exact mechanisms that lead to the characteristic epidermal blistering are not yet fully understood. In the present study, we used a variety of biophysical methods to examine the fate of membrane-bound Dsg1 after incubation with PF patients’ IgG. Dispase-based dissociation assays confirmed that PF-IgG used for this study reduced intercellular adhesion in a manner dependent on phospholipase C (PLC)/Ca2+ and extracellular signal-regulated kinase (ERK) 1/2 signaling. Atomic force microscopy (AFM) revealed that Dsg1 binding on single molecule level paralleled effects on keratinocyte adhesion under the different conditions. Stimulated emission depletion (STED) super-resolution microscopy was used to investigate the localization of Dsg1 after PF-IgG incubation for 24 h. Under control conditions, Dsg1 was found to be in part co-localized with desmoplakin and thus inside of desmosomes as well as extra-desmosomal along the cell border. Incubation with PF-IgG reduced the extra-desmosomal Dsg1 fraction. In line with this, fluorescence recovery after photobleaching (FRAP) experiments demonstrated a strongly reduced mobility of Dsg1 in the cell membrane after PF-IgG treatment indicating remaining Dsg1 molecules were primarily located inside desmosomes. Mechanistically, experiments confirmed the involvement of PLC/Ca2+ since inhibition of PLC or 1,4,5-trisphosphate (IP3) receptor to reduce cytosolic Ca2+ reverted the effects of PF-IgG on Dsg1 intra-membrane mobility and localization. Taken together, our findings suggest that during the first 24 h PF-IgG induce redistribution predominantly of membrane-bound extradesmosomal Dsg1 in a PLC/Ca2+ dependent manner whereas Dsg1-containing desmosomes remain.
Novel Insights Into the Immune-Regulatory Functions of Mast Cells in the Cutaneous Immune Response
Authors: Honda Tetsuya , Keith Yuki Honda
Published: May 2022

Skin is a frontline organ that is continuously exposed to external stimuli, including pathogens. Various immune cells reside in the skin under physiological conditions and protect the body from the entry of pathogens/antigens by interacting with each other and orchestrating diverse cutaneous immune responses. To avoid unnecessary inflammation and tissue damage during the elimination of external pathogens and antigens, skin possesses regulatory systems that fine-tune these immune reactions. Mast cells (MCs) are one of the skin-resident immune cell populations that play both effector and regulatory functions in the cutaneous immune response. So far, the interleukin-10-mediated mechanisms have mostly been investigated as the regulatory mechanisms of MCs. Recent studies have elucidated other regulatory mechanisms of MCs, such as the maintenance of regulatory T/B cells and the programmed cell death protein-1/programmed cell death-ligand 1-mediated inhibitory pathway. These regulatory pathways of MCs have been suggested to play important roles in limiting the excessive inflammation in inflammatory skin diseases, such as contact and atopic dermatitis. The regulatory functions of MCs may also be involved in the escape mechanisms of antitumor responses in skin cancers, such as melanoma. Understanding and controlling the regulatory functions of skin MCs may lead to novel therapeutic strategies for inflammatory skin diseases and skin cancers.
Coral Reef Electrotherapy: Field Observations
Authors: Goreau Thomas J. F.
Published: May 2022

Coral reefs are the fastest collapsing ecosystems from accelerating global warming, sea level, disease, and pollution. Urgent steps are essential to regenerate them, and their biodiversity and environmental services, if there is to be a sustainable “Blue Economy”. Methods that greatly increase settlement, growth, survival and resistance to extremely high temperature and pollutant stress are critically needed to regenerate coral reef and coastal ecosystems now and in the future. Safe Extremely Low Voltage (SELV) electrical fields generated by the Biorock electrolytic reef process have been documented for more than 35 years to greatly increase settlement, growth, healing, and survival of marine organisms in general under extreme stress conditions. The visibly observable benefits of electrical stress relief on marine organisms are summarized, and testable hypotheses are proposed to determine mechanisms and improve applications. Although these field observations strongly imply that electricity in the proper range improves stress resistance and health, the mechanisms have never been studied at cellular, biophysical, biochemical, molecular, or genetic levels. Electrical stimulation is the only method known to reverse the impacts of extreme stresses on corals and other marine organisms. Widespread regeneration of coral reef ecosystems by electrotherapy is urgently needed before they become functionally extinct.
Longitudinal Dynamics of Hydrological Connectivity in the Yellow River Delta, China
Authors: Xie Chengjie , Cui Baoshan , Ning Zhonghua , Yu Shuling , Xie Tian
Published: May 2022

