bluuebunny/crossref_metadata_2025 huggingface dataset:
hsa‐miR‐199b‐3p Prevents the Epithelial‐Mesenchymal Transition and Dysfunction of the Renal Tubule by Regulating E‐cadherin through Targeting KDM6A in Diabetic Nephropathy
Authors: Bai Shoujun , Xiong Xiaoyan , Tang Bo , Ji Tingting , Li Xiaoying , Qu Xiaolei , Li Weiliang
Published: June 2021

Diabetic nephropathy (DN) is the leading cause of end‐stage renal disease. The association between epithelial‐mesenchymal transition (EMT) and fibrosis is quite ascertained, but its link to eventual tubule dysfunction is missing. Here, we show that human microRNA‐ (hsa‐miR‐) 199b‐3p protects renal tubules from diabetic‐induced injury by repressing KDM6A, a histone lysine demethylase regulating E‐cadherin expression. Lower E‐cadherin expression is related to a higher level of KDM6A, while E‐cadherin is promoted upon treatment with the KDM6A inhibitor GSK‐J4 in both high glucose‐ (HG‐) induced HK2 cells and the kidneys from streptozotocin‐ (STZ‐) induced type 1 diabetic mice. However, overexpression or RNA silencing of E‐cadherin fails to alter KDM6A expression. We also show that the upregulation of KDM6A is associated with the increased methylation level of the E‐cadherin promoter. Then, the target prediction results and a dual‐luciferase assay show that hsa‐miR‐199b‐3p is a new miRNA that targets KDM6A. Overexpression of hsa‐miR‐199b‐3p increases E‐cadherin expression and prevents EMT through repressing KDM6A expression in HG‐induced HK2 cells. In contrast, inhibitor‐induced hsa‐miR‐199b‐3p knockdown has opposite effects, as it decreases E‐cadherin level and worsens EMT, accompanied by increased levels of KDM6A. Besides, Mir199b‐knockout mice without mmu‐miR‐119b‐3p expression exhibit more renal tubule dysfunction and more serious kidney tissue damage upon treatment with STZ. These results demonstrate that hsa‐miR‐199b‐3p improves E‐cadherin expression and prevents the progression of DN through targeting KDM6A. miR‐199b‐3p could be a future biomarker or target for the diagnosis or treatment of DN.
Network Pharmacology and Bioinformatics Methods Reveal the Mechanism of Zao-Jiao-Ci in the Treatment of LSCC
Authors: Xiang Feng , Li Linman , Lin Jieling , Li Shasha , Peng Guiyuan
Published: June 2021

Objective. Zao-Jiao-Ci (ZJC), a traditional Chinese medicine, is considered as a promising candidate to treat laryngeal squamous cell carcinoma (LSCC). However, the underlying molecular mechanism remains unclear. Methods. Gene expression profiles of GSE36668 were available from the GEO database, and differentially expressed genes (DEGs) of LSCC were obtained by R package; subsequently, enrichment analysis on KEGG and GO of DEGs was performed. The active ingredients of ZJC were screened from the TCMSP database, and the matched candidate targets were obtained by PharmMapper. Furthermore, we constructed protein-protein interaction (PPI) networks of DEGs and candidate targets, respectively, and we screened the core network from the merged network through combining the two PPI networks using Cytoscape 3.7.2. The key targets derived from the core network were analyzed to find out the associated KEGG signal enrichment pathway. By the GEPIA online website, Kaplan–Meier analysis was used to complete the overall survival and disease-free survival of the selected genes in the core module. Results. We identified 96 candidate targets of ZJC and 86 DEGs of LSCC, the latter including 50 upregulated genes and 36 downregulated genes. DEGs were obviously enriched in the following biological functions: extracellular structure organization, the extracellular matrix organization, and endodermal cell differentiation. The 60 key targets from the core network were enriched in the signal pathways including transcriptional misregulation cancer, cell cycle, and so on. We found that LSCC patients with high expression of HIST1H3J, HIST1H3F, and ITGA4 had worse overall survival, while higher expression of NTRK1, COPS5, HIST1H3A, and HIST1H3G had significantly worse disease-free survival. Conclusion. It suggested that the interaction between ZJC and LSCC was related to the signal pathways of transcriptional misregulation cancer and cell cycle, revealing that it may be the mechanism of ZJC in the treatment of LSCC.
Methods in Biosynthesis and Characterization of the Antifreeze Protein (AFP) for Potential Blood Cryopreservation
Authors: Liu Xiangjian , Peng Haiyan , Xie Jingxian , Hu Yuying , Liu Fenglin , Wang Xueying , Yang Shuting , Liu Zhaolin , Zhu Qubo , Tan Songwen
Published: June 2021

