bluuebunny/crossref_metadata_2025 huggingface dataset:
LncRNA SPANXA2-OT1 Participates in the Occurrence and Development of EMT in Calcium Oxalate Crystal-Induced Kidney Injury by Adsorbing miR-204 and Up-Regulating Smad5
Authors: Hu Haiyan , Zhang Jie , Li Yinhui , Ding Jiarong , Chen Wei , Guo Zhiyong
Published: September 2021

Objective: To explore the regulatory mechanism of long non-coding RNAs (lncRNAs) in the occurrence and development of epithelial-mesenchymal transition (EMT) in calcium oxalate crystal-induced kidney injury.

Materials and Methods: Gene core technique was used to screen differentially expressed lncRNAs and mRNAs in HK-2 cells before and after calcium oxalate monohydrate (COM) stimulation; differentially expressed mRNAs were then analyzed using GO and pathway analysis. The role of target lncRNA in EMT in renal tubular epithelial cells induced by COM was further investigated by applying a series of in vitro experiments.

Results: Four differentially expressed lncRNAs (ABCA9-AS1, SPANXA2-OT1, RP11-955H22.1, and RP11-748C4.1) were up-regulated after 48 h of COM stimulation compared to the control group, where up-regulated expression of lncRNA SPANXA2-OT1 was the most significant. Thus, lncRNA SPANXA2-OT1 was further examined. Interference lncRNA SPANXA2-OT1 reversed the down-regulation of E-cadherin and Pan-ck, and up-regulated Vimentin and α-SMA induced by COM stimulation. The application of miR204 inhibitor weakened the interference effect of interfering RNA on lncRNA SPANXA2-OT1 and promoted the occurrence of EMT. Moreover, the miR204 simulator alleviated the overexpression effect of lncRNA SPANXA2-OT1 on COM-stimulated renal tubular epithelial cells and inhibited the occurrence of EMT in renal tubular epithelial cells. Also, a dual-luciferase reporter assay showed that miR-204 could bind to lncRNA SPANXA2-OT1 and Smad5, while lncRNA SPANXA2-OT1 could inhibit cell proliferation and promote cell apoptosis.

Conclusion: The lncRNA SPANXA2-OT1 is involved in the occurrence and development of EMT in renal tubular epithelial cells induced by crystalline kidney injury by adsorbing miR-204 and up-regulating Smad5.
A Clinical Risk Model to Predict Rapidly Progressive Interstitial Lung Disease Incidence in Dermatomyositis
Authors: Li Yimin , Li Yuhui , Wang Yuguang , Shi Lianjie , Lin Fuan , Zhang Zongxue , Zhang Jingli , Liu Yanying , Liu Xu , Xu Fangjingwei , Sun Xiaolin
Published: September 2021

Background: Rapidly progressive interstitial lung disease (RP-ILD) is a fatal complication of dermatomyositis (DM) and clinically amyopathic DM (CADM). The objective of this study was to evaluate risk markers associated with RP-ILD incidence in patients with DM/CADM and to develop a RP-ILD risk prediction (RRP) model.

Methods: The clinical records of 229 patients with DM/CADM from Peking University People's Hospital, and 97 patients from four other independent clinical centers were retrospectively reviewed. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors associated with later RP-ILD incidence to build a risk score model. The concordance index (C-index) and calibration curve were calculated to evaluate the predictive accuracy of the RRP model.

Results: A multiparametric RRP model was established based on weighted clinical features, including fever (yes, 5; no, 0), periungual erythema (yes, 6; no, 0), elevated CRP (yes, 5; no, 0), anti-MDA5 antibody (positive, 8; negative, 0), and anti-Ro-52 antibody (positive, 6; negative, 0). Patients were divided into three risk groups according to the RRP total score: low, 0–9; medium, 10–19; high, 20–30. The C-index and calibration curve of the RRP model showed a promising predictive accuracy on the incidence of RP-ILD.

Conclusion: The RRP model might promisingly predict the incidence of RP-ILD in DM/CADM patients to guide early individual treatment and further improve the prognosis of DM/CADM patients.
Mitochondrial Regulation of Diabetic Kidney Disease
Authors: Galvan Daniel L. , Mise Koki , Danesh Farhad R.
Published: September 2021

The role and nature of mitochondrial dysfunction in diabetic kidney disease (DKD) has been extensively studied. Yet, the molecular drivers of mitochondrial remodeling in DKD are poorly understood. Diabetic kidney cells exhibit a cascade of mitochondrial dysfunction ranging from changes in mitochondrial morphology to significant alterations in mitochondrial biogenesis, biosynthetic, bioenergetics and production of reactive oxygen species (ROS). How these changes individually or in aggregate contribute to progression of DKD remain to be fully elucidated. Nevertheless, because of the remarkable progress in our basic understanding of the role of mitochondrial biology and its dysfunction in DKD, there is great excitement on future targeted therapies based on improving mitochondrial function in DKD. This review will highlight the latest advances in understanding the nature of mitochondria dysfunction and its role in progression of DKD, and the development of mitochondrial targets that could be potentially used to prevent its progression.
Genetic Microbial Source Tracking Support QMRA Modeling for a Riverine Wetland Drinking Water Resource
Authors: Derx Julia , Demeter Katalin , Linke Rita , Cervero-Aragó Sílvia , Lindner Gerhard , Stalder Gabrielle , Schijven Jack , Sommer Regina , Walochnik Julia , Kirschner Alexander K. T. , Komma Jürgen , Blaschke Alfred P. , Farnleitner Andreas H.
Published: September 2021

