bluuebunny/crossref_metadata_2025 huggingface dataset:
Wnt Activity and Cell Proliferation Are Coupled to Extracellular Vesicle Release in Multiple Organoid Models
Authors: Sándor Gyöngyvér Orsolya , Soós András Áron , Lörincz Péter , Rojkó Lívia , Harkó Tünde , Bogyó Levente , Tölgyes Tamás , Bursics Attila , Buzás Edit I. , Moldvay Judit , Wiener Zoltán
Published: June 2021

Extracellular vesicles (EV) are considered as a potential tool for early disease diagnosis; however, factors modifying EV release remain partially unknown. By using patient-derived organoids that capture the cellular heterogeneity of epithelial tissues, here we studied the connection between the Wnt-producing microniche and EV secretion in multiple tissues. Although nearly all cells in pancreatic ductal (PD) and pancreatic ductal adenocarcinoma (PDAC) samples expressed porcupine (PORCN), an enzyme critical for Wnt secretion, only a subpopulation of lung bronchiolar (NL) and lung adenocarcinoma (LUAD) organoid cells produced active Wnt. The microniche for proliferating cells was shaped not only by PORCN + cells in NL and LUAD organoids but also by fibroblast-derived EVs. This effect could be blocked by using Wnt secretion inhibitors. Whereas inhibiting Wnt secretion in PD NL or LUAD organoids critically changed both cell proliferation and EV release, these were uncoupled from each other in PDAC. Sorting for CD133 identified a cell population in the LUAD microniche that produced organoids with a high percentage of PORCN + and proliferating cells and an elevated EV secretion, which may explain that CD133 marks LUAD cells with malignant behavior. Collectively, we show here that high cell proliferation rate, induced by Wnt pathway activation, is coupled to a higher EV release, a critical finding that may be considered when developing EV-based diagnostic tools.
Hydrogen, Bicarbonate, and Their Associated Exchangers in Cell Volume Regulation
Authors: Li Yizeng , Zhou Xiaohan , Sun Sean X.
Published: June 2021

Cells lacking a stiff cell wall, e.g., mammalian cells, must actively regulate their volume to maintain proper cell function. On the time scale that protein production is negligible, water flow in and out of the cell determines the cell volume variation. Water flux follows hydraulic and osmotic gradients; the latter is generated by various ion channels, transporters, and pumps in the cell membrane. Compared to the widely studied roles of sodium, potassium, and chloride in cell volume regulation, the effects of proton and bicarbonate are less understood. In this work, we use mathematical models to analyze how proton and bicarbonate, combined with sodium, potassium, chloride, and buffer species, regulate cell volume upon inhibition of ion channels, transporters, and pumps. The model includes several common, widely expressed ion transporters and focuses on obtaining generic outcomes. Results show that the intracellular osmolarity remains almost constant before and after cell volume change. The steady-state cell volume does not depend on water permeability. In addition, to ensure the stability of cell volume and ion concentrations, cells need to develop redundant mechanisms to maintain homeostasis, i.e., multiple ion channels or transporters are involved in the flux of the same ion species. These results provide insights for molecular mechanisms of cell volume regulation with additional implications for water-driven cell migration.
Macrophages in Acute Myeloid Leukaemia: Significant Players in Therapy Resistance and Patient Outcomes
Authors: Miari Katerina E. , Guzman Monica L. , Wheadon Helen , Williams Mark T. S.
Published: June 2021

Acute Myeloid Leukaemia (AML) is a commonly occurring severe haematological malignancy, with most patients exhibiting sub-optimal clinical outcomes. Therapy resistance significantly contributes towards failure of traditional and targeted treatments, disease relapse and mortality in AML patients. The mechanisms driving therapy resistance in AML are not fully understood, and approaches to overcome therapy resistance are important for curative therapies. To date, most studies have focused on therapy resistant mechanisms inherent to leukaemic cells (e.g., TP53 mutations), overlooking to some extent, acquired mechanisms of resistance through extrinsic processes. In the bone marrow microenvironment (BMME), leukaemic cells interact with the surrounding bone resident cells, driving acquired therapy resistance in AML. Growing evidence suggests that macrophages, highly plastic immune cells present in the BMME, play a role in the pathophysiology of AML. Leukaemia-supporting macrophage subsets (CD163+CD206+) are elevated in preclinical in vivo models of AML and AML patients. However, the relationship between macrophages and therapy resistance in AML warrants further investigation. In this review, we correlate the potential links between macrophages, the development of therapy resistance, and patient outcomes in AML. We specifically focus on macrophage reprogramming by AML cells, macrophage-driven activation of anti-cell death pathways in AML cells, and the association between macrophage phenotypes and clinical outcomes in AML, including their potential prognostic value. Lastly, we discuss therapeutic targeting of macrophages, as a strategy to circumvent therapy resistance in AML, and discuss how emerging genomic and proteomic-based approaches can be utilised to address existing challenges in this research field.
SENP3-Mediated PPARγ2 DeSUMOylation in BM-MSCs Potentiates Glucocorticoid-Induced Osteoporosis by Promoting Adipogenesis and Weakening Osteogenesis
Authors: Zhang Yongxing , Chen Yang , Sun Hangxiang , Zhang Wenkan , Zhang Lingling , Li Hengyuan , Huang Xin , Yang Jie , Ye Zhaoming
Published: June 2021