The cryopreservation of red blood cells (RBCs) is very important to modern medicine. Cryoprotectants (CPAs) such as dimethyl sulfoxide (DMSO), proline, trehalose, and polyvinyl alcohol (PVA) have been used in the cryopreservation of RBCs, but the results are not satisfactory. Marinomonas primoryensis antifreeze protein (MpAFP) is a Ca2+-dependent AFP derived from Antarctic bacteria, which can prevent bacteria from freezing under extremely cold conditions and may be suitable for cryopreservation of RBCs. The active region of MpAFP is located in region IV and is called MPAFP_RIV. In this paper, the gene of region IV of MpAFP is introduced into BL21 (DE3) competent cells, and MpAFP_RIV is obtained after culture, separation, and purification. The improved splat assay is proposed, and this method first proves that MpAFP_RIV has strong ice recrystallization inhibition (IRI) activity without Ca2+. The improved splat assay is easier to operate and lower the cost compared to the traditional one, and the results are consistent with the classic sucrose sandwich assay, proving that this method can accurately detect IRI activity. The feasibility of MPAFP_RIV combined with classical CPA for cryopreservation of RBCs and the methods to increase the yield of MPAFP_RIV are proposed.
The Association between Hepcidin and Iron Status in Children and Adolescents with Obesity
Authors: Panichsillaphakit Ekkarit , Suteerojntrakool Orapa , Pancharoen Chitsanu , Nuchprayoon Issarang , Chomtho Sirinuch
Published: June 2021

Introduction. Iron deficiency (ID) is the most common nutritional deficiency found in pediatric practice. A higher prevalence of ID may be found in children with obesity. Obesity is a chronic low-grade inflammatory condition. It is postulated that inflammation increases hepcidin, a regulator of iron homeostasis. The aim of this study was to investigate the associations between iron status, hepcidin, and BMI-standard deviation score (BMI-SDS) in children with and without obesity. Methods. A cross-sectional study of Thai children with obesity (5 to 15 years old) versus age- and sex-matched, nonobese controls was conducted. A total of 63 children with obesity and 27 controls were enrolled. Complete blood count, serum iron, ferritin, transferrin saturation, and total iron binding capacity were analyzed. Serum hepcidin-25 was assayed using a hepcidin ELISA Kit (Human Hepc25). Results. There were 63 children with obesity, the median age (IQR) being 10 (9–13) years, and 27 controls. The median (IQR) BMI-SDS of the obese group was 2.3 (2.0–2.6) vs. −0.5 ((−1.3)−0.4) of the control group. ID was diagnosed in 27 children in the obese group (42.9%); 4 of the children with obesity and ID had anemia. Serum hepcidin-25 levels of the children with ID vs. without ID in the obese group were not significantly different (median (IQR) 25 (12.9–49.2) and 26.4 (12.6–43.6), respectively) but both of them were significantly higher than controls (19.7 (8.3–25.5) ng/ml,p = 0.04). BMI-SDS was positively correlated with hepcidin-25 (r = 0.28,p = 0.001). Conclusion. Prevalence of iron deficiency in Thai children with obesity and serum hepcidin-25 was higher than controls. Further study in a larger population, preferably with interventions such as weight loss program, is warranted to clarify this association.
Exosomes Containing LINC00636 Inhibit MAPK1 through the miR-450a-2-3p Overexpression in Human Pericardial Fluid and Improve Cardiac Fibrosis in Patients with Atrial Fibrillation
Authors: Liu Langsha , Luo Fanyan , Lei Kaibo
Published: June 2021