Riverine wetlands are important natural habitats and contain valuable drinking water resources. The transport of human- and animal-associated fecal pathogens into the surface water bodies poses potential risks to water safety. The aim of this study was to develop a new integrative modeling approach supported by microbial source tracking (MST) markers for quantifying the transport pathways of two important reference pathogens, Cryptosporidium and Giardia, from external (allochthonous) and internal (autochthonous) fecal sources in riverine wetlands considering safe drinking water production. The probabilistic-deterministic model QMRAcatch (v 1.1 python backwater) was modified and extended to account for short-time variations in flow and microbial transport at hourly time steps. As input to the model, we determined the discharge rates, volumes and inundated areas of the backwater channel based on 2-D hydrodynamic flow simulations. To test if we considered all relevant fecal pollution sources and transport pathways, we validated QMRAcatch using measured concentrations of human, ruminant, pig and bird associated MST markers as well as E. coli in a Danube wetland area from 2010 to 2015. For the model validation, we obtained MST marker decay rates in water from the literature, adjusted them within confidence limits, and simulated the MST marker concentrations in the backwater channel, resulting in mean absolute errors of < 0.7 log10 particles/L (Kruskal–Wallis p > 0.05). In the scenarios, we investigated (i) the impact of river discharges into the backwater channel (allochthonous sources), (ii) the resuspension of pathogens from animal fecal deposits in inundated areas, and (iii) the pathogen release from animal fecal deposits after rainfall (autochthonous sources). Autochthonous and allochthonous human and animal sources resulted in mean loads and concentrations of Cryptosporidium and Giardia (oo)cysts in the backwater channel of 3–13 × 109 particles/hour and 0.4–1.2 particles/L during floods and rainfall events, and in required pathogen treatment reductions to achieve safe drinking water of 5.0–6.2 log10. The integrative modeling approach supports the sustainable and proactive drinking water safety management of alluvial backwater areas.
relA Inactivation Converts Sulfonamides Into Bactericidal Compounds
Authors: Si Lizhen , Gu Jing , Wen Mi , Wang Ruiqi , Fleming Joy , Li Jinyue , Xu Jintian , Bi Lijun , Deng Jiaoyu
Published: September 2021

Folates are required for the de novo biosynthesis of purines, thymine, methionine, glycine, and pantothenic acid, key metabolites that bacterial cells cannot survive without. Sulfonamides, which inhibit bacterial folate biosynthesis and are generally considered as bacteriostats, have been extensively used as broad-spectrum antimicrobials for decades. Here we show that, deleting relA in Escherichia coli and other bacterial species converted sulfamethoxazole from a bacteriostat into a bactericide. Not as previously assumed, the bactericidal effect of SMX was not caused by thymine deficiency. When E. coli ∆relA was treated with SMX, reactive oxygen species and ferrous ion accumulated inside the bacterial cells, which caused extensive DNA double-strand breaks without the involvement of incomplete base excision repair. In addition, sulfamethoxazole showed bactericidal effect against E. coli O157 ∆relA in mice, suggesting the possibility of designing new potentiators for sulfonamides targeting RelA. Thus, our study uncovered the previously unknown bactericidal effects of sulfonamides, which advances our understanding of their mechanisms of action, and will facilitate the designing of new potentiators for them.
Leveraging Experimental Strategies to Capture Different Dimensions of Microbial Interactions
Authors: Gupta Gunjan , Ndiaye Amadou , Filteau Marie
Published: September 2021

Microorganisms are a fundamental part of virtually every ecosystem on earth. Understanding how collectively they interact, assemble, and function as communities has become a prevalent topic both in fundamental and applied research. Owing to multiple advances in technology, answering questions at the microbial system or network level is now within our grasp. To map and characterize microbial interaction networks, numerous computational approaches have been developed; however, experimentally validating microbial interactions is no trivial task. Microbial interactions are context-dependent, and their complex nature can result in an array of outcomes, not only in terms of fitness or growth, but also in other relevant functions and phenotypes. Thus, approaches to experimentally capture microbial interactions involve a combination of culture methods and phenotypic or functional characterization methods. Here, through our perspective of food microbiologists, we highlight the breadth of innovative and promising experimental strategies for their potential to capture the different dimensions of microbial interactions and their high-throughput application to answer the question; are microbial interaction patterns or network architecture similar along different contextual scales? We further discuss the experimental approaches used to build various types of networks and study their architecture in the context of cell biology and how they translate at the level of microbial ecosystem.
The Crossroads of Glycoscience, Infection, and Immunology
Authors: McKitrick Tanya R. , Ackerman Margaret E. , Anthony Robert M. , Bennett Clay S. , Demetriou Michael , Hudalla Gregory A. , Ribbeck Katharina , Ruhl Stefan , Woo Christina M. , Yang Loretta , Zost Seth J. , Schnaar Ronald L. , Doering Tamara L.
Published: September 2021