Glucocorticoid-induced osteoporosis (GIOP) is the most common secondary osteoporosis and reduced bone formation was the main pathological change in GIOP. Our previous studies have shown that there was an imbalance between adipogenic and osteogenic differentiation in GIOP BM-MSCs and peroxisome proliferator-activated receptor γ2 (PPARγ2) played a vital role in this disorders. Here, we reported that there was an increase in ROS level and SENP3 expression in Dex-induced osteoporotic BM-MSCs, and enhanced adipogenesis and weakened osteogenesis in osteoporotic BM-MSCs might be caused by upregulated SENP3. Then we found that SENP3 de-SUMOylated PPARγ2 on K107 site to potentiate adipogenesis and weaken osteogenesis. These results may provide new strategy and target in the clinical diagnosis and treatment of GIOP.
Catalytic Dyad Residues His41 and Cys145 Impact the Catalytic Activity and Overall Conformational Fold of the Main SARS-CoV-2 Protease 3-Chymotrypsin-Like Protease
Authors: Ferreira Juliana C. , Fadl Samar , Villanueva Adrian J. , Rabeh Wael M.
Published: June 2021

Coronaviruses are responsible for multiple pandemics and millions of deaths globally, including the current pandemic of coronavirus disease 2019 (COVID-19). Development of antivirals against coronaviruses, including the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) responsible for COVID-19, is essential for containing the current and future coronavirus outbreaks. SARS-CoV-2 proteases represent important targets for the development of antivirals because of their role in the processing of viral polyproteins. 3-Chymotrypsin-like protease (3CLpro) is one such protease. The cleavage of SARS-CoV-2 polyproteins by 3CLpro is facilitated by a Cys145–His41 catalytic dyad. We here characterized the catalytic roles of the cysteine–histidine pair for improved understanding of the 3CLpro reaction mechanism, to inform the development of more effective antivirals against Sars-CoV-2. The catalytic dyad residues were substituted by site-directed mutagenesis. All substitutions tested (H41A, H41D, H41E, C145A, and C145S) resulted in a complete inactivation of 3CLpro, even when amino acids with a similar catalytic function to that of the original residues were used. The integrity of the structural fold of enzyme variants was investigated by circular dichroism spectroscopy to test if the catalytic inactivation of 3CLpro was caused by gross changes in the enzyme secondary structure. C145A, but not the other substitutions, shifted the oligomeric state of the enzyme from dimeric to a higher oligomeric state. Finally, the thermodynamic stability of 3CLpro H41A, H41D, and C145S variants was reduced relative the wild-type enzyme, with a similar stability of the H41E and C145A variants. Collectively, the above observations confirm the roles of His41 and Cys145 in the catalytic activity and the overall conformational fold of 3CLpro SARS-CoV-2. We conclude that the cysteine–histidine pair should be targeted for inhibition of 3CLpro and development of antiviral against COVID-19 and coronaviruses.
High Neutrophil to Lymphocyte Ratio and Its Gene Signatures Correlate With Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction
Authors: Bai Bo , Cheng Min , Jiang Lingyan , Xu Jiabin , Chen Haibo , Xu Yun
Published: June 2021

Aims: To evaluate the interrelation between neutrophil to lymphocyte ratio (NLR) coupled with gene signatures, inflammation, and diastolic dysfunction in patients with heart failure (HF) with preserved ejection fraction (HFpEF).

Methods: The clinical profile of 172 patients with HFpEF (EF ≥ 50%) and 173 non-HF control individuals was analyzed retrospectively. The association between NLR and HFpEF and the predictive performance of NLR for HFpEF were assessed by the binary logistic regression analysis and the receiver operating characteristic curve (ROC). Multivariate linear regression models further examined the associations between NLR and high-sensitivity C-reactive protein (hs-CRP), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and average septal-lateral E/e', respectively. The freshly isolated neutrophils from 30 HFpEF patients and 42 non-HF controls were subjected to transcriptomic profiling. The biomarkers related to neutrophil activation and inflammation were detected in serum samples.

Results: The HFpEF patients in Southeast China were lean and had comorbidity burden and worse cardiac structure/function. Compared with non-HF control individuals, HFpEF patients had a rise in NLR. NLR displayed an independent association with HFpEF [adjusted odds ratio, 2.351; 95% CI, 1.464–3.776; p < 0.001] and it predicted HFpEF with the area under the ROC 0.796 (95% CI, 0.748–0.845, p < 0.001). The positive associations between NLR and hs-CRP, NT-proBNP, and mitral E/e' were found in HFpEF patients. Moreover, patients had significantly elevated serum levels of neutrophil elastase and inflammatory biomarkers, both of which correlated with the mitral E/e' ratio. Finally, multiple molecules that drive neutrophil degranulation and inflammation, such as S100A8/A9/A12 and PADI4, were transcriptionally up-regulated in neutrophils of HFpEF patients.