The purpose of this study was to investigate the regulatory mechanism of miR-450a-2-3p in myocardial fibrosis in patients with atrial fibrillation. For this purpose, the expression profile of GSE55296 was extracted from the GEO database, and differentially expressed lncRNAs were identified. Gene ontology analysis of the target genes of mir-450a-2-3p indicated that there was a regulatory relationship between LINC00636 and miR-450a-2-3p. Further, the expression levels of the analyzed RNAs were confirmed by RT-qPCR. TGF-β1-induced cardiac fibroblasts (CFs) and human umbilical vein endothelial cells (HUVECs) were used to establish a myocardial fibrosis model and endothelium-mesenchymal transformation (EMT) model in vivo. We hypothesized that exosomes containing LINC00636 regulate the expression of miR-450a-2-3p. LINC00636 was positively correlated with the expression of miR-450a-2-3p. The overexpression of miR-450a-2-3p suppressed the MAPK1 expression in CFs, thereby inhibiting the expression of α-SMA, COL1, and COL3 and preventing CF proliferation. In HUVECs, the miR-450a-2-3p overexpression upregulated the expression of VE-Cadherin (VE-Cad) and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) by inhibiting the mitogen-activated protein kinase 1 (MAPK1) expression, whereas the expression levels of vimentin, COL1, and COL3 decreased. These results indicate that LINC00636, which is present in human pericardial fluid, is an antifibrotic molecule that inhibits MAPK1 through the miR-450a-2-3p overexpression and improves cardiac fibrosis in patients with atrial fibrillation.
Prevalence of Missed Canals and Their Association with Apical Periodontitis in Posterior Endodontically Treated Teeth: A CBCT Study
Authors: Mashyakhy Mohammed , Hadi Fatimah Ali , Alhazmi Hashimah Alhassan , Alfaifi Rawan Ali , Alabsi Fatimah Saleem , Bajawi Hashim , Alkahtany Mazen , AbuMelha Abdulaziz
Published: June 2021

Background. This study aimed to assess the prevalence of missed canals in endodontically treated teeth and their association with apical periodontitis in a Saudi Arabian population using CBCT. Materials and Methods. A total of 208 CBCT radiographs were investigated. For each tooth, radiographs of axial, coronal, and sagittal segments were acquired to appraise the external as well as the internal structure of the root canal system and apical area. In root canal-treated teeth, unfilled canals appearing from the cementoenamel junction to the apex were defined as missed untreated canals; and a periapical lesion was considered when disruption of the lamina dura was detected, and the low-density area associated with the radiographic apex was at least twice the width of the periodontal ligament space. The data were presented as frequencies and percentages. The Z-test was used to analyze the differences in proportions with the significance level set at

P

value <0.05. Results. The overall prevalence of missed canals among endodontically treated teeth was 18%. The prevalence of missed canals was higher in maxillary first molars with 40.6%. The overall prevalence of apical periodontitis among teeth with missed canals was 90%. It was 84.2% in the maxilla and 100% in the mandible. The second mesiobuccal canal in the maxillary first molars and mesiobuccal and distobuccal canals in mandibular teeth were the most missed canals. Conclusion. Apical periodontitis in root canal-treated teeth with missed canals was high (90%), with most identified missed canals in maxillary and mandibular first molars.
Development of PMC Numerical Model for Soil and Stone Mixture
Authors: Sui Zhili , Li Zhaoguang , Gao Yanhua , Li Yuan , Zheng Yiwu , Meng Yuan
Published: June 2021

Soil and stone mixture is widely distributed in China, and its physical and mechanical properties are complex, which has a significant impact on geotechnical engineering. Usually soil and stone mixture shows anisotropic features along or perpendicular to the direction of settled layers, and the strength will be significantly affected by intermediate principal stress. True triaxial tests were carried on, Paul–Mohr–Coulomb (PMC) failure criterion was used for the strength analysis in soil‐stone mixture, and related parameters of PMC model were obtained. A user‐defined PMC numerical constitutive model was developed for FLAC3D. Composite failure criteria of shear failure and tension cut‐off were applied for numerical analysis, and nonassociated flow rule was proposed based on the Mohr–Coulomb model. Verification modelling was applied as well, and deviation between analytical and numerical solutions in strains of X direction, Y direction, and Z direction was 1.0013, 1.0003, and 1.002, respectively.
Chemical Composition Analysis Using HPLC‐UV/GC‐MS and Inhibitory Activity of Different Nigella sativa Fractions on Pancreatic α‐Amylase and Intestinal Glucose Absorption
Authors: Dalli Mohammed , Daoudi Nour Elhouda , Azizi Salah-eddine , Benouda Hind , Bnouham Mohamed , Gseyra Nadia
Published: June 2021