Advances in experimental capabilities in the glycosciences offer expanding opportunities for discovery in the broad areas of immunology and microbiology. These two disciplines overlap when microbial infection stimulates host immune responses and glycan structures are central in the processes that occur during all such encounters. Microbial glycans mediate host-pathogen interactions by acting as surface receptors or ligands, functioning as virulence factors, impeding host immune responses, or playing other roles in the struggle between host and microbe. In the context of the host, glycosylation drives cell–cell interactions that initiate and regulate the host response and modulates the effects of antibodies and soluble immune mediators. This perspective reports on a workshop organized jointly by the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research in May 2020. The conference addressed the use of emerging glycoscience tools and resources to advance investigation of glycans and their roles in microbe-host interactions, immune-mediated diseases, and immune cell recognition and function. Future discoveries in these areas will increase fundamental scientific understanding and have the potential to improve diagnosis and treatment of infections and immune dysregulation.
Controlled Complexity: Optimized Systems to Study the Role of the Gut Microbiome in Host Physiology
Authors: Glowacki Robert W. P. , Engelhart Morgan J. , Ahern Philip P.
Published: September 2021

The profound impact of the gut microbiome on host health has led to a revolution in biomedical research, motivating researchers from disparate fields to define the specific molecular mechanisms that mediate host-beneficial effects. The advent of genomic technologies allied to the use of model microbiomes in gnotobiotic mouse models has transformed our understanding of intestinal microbial ecology and the impact of the microbiome on the host. However, despite incredible advances, our understanding of the host-microbiome dialogue that shapes host physiology is still in its infancy. Progress has been limited by challenges associated with developing model systems that are both tractable enough to provide key mechanistic insights while also reflecting the enormous complexity of the gut ecosystem. Simplified model microbiomes have facilitated detailed interrogation of transcriptional and metabolic functions of the microbiome but do not recapitulate the interactions seen in complex communities. Conversely, intact complex communities from mice or humans provide a more physiologically relevant community type, but can limit our ability to uncover high-resolution insights into microbiome function. Moreover, complex microbiomes from lab-derived mice or humans often do not readily imprint human-like phenotypes. Therefore, improved model microbiomes that are highly defined and tractable, but that more accurately recapitulate human microbiome-induced phenotypic variation are required to improve understanding of fundamental processes governing host-microbiome mutualism. This improved understanding will enhance the translational relevance of studies that address how the microbiome promotes host health and influences disease states. Microbial exposures in wild mice, both symbiotic and infectious in nature, have recently been established to more readily recapitulate human-like phenotypes. The development of synthetic model communities from such “wild mice” therefore represents an attractive strategy to overcome the limitations of current approaches. Advances in microbial culturing approaches that allow for the generation of large and diverse libraries of isolates, coupled to ever more affordable large-scale genomic sequencing, mean that we are now ideally positioned to develop such systems. Furthermore, the development of sophisticated in vitro systems is allowing for detailed insights into host-microbiome interactions to be obtained. Here we discuss the need to leverage such approaches and highlight key challenges that remain to be addressed.
Integrated Management of Multiple Sclerosis Spasticity and Associated Symptoms Using the Spasticity-Plus Syndrome Concept: Results of a Structured Specialists' Discussion Using the Workmat® Methodology
Authors: Fernandez Oscar , Costa-Frossard Lucienne , Martínez-Ginés Maria Luisa , Montero Paloma , Prieto-González Jose María , Ramió-Torrentà Lluís
Published: September 2021

Background: Multiple sclerosis (MS) treatment has radically improved over the last years; however, MS symptom management is still challenging. The novel Spasticity-Plus syndrome was conceptualized to frame several spasticity-related symptoms that can be addressed together with broad-spectrum medication, such as certain cannabinoid-based drugs. The aim of this project was to gain insight into Spanish neurologists' clinical experience on MS spasticity and associated symptoms, and to assess the acknowledgment and applicability of the Spasticity-Plus syndrome concept in patients with MS.

Methods: Ten online meetings were conducted using the Workmat® methodology to allow structured discussions. Fifty-five Spanish neurologists, experts in MS management, completed and discussed a set of predefined exercises comprising MS symptom assessment and its management in clinical practice, MS symptoms clustering in clinical practice, and their perception of the Spasticity-Plus syndrome concept. This document presents the quantitative and qualitative results of these discussions.

Results: The specialists considered that polytherapy is a common concern in MS and that simplifying the management of MS spasticity and associated manifestations could be useful. They generally agreed that MS spasticity should be diagnosed before moderate or severe forms appear. According to the neurologists' clinical experience, symptoms commonly associated with MS spasticity included spasms/cramps (100% of the specialists), pain (85%), bladder dysfunction (62%), bowel dysfunction (42%), sleep disorders (42%), and sexual dysfunction (40%). The multiple correspondence analysis revealed two main symptom clusters: spasticity-spasms/cramps-pain, and ataxia-instability-vertigo. Twelve out of 16 symptoms (75%) were scored >7 in a 0–10 QoL impact scale by the specialists, representing a moderate–high impact. The MS specialists considered that pain, spasticity, spasms/cramps, bladder dysfunction, and depression should be a treatment priority given their frequency and chance of therapeutic success. The neurologists agreed on the usefulness of the new Spasticity-Plus syndrome concept to manage spasticity and associated symptoms together, and their experience with treatments targeting the cannabinoid system was satisfactory.