Conclusions: The high NLR coupled with transcriptional activation of neutrophils correlates with systemic inflammation and functional impairment in HFpEF patients, which may suggest a causative role of neutrophils in the pathogenesis of the disease.
B-Type Natriuretic Peptide Concentrations, COVID-19 Severity, and Mortality: A Systematic Review and Meta-Analysis With Meta-Regression
Authors: Zinellu Angelo , Sotgia Salvatore , Carru Ciriaco , Mangoni Arduino A.
Published: June 2021

Alterations in cardiac biomarkers have been reported in patients with coronavirus disease 2019 (COVID-19) in relation to disease severity and mortality. We conducted a systematic review and meta-analysis with meta-regression of studies reporting B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) plasma concentrations in COVID-19. We searched PubMed, Web of Science, and Scopus, between January 2020 and 2021, for studies reporting BNP/NT-proBNP concentrations, measures of COVID-19 severity, and survival status (PROSPERO registration number: CRD42021239190). Forty-four studies in 18,856 COVID-19 patients were included in the meta-analysis and meta-regression. In pooled results, BNP/NT-proBNP concentrations were significantly higher in patients with high severity or non-survivor status when compared to patients with low severity or survivor status during follow up (SMD = 1.07, 95% CI: 0.89–1.24, and p < 0.001). We observed extreme between-study heterogeneity (I2 = 93.9%, p < 0.001). In sensitivity analysis, the magnitude and the direction of the effect size were not substantially modified after sequentially removing individual studies and re-assessing the pooled estimates, (effect size range, 0.99 – 1.10). No publication bias was observed with the Begg's (p = 0.26) and Egger's (p = 0.40) t-tests. In meta-regression analysis, the SMD was significantly and positively associated with D-dimer (t = 2.22, p = 0.03), myoglobin (t = 2.40, p = 0.04), LDH (t = 2.38, p = 0.02), and procalcitonin (t = 2.56, p = 0.01) concentrations. Therefore, higher BNP/NT-proBNP plasma concentrations were significantly associated with severe disease and mortality in COVID-19 patients.
Effects of Altering Mitochondrial Antioxidant Capacity on Molecular and Phenotypic Drivers of Fibrocalcific Aortic Valve Stenosis
Authors: Roos Carolyn M. , Zhang Bin , Hagler Michael A. , Verzosa Grace C. , Huang Runqing , Oehler Elise A. , Arghami Arman , Miller Jordan D.
Published: June 2021

Background: While a small number of studies suggest that oxidative stress has an influential role in fibrocalcific aortic valve disease (FCAVD), the roles of specific antioxidant enzymes in progression of this disease remain poorly understood. Here, we focused on selectively altering mitochondrial-derived oxidative stress—which has been shown to alter progression of a myriad of age-associated diseases—on the progression of molecular and phenotypic drivers of FCAVD.

Methods: We generated low-density lipoprotein receptor-deficient, Apolipoprotein B100-only mice (LA) that were either haploinsufficient for MnSOD (LA-MnSOD+/−) or genetically overexpressing MnSOD (LA-MnSODTg/0). After 6 months of Western diet feeding, mice underwent echocardiography to assess valvular and cardiac function and tissues were harvested. Quantitative-RT PCR, immunohistochemistry, and histopathology were used to measure changes in molecular pathways related to oxidative stress, calcification, and fibrosis.

Results: While reductions in MnSOD increased oxidative stress, there was not an overt phenotypic effect of MnSOD deficiency on valvular and cardiac function in LA-MnSOD+/− mice. While markers of canonical bone morphogenetic protein signaling tended to increase in valve tissue from LA-MnSOD+/− (e.g., p-SMAD1/5/8 and osterix), we did not observe statistically significant increases in osteogenic signaling. We did, however, observe highly significant reductions in expression of osteopontin, which were associated with significant increases in calcium burden in LA-MnSOD+/− mice. Reciprocally, genetically increasing MnSOD did not preserve valve function in LA-MnSODTg/0, but we did observe slight reductions in p-SMAD1/5/8 levels compared to their non-transgenic littermates. Interestingly, overexpression of MnSOD dramatically increased expression of osteopontin in valve tissue from LA-MnSODTg/0 mice, but was not sufficient to attenuate calcium burden when compared to their LA-MnSOD0/0 littermates.

Conclusions: Collectively, this study demonstrates that maintenance of mitochondrial antioxidant capacity is important in preventing accelerated disease progression in a mouse model of FCAVD, but that effectively altering mitochondrial antioxidant capacity as a monotherapeutic approach to slow key histopathological and molecular drivers of FCAVD remains biologically and therapeutically challenging.
Thermodynamic Analysis of a Conceptual Fixed-Bed Solar Thermochemical Cavity Receiver–Reactor Array for Water Splitting Via Ceria Redox Cycling
Authors: Yang Song , Li Lifeng , Wang Bo , Li Sha , Wang Jun , Lund Peter , Lipiński Wojciech
Published: June 2021

We propose a novel solar thermochemical receiver–reactor array concept for hydrogen production via ceria redox cycling. The receiver–reactor array can improve the solar-to-fuel efficiency by realizing the heat recuperation, reduction, and oxidation processes synchronously. A linear matrix model and a lumped parameter model are developed to predict thermal performance of the new solar thermochemical system. The system thermal performance is characterized by heat recovery effectiveness of solid-phase and solar-to-fuel efficiency. Investigated parameters include reduction temperature, oxygen partial pressure, number of receiver–reactors, concentration ratio, and gas-phase heat recovery effectiveness. For baseline conditions, the solid-phase heat recovery effectiveness and the solar-to-fuel efficiency are found to be 81% and 27%, respectively. For perfect gas-phase heat recovery and a solar concentration ratio of 5,000, the solar-to-fuel efficiency exceeds 40%.
Blending Ecosystem Service and Resilience Perspectives in Planning of Natural Infrastructure: Lessons from the San Francisco Bay Area
Authors: Hamel Perrine , Hamann Maike , Kuiper Jan J. , Andersson Erik , Arkema Katie K. , Silver Jess M. , Daily Gretchen C. , Guerry Anne D.
Published: June 2021