Nigella sativa (NS) is a well‐known plant for its various benefits and multiuse in traditional medicine. This study is aimed at investigating the chemical composition of the different NS fractions by using GC‐MS for the esterified fatty acids or HPLC‐UV for organic fraction and at evaluating the inhibitory effect on pancreatic α‐amylase (in vitro, in vivo) and intestinal glucose absorption. Among all the investigated fractions, it was shown that they are rich with different molecules of great interest. The n‐hexane fraction was characterized by the presence of linoleic acid (44.65%), palmitic acid (16.32%), stearic acid (14.60%), and thymoquinone (8.7%), while among the identified peaks in EtOH fraction we found catechin (89.03 mg/100 g DW), rutin (6.46 mg/100 g DW), and kaempferol (0.032 mg/100 g DW). The MeOH fraction was distinguished with the presence of gallic acid (19.91 mg/100 g DW), catechin (13.79 mg/100 g DW), and rutin (21.07 mg/100 g DW). Finally, the aqueous fraction was marked by the existence of different molecules; among them, we mention salicylic acid (32.26 mg/100 g DW), rutin (21.46 mg/100 g DW), and vanillic acid (3.81 mg/100 g DW). Concerning the inhibitory effect on pancreatic α‐amylase, it was found that in the in vitro study, the best IC50 registered were those of EtOH (0.25 mg/ml), MeOH (0.10 mg/ml), aqueous (0.031 mg/ml), and n‐hexane fraction (0.76 mg/ml), while in the in vivo study an important inhibition of α‐amylase in normal and diabetic rats was observed. Finally, the percentage of intestinal glucose absorption was evaluated for all tested extracts and it was ranging from 24.82 to 60.12%. The results of the present study showed that the NS seed fractions exert an interesting inhibitory effect of α‐amylase and intestinal glucose absorption activity which could be associated with the existent bioactive compounds. Indeed, these compounds can be used as antidiabetic agents because of their nontoxic effect and high efficacy.
Comparative Analyses of the Subgingival Microbiome in Chronic Periodontitis Patients with and without Gingival Erosive Oral Lichen Planus Based on 16S rRNA Gene Sequencing
Authors: Liu Haohao , Chen Huiwen , Liao Yue , Li Huxiao , Shi Linjun , Deng Yiwen , Shen Xuemin , Song Zhongchen
Published: June 2021

The aim of the study was to compare the microbiota composition and bacterial diversity of subgingival plaque in chronic periodontitis patients with and without gingival erosive oral lichen planus. The subgingival plaque samples of 20 chronic periodontitis patients with gingival erosive oral lichen planus (CP‐OLP group) and 19 chronic periodontitis patients without gingival erosive oral lichen planus (CP group) were analyzed by 16S rRNA gene high‐throughput sequencing. Compared with the CP group, the richness and diversity of subgingival plaque microflora in the CP‐OLP group decreased significantly. There were some differences between the two groups in the composition of microflora on the levels of phylum and genus. Distributions of Prevotella and Leptotrichia in the CP‐OLP group were significantly lower than those in the CP group. The dominant genera in CP‐OLP group were Pseudomonas and Granulicatella. These results indicated that gingival erosive oral lichen planus may influence the structure and proportion of subgingival plaque microflora.
A Task Allocation Algorithm for Coal Mine Mobile Crowd Sensing Based on Weighted Undirected Graph
Authors: Wang Zimeng , Chen Wei , Jiang Haifeng , Xiao Shuo , Yang Haowen
Published: June 2021