Conclusions: The applicability of the new concept of Spasticity-Plus in MS clinical practice seems possible and may lead to an integrated management of several MS symptoms, thus reducing the treatment burden of disease symptoms.
Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies
Authors: Yuan Aidong , Nixon Ralph A.
Published: September 2021

Biomarkers of neurodegeneration and neuronal injury have the potential to improve diagnostic accuracy, disease monitoring, prognosis, and measure treatment efficacy. Neurofilament proteins (NfPs) are well suited as biomarkers in these contexts because they are major neuron-specific components that maintain structural integrity and are sensitive to neurodegeneration and neuronal injury across a wide range of neurologic diseases. Low levels of NfPs are constantly released from neurons into the extracellular space and ultimately reach the cerebrospinal fluid (CSF) and blood under physiological conditions throughout normal brain development, maturation, and aging. NfP levels in CSF and blood rise above normal in response to neuronal injury and neurodegeneration independently of cause. NfPs in CSF measured by lumbar puncture are about 40-fold more concentrated than in blood in healthy individuals. New ultra-sensitive methods now allow minimally invasive measurement of these low levels of NfPs in serum or plasma to track disease onset and progression in neurological disorders or nervous system injury and assess responses to therapeutic interventions. Any of the five Nf subunits – neurofilament light chain (NfL), neurofilament medium chain (NfM), neurofilament heavy chain (NfH), alpha-internexin (INA) and peripherin (PRPH) may be altered in a given neuropathological condition. In familial and sporadic Alzheimer’s disease (AD), plasma NfL levels may rise as early as 22 years before clinical onset in familial AD and 10 years before sporadic AD. The major determinants of elevated levels of NfPs and degradation fragments in CSF and blood are the magnitude of damaged or degenerating axons of fiber tracks, the affected axon caliber sizes and the rate of release of NfP and fragments at different stages of a given neurological disease or condition directly or indirectly affecting central nervous system (CNS) and/or peripheral nervous system (PNS). NfPs are rapidly emerging as transformative blood biomarkers in neurology providing novel insights into a wide range of neurological diseases and advancing clinical trials. Here we summarize the current understanding of intracellular NfP physiology, pathophysiology and extracellular kinetics of NfPs in biofluids and review the value and limitations of NfPs and degradation fragments as biomarkers of neurodegeneration and neuronal injury.
A Reversal in Hair Cell Orientation Organizes Both the Auditory and Vestibular Organs
Authors: Tarchini Basile
Published: September 2021

Sensory hair cells detect mechanical stimuli with their hair bundle, an asymmetrical brush of actin-based membrane protrusions, or stereocilia. At the single cell level, stereocilia are organized in rows of graded heights that confer the hair bundle with intrinsic directional sensitivity. At the organ level, each hair cell is precisely oriented so that its intrinsic directional sensitivity matches the direction of mechanical stimuli reaching the sensory epithelium. Coordinated orientation among neighboring hair cells usually ensures the delivery of a coherent local group response. Accordingly, hair cell orientation is locally uniform in the auditory and vestibular cristae epithelia in birds and mammals. However, an exception to this rule is found in the vestibular macular organs, and in fish lateral line neuromasts, where two hair cell populations show opposing orientations. This mirror-image hair cell organization confers bidirectional sensitivity at the organ level. Here I review our current understanding of the molecular machinery that produces mirror-image organization through a regional reversal of hair cell orientation. Interestingly, recent evidence suggests that auditory hair cells adopt their normal uniform orientation through a global reversal mechanism similar to the one at work regionally in macular and neuromast organs. Macular and auditory organs thus appear to be patterned more similarly than previously appreciated during inner ear development.
Development of a Nomogram for Predicting the Cumulative Incidence of Disease Recurrence of AML After Allo-HSCT
Authors: Zhang Tongtong , Bao Xiebing , Qiu Huiying , Tang Xiaowen , Han Yue , Fu Chengcheng , Sun Aining , Ruan Changgeng , Wu Depei , Chen Suning , Xu Yang
Published: September 2021

Using targeted exome sequencing, we studied correlations between mutations at diagnosis and transplant outcomes in 332 subjects with acute myeloid leukemia (AML) receiving allotransplantation. A total of 299 patients (299/332, 90.1%) had at least one oncogenic point mutation. In multivariable analyses, pretransplant disease status, minimal residual disease (MRD) before transplantation (pre-MRD), cytogenetic risk classification, and TP53 and FLT3-ITDhigh ratio mutations were independent risk factors for AML recurrence after allotransplantation (p < 0.05). A nomogram for the cumulative incidence of relapse (CIR) that integrated all the predictors in the multivariable model was then constructed, and the concordance index (C-index) values at 6, 12, 18, and 24 months for CIR prediction were 0.754, 0.730, 0.715, and 0.690, respectively. Moreover, calibration plots showed good agreements between the actual observation and the nomogram prediction for the 6, 12, 18, and 24 months posttransplantation CIR in the internal validation. The integrated calibration index (ICI) values were 0.008, 0.055, 0.094, and 0.136 at 6, 12, 18, and 24 months posttransplantation, respectively. With a median cutoff score of 9.73 from the nomogram, all patients could be divided into two groups, and the differences in 2-year CIR, disease-free survival (DFS), and overall survival (OS) between these two groups were significant (p < 0.05). Taken together, the results of our study indicate that gene mutations could help to predict the outcomes of patients with AML receiving allotransplantation.
RFWD2 Knockdown as a Blocker to Reverse the Oncogenic Role of TRIB2 in Lung Adenocarcinoma
Authors: Hao Ruimin , Hu Jinxia , Liu Yuemei , Liang Dongmin , Li Yan-Mei , Wang Ranran , Zhang Shucui , Wang Pingyu , Li You-Jie , Xie Shuyang
Published: September 2021