River deltas are formed by the interaction of connecting water and sediment, and they are among the most economically and ecologically valuable ecosystems on Earth. Because of their special locations, together with direct and indirect human interference, river deltas are expected to be more vulnerable and fragmented. The increasing fragmentation of deltas is largely due to longitudinal hydrological connectivity disruption caused by human activities. However, the dynamics of longitudinal connectivity are unknown, especially in the Yellow River Delta (YRD), which has been subjected to heavy reclamation in recent years. In this study, we divided the whole YRD into three subregions, the erosion zone, the oilfield zone and the deposition zone, and then we used indicators to explore the spatiotemporal variation in hydrological connectivity on the whole scale and on the zonal scale of the delta during 1984-2018 in the YRD. We found that the variation in longitudinal hydrological connectivity was closely related to the geometry of the tidal channel networks, and that the changes in longitudinal hydrological connectivity varied with research scales. A weak increasing trend of connectivity was found on the whole scale of the delta during the past three decades. A decreasing trend of connectivity was found in both the erosion zone and the oilfield zone. In the deposition zone, however, the connectivity degree was enhanced. Furthermore, we also identified the key impaired area and relatively stable area of hydrological connectivity in the YRD and implied that the key impaired area may be a priority restoration zone of the impaired hydrological connectivity zone. Our study provides useful scientific guidance for the subsequent restoration of damaged wetlands.
Age, Sex, and Race/Ethnicity in Clinical Outcomes Among Patients Hospitalized With COVID-19, 2020
Authors: Lee Jusung
Published: May 2022

The COVID-19 pandemic revealed the disproportionate risk of poor clinical outcomes among population subgroups. The study investigates length of stay (LOS), intensive care unit (ICU) admission, and in-hospital death across age, sex, and race among patients hospitalized with COVID-19. A pooled cross-sectional study analyzed hospital discharge data of state-licensed hospitals in Texas from April to December 2020. Of 98,879 patients, males accounted for 52.3%. The age distribution was 31.9% for the 65–79 age group, 29.6% for those aged 50–64, and 16.3% for those older than 79. Whites constituted the largest proportion (42.6%), followed by Hispanics (36.2%) and Blacks (13.1%). Higher in-hospital death rates were found among patients aged 80 and over (Adjusted Risk Ratio (aRR) 1.12, 95%CI 1.11–1.13) and patients aged 65–79 (aRR 1.08, 95%CI 1.07–1.09) compared to patients aged 19 and below. Hispanics (aRR 1.03, 95%CI 1.02–1.03) and other minorities (aRR 1.02, 95%CI 1.02–1.03) exhibited higher in-hospital death rates than whites, and these patients also had longer LOS and higher ICU admission rates. Patients aged 65–79, 50–64, and 80 and over all had longer hospital stays and higher ICU admission rates. Males experienced poor health outcomes in all assessed outcomes. Findings showed that disparities in clinical outcomes among population subgroups existed and remained throughout 2020. While the nation has to continue practicing public health measures to minimize the harm caused by the novel virus, serious consideration must be given to improving the health of marginalized populations during and beyond the pandemic.
Poor Outcomes in Patients With Transplant Glomerulopathy Independent of Banff Categorization or Therapeutic Interventions
Authors: Wu Kaiyin , Schmidt Danilo , López del Moral Covadonga , Osmanodja Bilgin , Lachmann Nils , Halleck Fabian , Choi Mira , Bachmann Friederike , Ronicke Simon , Duettmann Wiebke , Naik Marcel , Schrezenmeier Eva , Rudolph Birgit , Budde Klemens
Published: May 2022

Background

Transplant glomerulopathy (TG) may indicate different disease entities including chronic AMR (antibody-mediated rejection). However, AMR criteria have been frequently changed, and long-term outcomes of allografts with AMR and TG according to Banff 2017 have rarely been investigated.

Methods

282 kidney allograft recipients with biopsy-proven TG were retrospectively investigated and diagnosed according to Banff'17 criteria: chronic AMR (cAMR, n = 72), chronic active AMR (cAAMR, n = 76) and isolated TG (iTG, n = 134). Of which 25/72 (34.7%) patients of cAMR group and 46/76 (60.5%) of cAAMR group were treated with antihumoral therapy (AHT).

Results

Up to 5 years after indication biopsy, no statistically significant differences were detected among iTG, cAMR and cAAMR groups in annual eGFR decline (−3.0 vs. −2.0 vs. −2.8 ml/min/1.73 m2 per year), 5-year median eGFR (21.5 vs. 16.0 vs. 20.0 ml/min/1.73 m2), 5-year graft survival rates (34.1 vs. 40.6 vs. 31.8%) as well as urinary protein excretion during follow-up. In addition, cAMR and cAAMR patients treated with AHT had similar graft and patient survival rates in comparison with those free of AHT, and similar comparing with iTG group. The TG scores were not associated with 5-year postbiopsy graft failure; whereas the patients with higher scores of chronic allograft scarring (by mm-, ci- and ct-lesions) had significantly lower graft survival rates than those with mild scores. The logistic-regression analysis demonstrated that Banff mm-, ah-, t-, ci-, ct-lesions and the eGFR level at biopsy were associated with 5-year graft failure.