Globally, cities face massive environmental and societal challenges such as rapid population growth and climate change. In response, natural infrastructure is increasingly recognized for its potential to enhance resilience and improve human well-being. Here, we examine the role of the ecosystem services and resilience approaches in urban planning, which both aim to sustain the long-term benefits of natural infrastructure in cities. While the two approaches are intertwined and share deep roots in social-ecological systems framing, they confer complementary strengths in practice, which we illustrate with a case study in the San Francisco Bay Area, United States. We show that, at present, the main strength of ecosystem service practice is to provide actionable information, while urban resilience practice supports the development of holistic long-term strategies. We discuss operational limitations of both approaches and suggest that understanding and leveraging their complementary strengths could help bridge the implementation gap between research and practice in urban natural infrastructure planning.
A New Late Permian Burnetiamorph From Zambia Confirms Exceptional Levels of Endemism in Burnetiamorpha (Therapsida: Biarmosuchia) and an Updated Paleoenvironmental Interpretation of the Upper Madumabisa Mudstone Formation
Authors: Sidor Christian A. , Tabor Neil J. , Smith Roger M. H.
Published: June 2021

A new burnetiamorph therapsid, Isengops luangwensis, gen. et sp. nov., is described on the basis of a partial skull from the upper Madumabisa Mudstone Formation of the Luangwa Basin of northeastern Zambia. Isengops is diagnosed by reduced palatal dentition, a ridge-like palatine-pterygoid boss, a palatal exposure of the jugal that extends far anteriorly, a tall trigonal pyramid-shaped supraorbital boss, and a recess along the dorsal margin of the lateral temporal fenestra. The upper Madumabisa Mudstone Formation was deposited in a rift basin with lithofacies characterized by unchannelized flow, periods of subaerial desiccation and non-deposition, and pedogenesis, and can be biostratigraphically tied to the upper Cistecephalus Assemblage Zone of South Africa, suggesting a Wuchiapingian age. Isengops is the second burnetiamorph recognized from Zambia and is part of a tetrapod assemblage remarkably similar to others across southern Pangea during the Wuchiapingian. A revised cladistic analysis of Biarmosuchia yielded over 500 most parsimonious trees that generally reaffirm the results of previous analyses for burnetiamorphs: Lemurosaurus is basal, Lobalopex and Isengops are proximate burnetiid outgroups, and Bullacephalus, Burnetia, Mobaceras, Niuksenitia, and Pachydectes are burnetiines. Furthermore, Russian biarmosuchians are scattered throughout the tree and do not form sister taxon relationships with each other. Burnetiamorphs display a wide disparity of cranial adornments and are relatively speciose (13 species), especially when compared to the number of specimens discovered to date (∼16 specimens). As has been suggested in some other tetrapod clades (e.g., ceratopsian dinosaurs), the burnetiamorph fossil record supports an inferred macroevolutionary relationship between cranial adornment and increased speciation rate.
Reliability of Data Collected by Volunteers: A Nine-Year Citizen Science Study in the Red Sea
Authors: Meschini Marta , Machado Toffolo Mariana , Marchini Chiara , Caroselli Erik , Prada Fiorella , Mancuso Arianna , Franzellitti Silvia , Locci Laura , Davoli Marco , Trittoni Michele , Nanetti Enrico , Tittarelli Mara , Bentivogli Riccardo , Branchini Simone , Neri Patrizia , Goffredo Stefano
Published: June 2021

The quality of data collected by non-professional volunteers in citizen science programs is crucial to render them valid for implementing environmental resources management and protection plans. This study assessed the reliability of data collected by non-professional volunteers during the citizen science project Scuba Tourism for the Environment (STE), carried out in mass tourism facilities of the Red Sea between 2007 and 2015. STE involved 16,164 volunteer recreational divers in data collection on marine biodiversity using a recreational citizen science approach. Through a specifically designed questionnaire, volunteers indicated which of the seventy-two marine taxa surveyed were observed during their recreational dive, giving an estimate of their abundance. To evaluate the validity of the collected data, a reference researcher randomly dived with the volunteers and filled in the project questionnaire separately. Correlation analyses between the records collected by the reference researcher and those collected by volunteers were performed based on 513 validation trials, testing 3,138 volunteers. Data reliability was analyzed through 7 parameters. Consistency showed the lowest mean score (51.6%, 95% Confidence Interval CI 44.1–59.2%), indicating that volunteers could direct their attention to different taxa depending on personal interests; Percent Identified showed the highest mean score (66.7%, 95% CI 55.5–78.0), indicating that volunteers can correctly identify most surveyed taxa. Overall, results confirmed that the recreational citizen science approach can effectively support reliable data for biodiversity monitoring, when carefully tailored for the volunteer skills required by the specific project. The use of a recreational approach enhances massive volunteer participation in citizen science projects, thus increasing the amount of sufficiently reliable data collected in a reduced time.
Immune and Metabolic Dysregulated Coding and Non-coding RNAs Reveal Survival Association in Uterine Corpus Endometrial Carcinoma
Authors: Liu Da , Qiu Min
Published: June 2021