RFWD2, an E3 ubiquitin ligase, is overexpressed in numerous human cancers, including leukemia, lung cancer, breast cancer, renal cell carcinoma, and colorectal cancer. The roles of RFWD2 in cancer are related to the targeting of its substrates for ubiquitination and degradation. This study aimed to investigate the role of TRIB2 in relation to the regulation of protein degradation through RFWD2. inBio Discover™ results demonstrated that TRIB2 can perform its functions by interacting with RFWD2 or other factors. TRIB2 can interact with and regulate RFWD2, which further attends the proteasome-mediated degradation of the RFWD2 substrate p-IκB-α. TRIB2 colocalizes with RFWD2-related IκB-α to form a ternary complex and further affects the IκB-α degradation by regulating its phosphorylation. Specific domain analysis showed that TRIB2 may bind to RFWD2 via its C-terminus, whereas it binds to IκB via its pseudokinase domain. TRIB2 acts as an oncogene and promotes cancer cell proliferation and migration, whereas RFWD2 knockdown reversed the role of TRIB2 in promoting cancer cell growth and colony formation in vitro and in vivo. In summary, this study reveals that TRIB2 promotes the progression of cancer by affecting the proteasome-mediated degradation of proteins through the interaction with RFWD2.
Application of Organoid Models in Prostate Cancer Research
Authors: Zhou Ligui , Zhang Caiqin , Zhang Yongbin , Shi Changhong
Published: September 2021

Complex heterogeneity is an important characteristic in the development of prostate cancer (PCa), which further leads to the failure of known therapeutic options. PCa research has been hampered by the current in vitro model systems that cannot fully reflect the biological characteristics and clinical diversity of PCa. The tumor organoid model in three-dimensional culture retains the heterogeneity of primary tumor tissues in vitro well and enables high-throughput screening and genome editing. Therefore, the establishment of a PCa organoid model that recapitulates the diverse heterogeneity observed in clinical settings is of great significance for the study of PCa. In this review, we summarize the culture conditions, establishments, and limitations of PCa organoids and further review their application for the study of pathogenesis, drug screening, mechanism of drug resistance, and individualized treatment for PCa. Additionally, we look forward to other potential developmental directions of PCa organoids, such as the interaction between prostate cancer tumor cells and their microenvironment, clinical individualized treatments, heterogeneous transformation model, tumor immunotherapy, and organoid models combined with liquid biopsy. Through this, we provide more effective preclinical experimental schemes using the PCa organoid model.
Comparative Study of a Modified Sub-Tenon’s Capsule Injection of Triamcinolone Acetonide and the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Retinitis Pigmentosa Combined With Macular Edema
Authors: Zhao Tongtao , Lie Hongxuan , Wang Fang , Liu Yong , Meng Xiaohong , Yin Zhengqin , Li Shiying
Published: September 2021

Retinitis pigmentosa (RP) is a hereditary retinal degenerative disease leading to eventual blindness. When RP is combined with macular edema (ME), the visual impairment further worsens. We compared a modified sub-Tenon’s capsule injection of triamcinolone acetonide (TA) and the intravenous infusion of umbilical cord mesenchymal stem cells (UCMSCs) in the treatment of RP combined with ME (RP-ME) to assess their safety and efficacy in eliminating ME and restoring visual function. A phase I/II clinical trial enrolled 20 patients was conducted. All patients were followed up for 6 months. There were no severe adverse effects in both groups. In retinal morphological tests, the central macular thickness (CMT) in TA group significantly decreased at first week, first and second month after injection (p < 0.05). The CMT in UCMSCs group significantly decreased at first month after infusion. The rate of reduction of CMT in TA group was significantly greater than that in UCMSCs group at second month (p < 0.05). Reversely, the rate of reduction of CMT in UCMSCs group was significantly greater than that in TA group at sixth month (p < 0.05). In visual functional test, although there were no significant differences in visual acuity or visual fields within each group or between groups, but the amplitude of P2 wave of flash visual evoked potential (FVEP) showed significant increasing in TA group at second month in UCMSCs group at sixth month (p < 0.05). At 6th month, the rate of growth in the amplitude of P2 wave in USMCSs group was significantly greater than that in TA group (p < 0.05). This study suggests both modified sub-Tenon’s capsule injection of TA and intravenous infusion of UCMSCs are safe for RP-ME patients. TA injection is more effective at alleviating ME while improving visual function in a short term. UCMSC intravenous infusion shows slow but persistent action in alleviating ME, and can improve the visual function for a longer time. These approaches can be applied separately or jointly depending on the disease condition for patients to benefit maximumly.

Clinical Trial Registration:http://www.chictr.org.cn, identifier ChiCTR-ONC-16008839
WTD Attenuating Rheumatoid Arthritis via Suppressing Angiogenesis and Modulating the PI3K/AKT/mTOR/HIF-1α Pathway
Authors: Ba Xin , Huang Ying , Shen Pan , Huang Yao , Wang Hui , Han Liang , Lin Wei Ji , Yan Hui Jia , Xu Li Jun , Qin Kai , Chen Zhe , Tu Sheng Hao
Published: September 2021

Background: Wutou Decoction (WTD), as a classic prescription, has been generally used to treat rheumatoid arthritis (RA) for two thousand years in China. However, the potential protective effects of WTD on rheumatoid arthritis and its possible mechanism have rarely been reported.

Purpose: The aim of this study was to explore the possible mechanism of WTD against RA and a promising alternative candidate for RA therapy.