Existing applications of mining intelligent mobile terminals are all for the sensing of individual terminals, without considering the group attributes of terminal carriers and the cooperation opportunities brought by terminal movement, which is unable to complete large-scale and complex sensing tasks. In this article, mobile crowd sensing and mine safety monitoring are combined to construct the mobile crowd sensing network for coal mine. Aiming at the task allocation problem, a task allocation mechanism based on a weighted undirected graph is proposed. First, considering the similarity of task completion location and time and quality of data collected, the reputation evaluation model of miners is designed. In order to optimize the reputation of miners participating in the task, an emergency task allocation algorithm based on the weighted undirected graph is proposed. Second, based on the fatigue degree of miners and the residual energy of intelligent mobile terminals, the miner status evaluation model is constructed, which is combined with the reputation model to design a nonemergency task allocation algorithm, aiming at further optimizing the task allocation results. The simulation results show that the proposed algorithm has better performance in allocation time for sensing task, task allocation success rate, average reputation, and status value of miners.
Mitochondrial Tumor Suppressors—The Energetic Enemies of Tumor Progression
Authors: Jakoube Pavel , Cutano Valentina , González-Morena Juan M. , Keckesova Zuzana
Published: June 2021

Tumor suppressors represent a critical line of defense against tumorigenesis. Their mechanisms of action and the pathways they are involved in provide important insights into cancer progression, vulnerabilities, and treatment options. Although nuclear and cytosolic tumor suppressors have been extensively investigated, relatively little is known about tumor suppressors localized within the mitochondria. However, recent research has begun to uncover the roles of these important proteins in suppressing tumorigenesis. Here, we review this newly developing field and summarize available information on mitochondrial tumor suppressors.
Volatile Organic Compounds to Identify Infectious (Bacteria/Viruses) Diseases of the Central Nervous System: A Pilot Study
Authors: Guo Lei , Qiu Zhongzhi , Wang Yue , Yu Kaili , Zheng Xiaoya , Li Yuhang , Liu Miao , Wang Guiyue , Guo Nana , Yang Mengyuan , Li Enyou , Wang Changsong
Published: June 2021

Background: Central nervous system (CNS) infectious diseases are common diseases in emergency rooms and neurology departments. CNS pathogen identification methods are time consuming and expensive and have low sensitivity and poor specificity. Some studies have shown that bacteria and viruses can produce specific volatile organic compounds (VOCs). The aim of this study is to find potential biomarkers by VOC analysis of cerebrospinal fluid (CSF) in patients with bacterial and viral meningitis/encephalitis (ME). Methods: CSF samples from 16 patients with bacterial ME and 42 patients with viral ME were collected, and solid-phase microextraction combined with gas chromatography-mass spectrometry was used to analyze the metabolites in the CSF. Results: There are 2 substances (ethylene oxide and phenol) that were found to be different between the 2 groups. Ethylene oxide was significantly greater in the group of bacterial ME patients than in the viral ME group of patients (p < 0.05). In addition, phenol was remarkably increased in the group of ME patients compared with the bacterial ME patients (p < 0.05). Conclusions: Ethylene oxide and phenol may be potential biomarkers to distinguish bacterial ME and viral ME. VOC analysis of CSF may be used as a supporting tool for clinical diagnosis.
Diagnostic Validity of the Sleep Condition Indicator to Screen for Diagnostic and Statistical Manual-5 Insomnia Disorder in Patients with Parkinson’s Disease
Authors: Bayard Sophie , Lebrun Cindy , Arifi-Rossignol Alexia , Geny Christian , Gély-Nargeot Marie-Christine , Luik Annemarie I.
Published: June 2021

Background: Insomnia is a highly common sleep disorder in patients with Parkinson’s disease (PD). Yet, no screening questionnaires following the Diagnostic and Statistical Manual-5 (DSM-5) criteria have been validated in PD patients. Objectives: We assessed the validity and reliability of the French version of the sleep condition indicator (SCI), in patients with PD. Methods: In a sample of 65 patients (46% women, mean age 63.8 ± 7.9 years) with PD, but without dementia, insomnia was assessed with a clinical interview and the SCI. Statistical analyses were performed to determine the reliability, construct validity, and divergent validity of the SCI. In addition, an explanatory factor analysis was performed to assess the underlying structure of the SCI. Results: Of the 65 patients (mean duration PD 9.7 ± 6.9 years), 51% met the criteria for insomnia disorder when measured with a clinical interview. The mean SCI score was 18.05 ± 8.3. The internal consistency (α = 0.89) of the SCI was high. Using the previously defined cutoff value of ≤16, the area under the receiver operating characteristic curve was 0.86 with a sensitivity of 86% and a specificity of 87%. Exploratory factor analysis showed a 2-factor structure with a focus on sleep and daytime effects. Additionally, good construct and divergent validity were demonstrated. Conclusion: The SCI can be used as a valid and reliable screener for DSM-5 insomnia disorder in PD patients. Due to its short length, it is useful in both clinical practice and scientific research.
The Burden of Dementia due to Down Syndrome, Parkinson’s Disease, Stroke, and Traumatic Brain Injury: A Systematic Analysis for the Global Burden of Disease Study 2019
Authors:   GBD 2019 Dementia Collaborators
Published: June 2021