Uterine corpus endometrial carcinoma (UCEC) is one of the most common gynecologic malignancies, but only a few biomarkers have been proven to be effective in clinical practice. Previous studies have demonstrated the important roles of non-coding RNAs (ncRNAs) in diagnosis, prognosis, and therapy selection in UCEC and suggested the significance of integrating molecules at different levels for interpreting the underlying molecular mechanism. In this study, we collected transcriptome data, including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs), of 570 samples, which were comprised of 537 UCEC samples and 33 normal samples. First, differentially expressed lncRNAs, miRNAs, and mRNAs, which distinguished invasive carcinoma samples from normal samples, were identified, and further analysis showed that cancer- and metabolism-related functions were enriched by these RNAs. Next, an integrated, dysregulated, and scale-free biological network consisting of differentially expressed lncRNAs, miRNAs, and mRNAs was constructed. Protein-coding and ncRNA genes in this network showed potential immune and metabolic functions. A further analysis revealed two clinic-related modules that showed a close correlation with metabolic and immune functions. RNAs in the two modules were functionally validated to be associated with UCEC. The findings of this study demonstrate an important clinical application for improving outcome prediction for UCEC.
Gene Expression Profiles Analyzed Using Integrating RNA Sequencing, and Microarray Reveals Increased Inflammatory Response, Proliferation, and Osteoclastogenesis in Pigmented Villonodular Synovitis
Authors: Zhao Yang , Lv Jiaoyun , Zhang Hongwei , Xie Jiawei , Dai Hui , Zhang Xin
Published: June 2021

Background

Pigmented villonodular synovitis (PVNS) is a rare condition that involves benign proliferation of the synovial tissue and is characterized by severe joint destruction and high recurrence even after surgical resection. However, poor understanding of the pathogenesis limits its effective therapy.

Method

In this study, gene expression profiles of six patients with PVNS, 11 patients with osteoarthritis (OA), nine patients with rheumatoid arthritis (RA) (E-MTAB-6141), and three healthy subjects (GSE143514) were analyzed using integrating RNA sequencing (RNA-seq) and microarray to investigate the PVNS transcriptome. Gene ontology, string, and cytoscape were used to determine the gene functional enrichment. Cell functional molecules were detected using flow cytometry or immunohistochemical test to identify the cell subset and function. CD14+cells were isolated and induced to osteoclast to evaluate the monocyte/macrophage function.

Results

The most obvious local manifestations of PVNS were inflammation, including increased immune cells infiltration and cytokine secretion, and tumor phenotypes. High proportion of inflammatory cells, including T cells, natural killer (NK) cells, NKT cells, and B cells were recruited from the blood. Th17 and monocytes, especially classical monocytes but not nonclassical monocytes, increased in PVNS synovium. An obvious increase in osteoclastogenesis and macrophage activation was observed locally. Elevated expression of MMP9, SIGLEC 15, and RANK were observed in myeloid cell of PVNS than OA. When compared with RA, osteoclast differentiation and myeloid cell activation are PVNS-specific characters, whereas T cell activation is shared by PVNS and RA.

Conclusion

The transcriptional expression characteristics of PVNS showed increased immune response, cell migration, and osteoclastogenesis. Osteoclast differentiation is only observed in PVNS but not RA, whereas T-cell activation is common in inflammatory arthritis.
Targeting JAK-STAT Signalling Alters PsA Synovial Fibroblast Pro-Inflammatory and Metabolic Function
Authors: O’Brien Aisling , Hanlon Megan Mary , Marzaioli Viviana , Wade Siobhan C. , Flynn Keelin , Fearon Ursula , Veale Douglas J.
Published: June 2021

Objectives

Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with psoriasis. Janus Kinase inhibitors (JAKi) have emerged as an encouraging class of drugs for the treatment of PsA. Here, we compare the effect of four JAKi on primary PsA synovial fibroblasts (PsAFLS) activation, metabolic function, and invasive and migratory capacity.

Methods

Primary PsAFLS were isolated and cultured with JAKi (Peficitinib, Filgotinib, Baricitinib and Upadacitinib) in the presence of Oncostatin M (OSM). pSTAT3 expression in response to OSM was quantified by Western Blot analysis. Pro-inflammatory cytokines/chemokines were quantified by ELISA and cell migration by wound-repair scratch assays. Invasive capacity was examined using Matrigel™ invasion chambers and MMP multiplex MSD assays. PsAFLS bioenergetics was assessed using the Seahorse XFe Extracellular Flux Analyzer, which simultaneously quantifies two energetic pathways- glycolysis (ECAR) and oxidative phosphorylation (OCR). In parallel, inflammatory, invasive, and migratory genes were quantified by RT-PCR.

Results

OSM induces pSTAT3 expression in PsAFLS. OSM-induced secretion of MCP-1 and IL-6 was inhibited by all JAKi with Peficitinib, Baricitinib and Upadacitinib showing the greatest effect. In contrast, JAKi had no significant impact on IL-8 expression in response to OSM. PsAFLS cell invasion, migratory capacity and MMP1, 3, and 9 were suppressed following JAKi treatment, with Peficitinib showing the greatest effect. These functional effects were accompanied by a change in the cellular bioenergetic profile of PsAFLS, where JAKi significantly decreased glycolysis and the ECAR/OCR, resulting in a shift to a more quiescent phenotype, with Peficitinib demonstrating the most pronounced effect.