Methods: A model of collagen-induced arthritis (CIA) was constructed in rats to assess the therapeutic effects of WTD. Histopathological staining, immunofluorescence, and western blotting of synovial sections were conducted to detect the antiangiogenic effects of WTD. Then, cell viability assays, flow cytometry, scratch healing assays, and invasion assays were conducted to explore the effects of WTD on MH7A human fibroblast-like synoviocyte (FLS) cell proliferation, apoptosis, migration, and invasion in vitro. The ability of WTD to induce blood vessel formation after MH7A cell and human umbilical vein endothelial cell line (HUVEC) coculture with WTD intervention was detected by a tube formation assay. The mechanisms of WTD were screened by network pharmacology and confirmed by in vivo and in vitro experiments.

Results: WTD ameliorated the symptoms and synovial pannus hyperplasia of CIA rats. Treatment with WTD inhibited MH7A cell proliferation, migration, and invasion and promoted MH7A apoptosis. WTD could inhibit MH7A cell expression of proangiogenic factors, including VEGF and ANGI, to induce HUVEC tube formation. Furthermore, the PI3K-AKT-mTOR-HIF-1α pathway was enriched as a potential target of WTD for the treatment of RA through network pharmacology enrichment analysis. Finally, it was confirmed in vitro and in vivo that WTD inhibits angiogenesis in RA by interrupting the PI3K-AKT-mTOR-HIF-1α pathway.

Conclusion: WTD can inhibit synovial hyperplasia and angiogenesis, presumably by inhibiting the migration and invasion of MH7A cells and blocking the production of proangiogenic effectors in MH7A cells. The possible underlying mechanism by which WTD ameliorates angiogenesis in RA is the PI3K-AKT-mTOR-HIF-1α pathway.
Mesencephalic Astrocyte-Derived Neurotrophic Factor Regulates Morphology of Pigment-Dispersing Factor-Positive Clock Neurons and Circadian Neuronal Plasticity in Drosophila melanogaster
Authors: Krzeptowski Wojciech , Walkowicz Lucyna , Krzeptowska Ewelina , Motta Edyta , Witek Kacper , Szramel Joanna , Al Abaquita Terence , Baster Zbigniew , Rajfur Zenon , Rosato Ezio , Stratoulias Vassilis , Heino Tapio I. , Pyza Elżbieta M.
Published: September 2021

Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) is one of a few neurotrophic factors described in Drosophila melanogaster (DmMANF) but its function is still poorly characterized. In the present study we found that DmMANF is expressed in different clusters of clock neurons. In particular, the PDF-positive large (l-LNv) and small (s-LNv) ventral lateral neurons, the CRYPTOCHROME-positive dorsal lateral neurons (LNd), the group 1 dorsal neurons posterior (DN1p) and different tim-positive cells in the fly’s visual system. Importantly, DmMANF expression in the ventral lateral neurons is not controlled by the clock nor it affects its molecular mechanism. However, silencing DmMANF expression in clock neurons affects the rhythm of locomotor activity in light:dark and constant darkness conditions. Such phenotypes correlate with abnormal morphology of the dorsal projections of the s-LNv and with reduced arborizations of the l-LNv in the medulla of the optic lobe. Additionally, we show that DmMANF is important for normal morphology of the L2 interneurons in the visual system and for the circadian rhythm in the topology of their dendritic tree. Our results indicate that DmMANF is important not only for the development of neurites but also for maintaining circadian plasticity of neurons.
Time-Averaged Wavefront Analysis Demonstrates Preferential Pathways of Atrial Fibrillation, Predicting Pulmonary Vein Isolation Acute Response
Authors: Roney Caroline H. , Child Nicholas , Porter Bradley , Sim Iain , Whitaker John , Clayton Richard H. , Laughner Jacob I. , Shuros Allan , Neuzil Petr , Williams Steven E. , Razavi Reza S. , O'Neill Mark , Rinaldi Christopher A. , Taggart Peter , Wright Matt , Gill Jaswinder S. , Niederer Steven A.
Published: September 2021

Electrical activation during atrial fibrillation (AF) appears chaotic and disorganised, which impedes characterisation of the underlying substrate and treatment planning. While globally chaotic, there may be local preferential activation pathways that represent potential ablation targets. This study aimed to identify preferential activation pathways during AF and predict the acute ablation response when these are targeted by pulmonary vein isolation (PVI). In patients with persistent AF (n = 14), simultaneous biatrial contact mapping with basket catheters was performed pre-ablation and following each ablation strategy (PVI, roof, and mitral lines). Unipolar wavefront activation directions were averaged over 10 s to identify preferential activation pathways. Clinical cases were classified as responders or non-responders to PVI during the procedure. Clinical data were augmented with a virtual cohort of 100 models. In AF pre-ablation, pathways originated from the pulmonary vein (PV) antra in PVI responders (7/7) but not in PVI non-responders (6/6). We proposed a novel index that measured activation waves from the PV antra into the atrial body. This index was significantly higher in PVI responders than non-responders (clinical: 16.3 vs. 3.7%, p = 0.04; simulated: 21.1 vs. 14.1%, p = 0.02). Overall, this novel technique and proof of concept study demonstrated that preferential activation pathways exist during AF. Targeting patient-specific activation pathways that flowed from the PV antra to the left atrial body using PVI resulted in AF termination during the procedure. These PV activation flow pathways may correspond to the presence of drivers in the PV regions.
The Impact of COVID-19 Infection on Oxygen Homeostasis: A Molecular Perspective
Authors: Alayash Abdu I.
Published: September 2021