Background: In light of the increasing trend in the global number of individuals affected by dementia and the lack of any available disease-modifying therapies, it is necessary to fully understand and quantify the global burden of dementia. This work aimed to estimate the proportion of dementia due to Down syndrome, Parkinson’s disease, clinical stroke, and traumatic brain injury (TBI), globally and by world region, in order to better understand the contribution of clinical diseases to dementia prevalence. Methods: Through literature review, we obtained data on the relative risk of dementia with each condition and estimated relative risks by age using a Bayesian meta-regression tool. We then calculated population attributable fractions (PAFs), or the proportion of dementia attributable to each condition, using the estimates of relative risk and prevalence estimates for each condition from the Global Burden of Disease Study 2019. Finally, we multiplied these estimates by dementia prevalence to calculate the number of dementia cases attributable to each condition. Findings: For each clinical condition, the relative risk of dementia decreased with age. Relative risks were highest for Down syndrome, followed by Parkinson’s disease, stroke, and TBI. However, due to the high prevalence of stroke, the PAF for dementia due to stroke was highest. Together, Down syndrome, Parkinson’s disease, stroke, and TBI explained 10.0% (95% UI: 6.0–16.5) of the global prevalence of dementia. Interpretation: Ten percent of dementia prevalence globally could be explained by Down syndrome, Parkinson’s disease, stroke, and TBI. The quantification of the proportion of dementia attributable to these 4 conditions constitutes a small contribution to our overall understanding of what causes dementia. However, epidemiological research into modifiable risk factors as well as basic science research focused on elucidating intervention approaches to prevent or delay the neuropathological changes that commonly characterize dementia will be critically important in future efforts to prevent and treat disease.
Determinants of Final Height in Patients Born Small for Gestational Age Treated with Recombinant Growth Hormone
Authors: Adler Elodie , Lambert Anne-Sophie , Bouvattier Claire , Thomas-Teinturier Cécile , Rothenbuhler Anya , de Boissieu Paul , Linglart Agnès
Published: June 2021

Introduction: About 8% of children born small for gestational age (SGA) do not reach a final height within the normal range. Recombinant human growth hormone (rhGH) has been shown to be effective in increasing the final height in children born SGA. Our objective was to identify predictive factors of final height in children born SGA treated with rhGH. Materials and Methods: In this retrospective study, conducted in a tertiary pediatric endocrinology referral center, we recruited all patients born SGA (defined as birth length or weight <10th percentile) treated with rhGH for more than 12 months for whom final height data were available. Some patients had received gonadotropin-releasing hormone (GnRH) analog therapy. Results: We included 252 patients with an average birth length of −2.0 ± 0.7 SD and birth weight of −1.7 ± 1.0 SD. After 4.6 ± 2.8 years of rhGH treatment, their height increased from −2.2 ± 0.9 SD to −1.5 ± 0.9 SD. In multivariate analysis, we identified 8 factors that predict 46% of the final height, namely, cause of SGA (p < 0.0001), GnRH analog therapy >2 years (p = 0.006), birth length (p < 0.02), height at the start of rhGH (p < 0.0001), IGF-1 level at the start of rhGH (p = 0.0002), growth velocity during the 1st year of treatment (p = 0.0002), and age and height at the onset of puberty (p < 0.0001, p = 0.0007, respectively). Conclusion: In this large cohort of SGA patients who had reached their final height, we were able to confirm that growth hormone increases final height in short SGA children. In addition, we identified several factors associated with a better response to growth hormone treatment.
Management of Older Outpatients during the COVID-19 Pandemic: The GeroCovid Ambulatory Study
Authors: Gareri Pietro , Fumagalli Stefano , Malara Alba , Mossello Enrico , Trevisan Caterina , Volpato Stefano , Coin Alessandra , Calsolaro Valeria , Bellelli Giuseppe , Del Signore Susanna , Zia Gianluca , Ranhoff Anette Hylen , Incalzi Raffaele Antonelli ,   the GeroCovid Ambulatory Study Group
Published: June 2021