Conclusion

This study demonstrates that JAK/STAT signalling mediates the complex interplay between inflammation and cellular metabolism in PsA pathogenesis. This inhibition shows effective suppression of inflammatory mechanisms that drive pathogenic functions of PsAFLS, further supporting the role of JAKi as a therapeutic target for the treatment of PsA.
Cellular Basis for the Enhanced Efficacy of the Fms-Like Tyrosine Kinase 3 Ligand (FL) Adjuvanted VCG-Based Chlamydia abortus Vaccine
Authors: Richardson Shakyra , Medhavi Fnu , Tanner Tayhlor , Lundy Stephanie , Omosun Yusuf , Igietseme Joseph U. , Carroll Darin , Eko Francis O.
Published: June 2021

Efficacious vaccines are needed to control genital chlamydial diseases in humans and the veterinary industry. We previously reported a C. abortus (Cab) vaccine comprising recombinant Vibrio cholerae ghosts (rVCG) expressing the conserved and immunogenic N-terminal region of the Cab polymorphic membrane protein D (rVCG-Pmp18.1) protein that protected mice against intravaginal challenge. In this study, we investigated the immunomodulatory effect of the hematopoietic progenitor activator cytokine, Fms-like tyrosine kinase 3-ligand (FL) when co-administered with the rVCG-Pmp18.1 vaccine as a strategy to enhance the protective efficacy and the potential mechanism of immunomodulation. Groups of female C57BL/6J mice were immunized and boosted twice intranasally (IN) with rVCG-PmpD18.1 with and without FL or purified rPmp18.1 or rVCG-gD2 (antigen control) or PBS (medium) per mouse. The results revealed that co-administration of the vaccine with FL enhanced antigen-specific cellular and humoral immune responses and protected against live Cab genital infection. Comparative analysis of immune cell phenotypes infiltrating mucosal and systemic immune inductive tissue sites following immunization revealed that co-administration of rVCG-Pmp18.1 with FL significantly enhanced the number of macrophages, dendritic and NK cells, γδ and NK T cells in the spleen (systemic) and iliac lymph nodes (ILN) draining the genital tract (mucosal) tissues compared to rVCG-Pmp18.1 alone. Furthermore, FL enhanced monocyte infiltration in the ILN, while CD19+ B cells and CD4+ T cells were enhanced in the spleen. These results indicate that the immunomodulatory effect of FL is associated with its ability to mobilize innate immune cells and subsequent activation of robust antigen-specific immune effectors in mucosal and systemic lymphoid tissues.
Interfering With Inflammation: Heterogeneous Effects of Interferons in Graft-Versus-Host Disease of the Gastrointestinal Tract and Inflammatory Bowel Disease
Authors: Haring Eileen , Zeiser Robert , Apostolova Petya
Published: June 2021

The intestine can be the target of several immunologically mediated diseases, including graft-versus-host disease (GVHD) and inflammatory bowel disease (IBD). GVHD is a life-threatening complication that occurs after allogeneic hematopoietic stem cell transplantation. Involvement of the gastrointestinal tract is associated with a particularly high mortality. GVHD development starts with the recognition of allo-antigens in the recipient by the donor immune system, which elicits immune-mediated damage of otherwise healthy tissues. IBD describes a group of immunologically mediated chronic inflammatory diseases of the intestine. Several aspects, including genetic predisposition and immune dysregulation, are responsible for the development of IBD, with Crohn’s disease and ulcerative colitis being the two most common variants. GVHD and IBD share multiple key features of their onset and development, including intestinal tissue damage and loss of intestinal barrier function. A further common feature in the pathophysiology of both diseases is the involvement of cytokines such as type I and II interferons (IFNs), amongst others. IFNs are a family of protein mediators produced as a part of the inflammatory response, typically to pathogens or malignant cells. Diverse, and partially paradoxical, effects have been described for IFNs in GVHD and IBD. This review summarizes current knowledge on the role of type I, II and III IFNs, including basic concepts and controversies about their functions in the context of GVHD and IBD. In addition, therapeutic options, research developments and remaining open questions are addressed.
Trash or Treasure? Considerations for Future Ecological Research to Inform Oil and Gas Decommissioning
Authors: Schläppy Marie-Lise , Robinson Lucy M. , Camilieri-Asch Victoria , Miller Karen
Published: June 2021

Numerous oil and gas (O&G) installations worldwide will need to be decommissioned in the near future. Complete removal of subsea structures is often the default approach although some regions retain structures under rigs-to-reefs programs. Here, we reviewed the published literature to understand the status of global research on decommissioning, and specifically identify gaps in ecological knowledge. We estimated the frequency of different research categories (i.e., themes, and spatial/temporal scales), and tested the assumption that the number of papers across the categories of each research aspect was even in distribution. However, the frequency of studies focusing on biodiversity at a local (≤100 km2) scale (relative to regional and oceanic and pan-oceanic scales) were significantly higher; while other theme categories (e.g., eco-toxicology, connectivity, structural-integrity, restoration and other) were significantly lower than expected. Temporally, ≤1-year studies were more frequent than multi-year studies, but these frequencies did not significantly deviate from the assumed distribution of equal frequencies. We propose that further research be carried out to evaluate the benefits of both retention and removal of structures. Ecological research on decommissioning should extend its focus beyond biodiversity, to include eco-toxicology, structural-integrity, connectivity at larger spatial and temporal scales. This would provide a more holistic assessment of ecological impacts to inform sustainable and equitable development choices in multiple Blue Economy sectors, as we transition from offshore O&G to marine renewables.
Genome-Wide SNP Data Revealed Notable Spatial Genetic Structure in the Deep-Sea Precious Coral Corallium japonicum
Authors: Takata Kenji , Iwase Fumihito , Iguchi Akira , Yuasa Hideaki , Taninaka Hiroki , Iwasaki Nozomu , Uda Kouji , Suzuki Tomohiko , Nonaka Masanori , Kikuchi Taisei , Yasuda Nina
Published: June 2021