Conclusions

The occurrence of TG is closely associated with graft failure independent of disease categories and TG score, and the long-term clinical outcomes were not influenced by AHT. The Banff lesions indicating progressive scarring might be better suited to predict an unfavorable outcome.
A Novel Algorithm for the Evaluation of Corneal Nerve Beadings by in vivo Confocal Microscopy in Patients With Type 1 Diabetes Mellitus
Authors: Abicca Irene , Giannini Daniela , Gilardi Marta , Roszkowska Anna Maria , Parravano Mariacristina , Picconi Fabiana , Frontoni Simona , Schiano-Lomoriello Domenico
Published: May 2022

Purpose

Peripheral neuropathy could complicate diabetes mellitus (DM). In vivo confocal microscopy (IVCM) is an ocular examination for the diagnosis of small fiber neuropathies and the detection of the earliest corneal sub-basal nerve plexus (SBP) alterations. Corneal SBP characteristics include focal enlargement along with the nerve fiber, called corneal beadings. These dilatations represent a mitochondrial accumulation induced by the reactive oxygen stress, as a consequence of hyperglycemia. For this reason, corneal beadings are considered indicative of metabolic activity. This study aimed to describe the corneal characteristics of a population of type 1 diabetes mellitus (T1DM) well metabolically controlled, using a new algorithm for the analysis of corneal beading size (BS).

Methods

Patients aged ≥18 years affected by T1DM were compared with healthy subjects who underwent IVCM (Confoscan 4; Nidek Technologies Padova, Italy). Starting from the coordinates of the beadings detected by the IVCM, we implemented a new algorithm for automatically measuring BS in corneal SBP images.

Results

We compared 20 eyes of T1DM patients with 26 healthy controls. The corneal nerves' fiber length (p = 0.008), corneal nerves' fiber length density (p = 0.008), and the number of fibers (p = 0.017) were significantly lower in the diabetic group compared with controls. There was no difference between diabetic and healthy eyes in the mean number of corneal beadings both in the frame of analysis (p = 0.606) and for 0.1 mm of SBP nerve (p = 0.145). Regarding the BS, patients with T1DM had corneal beadings larger than controls (p = 0.036).

Conclusions

We found that the corneal beadings parameters are similar in healthy and T1DM individuals. Nevertheless, measuring the BS with our algorithm, we showed that corneal beadings are enlarged in patients affected by T1DM when compared with healthy controls. Identifying beading expansion in corneal nerve fiber using IVCM should become a useful tool to predict peripheral neuropathy at an early stage.
Fecal Capsule as a Therapeutic Strategy in IgA Nephropathy: A Brief Report
Authors: Zhi Wenqiang , Song Wenzhu , Abdi Saed Yasin , Wang Yi , Li Yafeng
Published: May 2022

In this brief report, we reported an IgA nephropathy (IgAN) patient who presented in November 2020 with an acute exacerbation with massive proteinuria and diarrhea. He had the earliest onset in 2018 when his IgAN was diagnosed by renal biopsy. He has been treated with active ACEI/ARB drugs for more than 90 days, intermittent steroid therapy, combined with anti-infective therapy. Although his acute symptoms resolved with each episode, he became increasingly severe as the interval between episodes shortened. Accordingly, the immunosuppressive drugs were administered under the KDIGO guidelines and related guidelines. However, the patient and his family refused this treatment. We pondered over the possible pathogenesis of IgAN, and after a full discussion with the patient and his family, FMT was administered to him after obtaining his informed consent. During the FMT procedure, one healthy volunteer (the doctor himself) also took the FMT capsules. In the end, the patient’s urine protein dropped significantly and even turned negative after treatment. Neither the patient nor the healthy volunteer experienced any serious adverse effects during the use of the capsules and the subsequent 6-month follow-up period. We also used metagenomic sequencing to analyze the intestinal flora of patients before and after treatment, and a gradual increase stood out in the abundance of the patient’s intestinal flora after drug administration.
Metabolomic Profile of the Fungus Cryomyces antarcticus Under Simulated Martian and Space Conditions as Support for Life-Detection Missions on Mars
Authors: Gevi Federica , Leo Patrick , Cassaro Alessia , Pacelli Claudia , de Vera Jean-Pierre Paul , Rabbow Elke , Timperio Anna Maria , Onofri Silvano
Published: May 2022

The identification of traces of life beyond Earth (e.g., Mars, icy moons) is a challenging task because terrestrial chemical-based molecules may be destroyed by the harsh conditions experienced on extraterrestrial planetary surfaces. For this reason, studying the effects on biomolecules of extremophilic microorganisms through astrobiological ground-based space simulation experiments is significant to support the interpretation of the data that will be gained and collected during the ongoing and future space exploration missions. Here, the stability of the biomolecules of the cryptoendolithic black fungus Cryomyces antarcticus, grown on two Martian regolith analogues and on Antarctic sandstone, were analysed through a metabolomic approach, after its exposure to Science Verification Tests (SVTs) performed in the frame of the European Space Agency (ESA) Biology and Mars Experiment (BIOMEX) project. These tests are building a set of ground-based experiments performed before the space exposure aboard the International Space Station (ISS). The analysis aimed to investigate the effects of different mineral mixtures on fungal colonies and the stability of the biomolecules synthetised by the fungus under simulated Martian and space conditions. The identification of a specific group of molecules showing good stability after the treatments allow the creation of a molecular database that should support the analysis of future data sets that will be collected in the ongoing and next space exploration missions.