The novel coronavirus (2019-nCoV/SARS-CoV-2) causes respiratory symptoms including a substantial pulmonary dysfunction with worsening arterial hypoxemia (low blood oxygenation), eventually leading to acute respiratory distress syndrome (ARDS). The impact of the viral infection on blood oxygenation and other elements of oxygen homeostasis, such as oxygen sensing and respiratory mitochondrial mechanisms, are not well understood. As a step toward understanding these mechanisms in the context of COVID-19, recent experiments revealed contradictory data on the impact of COVID-19 infection on red blood cells (RBCs) oxygenation parameters. However, structural protein damage and membrane lipid remodeling in RBCs from COVID-19 patients that may impact RBC function have been reported. Moreover, COVID-19 infection could potentially disrupt one, if not all, of the other major pathways of homeostasis. Understanding the nature of the crosstalk among normal homeostatic pathways; oxygen carrying, oxygen sensing (i.e., hypoxia inducible factor, HIF) proteins, and the mitochondrial respiratory machinery may provide a target for therapeutic interventions.
Soluble Epoxide Hydrolase Inhibitors Regulate Ischemic Arrhythmia by Targeting MicroRNA-1
Authors: Chen Yanying , Liu Qiong , Yang Tian , Shen Li , Xu Danyan
Published: September 2021

Background: Soluble epoxide hydrolase inhibitors (sEHis) inhibit the degradation of epoxyeicosatrienoic acids (EETs) in cells, and EETs have antiarrhythmic effects. Our previous experiments confirmed that t-AUCB, a preparation of sEHis, inhibited ischemic arrhythmia by negatively regulating microRNA-1 (miR-1), but its specific mechanism remained unclear.

Aim: This study aimed to examine the role of serum response factor (SRF) and the PI3K/Akt/GSK3β pathway in t-AUCB-mediated regulation of miR-1 and the interaction between them.

Methods/Results: We used SRF small interfering RNA (siSRF), SRF small hairpin (shSRF) RNA sequence adenovirus, PI3K/Akt/GSK3β pathway inhibitors, t-AUCB, and 14,15-EEZE (a preparation of EETs antagonists) to treat mouse cardiomyocytes overexpressing miR-1 and mice with myocardial infarction (MI). We found that silencing SRF attenuated the effects on miR-1 and its target genes KCNJ2 and GJA1 in the presence of t-AUCB, and inhibition of the PI3K/Akt/GSK3β pathway antagonized the effects of t-AUCB on miR-1, KCNJ2, and GJA1, which were associated with PI3Kα, Akt, and Gsk3β but not PI3Kβ or PI3Kγ. Moreover, the PI3K/Akt/GSK3β pathway was involved in the regulation of SRF by t-AUCB, and silencing SRF inhibited the t-AUCB-induced increases in Akt and Gsk3β phosphorylation.

Conclusions: Both the SRF and the PI3K/Akt/GSK3β pathway are involved in the t-AUCB-mediated regulation of miR-1, and these factors interact with each other.
Ex vivo Demonstration of Functional Deficiencies in Popliteal Lymphatic Vessels From TNF-Transgenic Mice With Inflammatory Arthritis
Authors: Scallan Joshua P. , Bouta Echoe M. , Rahimi Homaira , Kenney H. Mark , Ritchlin Christopher T. , Davis Michael J. , Schwarz Edward M.
Published: September 2021

Background: Recent studies demonstrated lymphangiogenesis and expansion of draining lymph nodes during chronic inflammatory arthritis, and lymphatic dysfunction associated with collapse of draining lymph nodes in rheumatoid arthritis (RA) patients and TNF-transgenic (TNF-Tg) mice experiencing arthritic flare. As the intrinsic differences between lymphatic vessels afferent to healthy, expanding, and collapsed draining lymph nodes are unknown, we characterized the ex vivo behavior of popliteal lymphatic vessels (PLVs) from WT and TNF-Tg mice. We also interrogated the mechanisms of lymphatic dysfunction through inhibition of nitric oxide synthase (NOS).

Methods: Popliteal lymph nodes (PLNs) in TNF-Tg mice were phenotyped as Expanding or Collapsed by in vivo ultrasound and age-matched to WT littermate controls. The PLVs were harvested and cannulated for ex vivo functional analysis over a relatively wide range of hydrostatic pressures (0.5–10 cmH2O) to quantify the end diastolic diameter (EDD), tone, amplitude (AMP), ejection fraction (EF), contraction frequency (FREQ), and fractional pump flow (FPF) with or without NOS inhibitors Data were analyzed using repeated measures two-way ANOVA with Bonferroni’s post hoc test.

Results: Real time videos of the cannulated PLVs demonstrated the predicted phenotypes of robust vs. weak contractions of the WT vs. TNF-Tg PLV, respectively. Quantitative analyses confirmed that TNF-Tg PLVs had significantly decreased AMP, EF, and FPF vs. WT (p < 0.05). EF and FPF were recovered by NOS inhibition, while the reduction in AMP was NOS independent. No differences in EDD, tone, or FREQ were observed between WT and TNF-Tg PLVs, nor between Expanding vs. Collapsed PLVs.