Estimating the spatial extent of gamete and larval dispersal of deep-sea coral species, is challenging yet important for their conservation. Spatial autocorrelation analysis is useful for estimating the spatial range of dispersal of corals; however, it has not been performed for deep-sea coral species using genome-wide single nucleotide polymorphisms (SNPs). In this study, we examined the spatial genetic structure of a deep-sea coral species—the Japanese red coral, Corallium japonicum, sampled off the coast of Kochi, which lies to the southwest of the Shikoku Island in Japan; the Kochi region suffers from over-harvesting because of its high commercial value. We also examined the power of detecting significant spatial genetic structure by changing the number of loci and the proportion of missing data using both de novo analysis and mapping analysis. Similar results were obtained for both de novo and mapping analysis, although a higher number of loci were obtained by the mapping method. In addition, “many SNPs with a lot of missing data” was generally more useful than “a small number of SNPs with a small amount of missing data” to detect significant fine-scale spatial genetic structure. Our data suggested that more than 700 neutral SNPs were needed to detect significant fine-scale spatial genetic structure. The maximum first distance class that can detect significant spatial genetic structure within Kochi for the C. japonicum population was less than 11 km, suggesting that the over-harvesting of C. japonicum within a diameter of approximately 11 km in the Kochi area should be avoided, because this can cause the local extinction of this species.
Visualising the Uncertainty Cascade in Multi-Ensemble Probabilistic Coastal Erosion Projections
Authors: Toimil Alexandra , Camus Paula , Losada Iñigo J. , Alvarez-Cuesta Moises
Published: June 2021

Future projections of coastal erosion, which are one of the most demanded climate services in coastal areas, are mainly developed using top-down approaches. These approaches consist of undertaking a sequence of steps that include selecting emission or concentration scenarios and climate models, correcting models bias, applying downscaling methods, and implementing coastal erosion models. The information involved in this modelling chain cascades across steps, and so does related uncertainty, which accumulates in the results. Here, we develop long-term multi-ensemble probabilistic coastal erosion projections following the steps of the top-down approach, factorise, decompose and visualise the uncertainty cascade using real data and analyse the contribution of the uncertainty sources (knowledge-based and intrinsic) to the total uncertainty. We find a multi-modal response in long-term erosion estimates and demonstrate that not sampling internal climate variability’s uncertainty sufficiently could lead to a truncated outcomes range, affecting decision-making. Additionally, the noise arising from internal variability (rare outcomes) appears to be an important part of the full range of results, as it turns out that the most extreme shoreline retreat events occur for the simulated chronologies of climate forcing conditions. We conclude that, to capture the full uncertainty, all sources need to be properly sampled considering the climate-related forcing variables involved, the degree of anthropogenic impact and time horizon targeted.
FABP5, a Novel Immune-Related mRNA Prognostic Marker and a Target of Immunotherapy for Multiple Myeloma
Authors: Jia Haipeng , Zhang Xiaofen , Liu Xinxin , Qiao Ruifang , Liu Yan , Lv Sulong , Zhu Hongbo , Wang Jie , Kong Qiuhong , Zhang Hong , Zhang Zhirong
Published: June 2021

Objective: Multiple myeloma is an incurable hematological malignancy. It is imperative to identify immune markers for early diagnosis and therapy. Here, this study analyzed immune-related mRNAs and assessed their prognostic value and therapeutic potential.

Methods: Abnormally expressed immune-related mRNAs were screened between multiple myeloma and normal bone marrow specimens in the GSE47552 and GSE6477 datasets. Their biological functions were then explored. Survival analysis was presented for assessing prognosis-related mRNAs. CIBERSORT was utilized for identifying 22 immune cell compositions of each bone marrow specimen. Correlation between FABP5 mRNA and immune cells was then analyzed in multiple myeloma.

Results: Thirty-one immune-related mRNAs were abnormally expressed in multiple myeloma, which were primarily enriched in B cells-related biological processes and pathways. Following validation, FABP5 mRNA was a key risk factor of multiple myeloma. Patients with its up-regulation usually experienced unfavorable outcomes. There were distinct differences in the infiltration levels of B cells naïve, B cells memory, plasma cells, T cells CD4 naïve, resting memory CD4 T cells, activated memory CD4 T cells, Tregs, resting NK cells, M0 macrophages, M1 macrophages, M2 macrophages, and neutrophils between multiple myeloma and normal samples. FABP5 mRNA had correlations to B cells memory, B cells naïve, dendritic cells activated, macrophages M0, macrophages M1, macrophages M2, neutrophils, activated NK cells, resting memory CD4 T cells, CD8 T cells and Tregs.

Conclusion: Collectively, our data showed that FABP5 mRNA was related to immune microenvironment, which could be a target of immunotherapy and prognostic marker for multiple myeloma.
Approaches in the Treatment of Cesarean Scar Pregnancy and Risk Factors for Intraoperative Hemorrhage: A Retrospective Study
Authors: Lin Yaying , Xiong Chang , Dong Chunlin , Yu Jinjin
Published: June 2021

Background: Cesarean scar pregnancy (CSP) involves a rare form of placental attachment that often leads to life-threatening conditions. The best treatment for CSP has been debated for decades. We aimed to evaluate the different treatments for CSP and analyzed the risk factors for intraoperative hemorrhage.

Methods: CSP patients treated at the Affiliated Hospital of Jiangnan University were reviewed retrospectively from January 2014 to 2020. CSP was classified into three types based on the location and shape of gestational tissue, blood flow features, and thickness of the myometrium at the incision site. The clinical characteristics, types, approaches of treatment, and clinical outcomes of CSP were analyzed.

Results: A total of 55 patients were included in this study, 29 (52.7%) of whom underwent transvaginal curettage after uterine artery embolization (UAE) and 22 (40%) of whom underwent transabdominal ultrasound-guided hysteroscopic curettage (USHC) in type I and II. Four patients (7.3%) classified as type III underwent laparoscopic cesarean scar resection (LCSR). Intraoperative blood loss, blood transfusion rate, and scar diverticulum were significantly higher in type II than in type I (P < 0.05). Even though USHC showed no differences in intraoperative blood loss, length of stay, and scar diverticulum compared with curettage after UAE (P > 0.05), superiority was found in surgical time and hospitalization cost (P < 0.05). Furthermore, the type of CSP (OR = 10.53, 95% CI: 1.69–65.57; P = 0.012) and diameter of the gestational sac (OR = 25.76, 95% CI: 2.67–248.20; P = 0.005) were found to be risk factors for intraoperative hemorrhage.

Conclusions: Transabdominal ultrasound-guided hysteroscopic curettage is an effective and relatively safe treatment option for patients with CSP. Type of CSP and diameter of the gestational sac were found to be associated with excessive intraoperative hemorrhage.
The Auxiliary Diagnostic Value of a Novel Wearable Electrocardiogram-Recording System for Arrhythmia Detection: Diagnostic Trial
Authors: Zhang Shaomin , Xian Hong , Chen Yi , Liao Yue , Zhang Nan , Guo Xinyu , Yang Ming , Wu Jinhui
Published: June 2021

Background: AMAZFIT®, a novel wearable electrocardiogram (ECG)-recording system is used for the measurement, acquisition, and storage of single-lead cardiac waveforms for adults. The aim of the study was to evaluate the accuracy of AMAZFIT® for diagnosing arrhythmia in older patients.

Methods: From May to December 2019, we recruited 291 elderly individuals with an average age of 78±10 years old, and 41.9% women. All cardiac waveforms were obtained from the AMAZFIT® which included limb and chest leads. Two trained technicians reviewed all ECG data to determine cardiac rhythm using standard diagnostic criteria. We evaluated the accuracy of AMAZFIT® for identifying arrhythmia by comparing the sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), and positive and negative likelihood ratios with those of a standard 12-lead ECG.

Results: Of the 291 participants, 197 older adults had arrhythmias, including AF (n = 119), first-degree AVB (n = 28), PACs (n = 25), and PVCs (n = 28). Three of these participants had arrhythmias of AF and PVCs. Chest lead data from 100% and limb lead data from 4.7% of the participants were analyzed. An evaluation of AMAZFIT® for atrial fibrillation (AF) reported a sensitivity, specificity, PPV, NPV PLR, and negative likelihood ratio (NLR) of 93.28, 95.35, 93.28, 95.35, 20.06, and 0.07%, respectively. AMAZFIT® also demonstrated excellent sensitivity for premature atrial contractions (PACs) (84.00%) and premature ventricular contractions (PVCs) (89.29%). However, the device demonstrated a low sensitivity for first-degree atrioventricular block (32.14%).

Conclusions: The AMAZFIT® showed significantly higher sensitivity and specificity for AF, PACs, and PVCs. This portable ECG-recording device based on an algorithm has a potential auxiliary diagnostic value for identifying arrhythmia compared with a standard 12-lead ECG device.
Behçet's Syndrome in a Chinese Pedigree of NLRP3-Associated Autoinflammatory Disease: A Coexistence or Novel Presentation?
Authors: Liu Jinjing , Yu Xin , Li Chaoran , Wang Yi , Yu Weihong , Shen Min , Zheng Wenjie
Published: June 2021

Objectives:NLRP3-associated autoinflammatory disease (NLRP3-AID) and Behçet's syndrome (BS) both belong to autoinflammatory diseases and rarely co-occur. Here we reported a Chinese pedigree of NLRP3-AID presented with BS.

Methods: We recorded a Chinese pedigree of NLRP3-AID presented with BS. Whole-exome sequencing was performed to find the hereditary susceptibility gene, and Sanger sequencing was performed on a consecutive cohort of 30 BS patients. We also reviewed the English literature on vasculitis associated with NLRP3-AID.

Results: The proband was a 45-year-old Chinese Han woman. She and her 12-year-old daughter presented with recurrent fevers, cold-induced urticaria, oral, and genital ulcers, conjunctivitis, uveitis, optic atrophy, erythema nodosum, headache, and hearing loss. They were initially suspected of having BS, and both responded poorly to corticosteroids and immunosuppressants, while anti-TNF therapy was moderately effective. Pedigree analysis revealed another four relatives with similar symptoms, and a heterozygous NLRP3 gene mutation c.1316C>T, p.Ala439Val was identified by whole-exome sequencing and Sanger sequencing. However, we did not discover NLRP3 gene mutation by Sanger sequencing in a confirmative cohort of 30 BS cases. A few case reports of vasculitis coexisting with NLRP3-AID, including a case of glomerulonephritis, and five cases of retinal vasculitis, were summarized through literature review.

Conclusions: Our study is the first report of NLRP3-AID associated with BS. The coexistence of NLRP3-AID and BS reveals the extensive heterogeneity of the pathogenesis of systemic autoinflammatory diseases and calls for specific therapeutics.