Conclusion: These findings support the concept that chronic inflammatory arthritis leads to NOS dependent and independent draining lymphatic vessel dysfunction that exacerbates disease, and may trigger arthritic flare due to decreased egress of inflammatory cells and soluble factors from affected joints.
Deciphering the Role of microRNAs in Large-Artery Stiffness Associated With Aging: Focus on miR-181b
Authors: Baraban Jay M. , Tuday Eric , Berkowitz Dan E. , Das Sam
Published: September 2021

Large artery stiffness (LAS) is a major, independent risk factor underlying cardiovascular disease that increases with aging. The emergence of microRNA signaling as a key regulator of vascular structure and function has stimulated interest in assessing its role in the pathophysiology of LAS. Identification of several microRNAs that display age-associated changes in expression in aorta has focused attention on defining their molecular targets and deciphering their role in age-associated arterial stiffening. Inactivation of the microRNA-degrading enzyme, translin/trax, which reverses the age-dependent decline in miR-181b, confers protection from aging-associated arterial stiffening, suggesting that inhibitors targeting this enzyme may have translational potential. As LAS poses a major public health challenge, we anticipate that future studies based on these advances will yield innovative strategies to combat aging-associated arterial stiffening.
Teaching Cognitive Behavior Therapy to Postgraduate Health Care Professionals in Times of COVID 19 – An Asynchronous Blended Learning Environment Proved to Be Non-inferior to In-Person Training
Authors: Soll Daniel , Fuchs Raphael , Mehl Stephanie
Published: September 2021

Training of postgraduate health professionals on their way to becoming licensed therapists for Cognitive Behavior Therapy (CBT) came to a halt in Germany in March 2020 when social distancing regulations came into effect. Since the German healthcare system almost exclusively relies on this profession when it comes to the implementation of CBT and 80% of those therapists active in 2010 will have retired at the end of 2030, it is critical to assess whether online CBT training is as satisfactory as classroom on-site CBT training. An asynchronous, blended, inverted-classroom online learning environment for CBT training (CBT for psychosis) was developed as an emergency solution. It consisted of pre-recorded CBT video lectures, exercises to train interventions in online role-plays, and regular web conferences. Training was provided at five different training institutes in Germany (duration 8–16 h). Postgraduate health care professionals (psychiatrists and psychologists) (n= 43) who received the online CBT training filled out standard self-report evaluations that assessed satisfaction and didactic quality. These evaluations were compared to those evaluations of students (n= 142) who had received in-person CBT training with identical content offered by the same CBT trainer at the same training institutes before the COVID-19 crisis. Both groups were comparable with respect tointerest in the subjectandprior knowledge. We tested non-inferiority hypotheses using Wilcoxon-Mann-Whitney ROC-curve analyses with an equivalence margin corresponding to a small-to-medium effect size (d= 0.35). The online training evaluations were non-inferior concerninginformation content, conception of content, didactic presentation, assessment of the trainer as a suitable role-model, working atmosphere, own commitment, andpractical relevance. In contrast, we could not exclude a small effect in favor of in-person training inprofessional benefitandroom for active participation. Our results suggest that delivering substantial CBT knowledge online to postgraduate health-professionals is sufficient, and at most incurs minimal loss to the learning experience. These encouraging findings indicate that integrating online elements in CBT teaching is an acceptable option even beyond social distancing requirements.
Player-Character Relationship and Game Satisfaction in Narrative Game: Focus on Player Experience of Character Switch in The Last of Us Part II
Authors: Erb Valérie , Lee Seyeon , Doh Young Yim
Published: September 2021

While player characters (PCs) are the key element in engaging players in narrative games, the experience and relationship of the player with the PC have received scarce attention from the perspective of the subjective player experience. The diversity of players and the importance of the PC in the game suggests meaningful connections between how players relate to their PC and the resulting satisfaction with the game. We, therefore, investigated in this study how the player-character relationship influences satisfaction of the player with the game. We performed semi-structured in-depth interviews with 12 players ofThe Last of Us Part II, a game that has elicited highly polarized reactions in relation to how players responded to a switch of the PC in the game. Through thematic analysis, three themes were found, illustrating the connection between aspects of the player-character relationship and the overall game satisfaction. The themes are “Tolerance of forced character switch”, “Malleability of character image” and “Flexibility of character attachment”. We discuss how those findings should be taken into consideration when designing diverse and meaningful gaming experiences.
Let Others Buy First: Identity Fusion Buffers the Effect of COVID-19 Phobia on Panic Buying Behavior From an Economic Perspective
Authors: Seih Yi-Tai , Tra Vi Thanh , Lepicovsky Marketa , Chang Yi-Ying
Published: September 2021

The coronavirus 2019 (COVID-19) pandemic has caused hundreds of millions of cases and millions of deaths, resulting in the development of COVID-19 phobia. To prevent getting COVID-19, Centers for Disease Control and Prevention (CDC) in many countries encourage people to protect themselves via several strategies, such as wearing face masks or using sanitizers when washing hands. However, at times, such supplies for preventing COVID-19 are limited. In this study, we examine the relationship between COVID-19 phobia and panic buying behavior from an economic perspective and test if identity fusion plays a buffering role for this phenomenon. Data was collected from September 4th to November 1st in 2020 across three countries (the United States, Germany, and Taiwan). A self-report measure of panic buying behavior was developed and culturally cross-validated. Moderation analyses were conducted focusing on the study objectives. Results show that the economic factor in COVID-19 phobia predicts panic buying behavior, and this effect is buffered by identity fusion. It is worthy to note that this buffering effect emerged only in the Taiwanese sample, not in the American or German samples. Implications of identity fusion theory in human behavior are discussed.