Objectives: The GeroCovid Study is a multi-setting, multinational, and multi-scope registry that includes the GeroCovid home and outpatients’ care cohort. The present study aims to evaluate whether outpatient and home care services with remote monitoring and consultation could mitigate the impact of the COVID-19 pandemic on mental and affective status, perceived well-being, and personal capabilities of outpatients and home care patients with cognitive disorders. Methods: Prospectively recorded patients in an electronic web registry provided by BlueCompanion Ltd. Up to October 31, 2020, the sample included 90 patients receiving regular care from the Center for Cognitive Disorders and Dementia in Catanzaro Lido, Italy. It was made of 52 ambulatory outpatients and 38 home care patients, mean age 83.3 ± 7.54 years. Participants underwent a multidimensional assessment at baseline (T0) and after 90 days (T1). For each patient, we administered the Mini-Mental State Examination (MMSE) for cognitive functions, the Activities of Daily Living (ADL) and Instrumental ADL (IADL) scales for functional capabilities, the Cumulative Illness Rating Scale (CIRS) for comorbidities and their impact on patients’ health, the 5-items Geriatric Depression Scale (GDS) for mood, and the Euro Quality of Life (EuroQoL) for perceived quality of life. Contacts with both ambulatory and home care patients were managed in person or via telephone, preferably through video calls (WhatsApp or FaceTime). Results: Contacts with patients were kept at T0 through telephone. At T1, visits were made in person for over 95% out of the cases. The ADL, IADL, CIRS, GDS, MMSE, and EuroQoL changed slightly between T0 and T1. Most of the patients were clinically stable over time on the majority of the scales explored, but behavioral changes were found in 24.4% of patients and anxiety and insomnia in 17.7% of patients. Conclusion: Our study suggests that contacts through telephone and video consultations are likely associated with a health status preservation of the patients.
Comunidade de práticas: revisão sistemática em prol das bibliotecas públicas
Authors: Achilles Daniele , Kornalewski Alex Medeiros
Published: June 2021

No contexto atual, marcado por uma crise sanitária, produção e disseminação cada vez mais rápida da informação e do conhecimento, tornam-se mais urgente as bibliotecas públicas se adaptarem aos novos desafios impostos tecido social. Nesse sentido, a escassez de recursos financeiros e materiais, bem como a carência de políticas públicas, dentre outros fatores, vem acelerando o sucateamento dessas instituições que direcionam suas ações para a educação, cultura, lazer, memória. Esse artigo tem como objetivo discorrer sobre a importância da metodologia comunidade de práticas, destacando possibilidades de gestão colaborativa. E, para tal, apresenta um percurso conceitual e aplicações voltadas ao provimento de recursos inerentes à tomada de decisão nos fazeres das bibliotecas públicas, da Rede de Bibliotecas Populares de Niterói, do estado do Rio de Janeiro. Desse modo, o caminho metodológico se definiu a partir da revisão sistemática sobre o conceito comunidade de práticas, subsidiando a compreensão teórica e prática dos fazeres biblioteconômicos nessas instituições e direcionando a construção de boas práticas, o que auxilia em certa medida o reconhecimento e a ressonância social dessas bibliotecas. Conclui-se a urgência de empreendimentos que adotem o processo dialógico, o intercâmbio de experiências, a ressonância junto à sociedade e o engajamento de setores como as universidades e o Estado, convertendo-se em fatores essenciais à manutenção, atuação e desenvolvimento das bibliotecas públicas.
Patrimônio natural em contexto urbano: a gestão da conservação do Parque dos Manguezais, Recife-PE
Authors: Moura Célio Henrique Rocha , Bezerra Onilda Gomes , Lapa Tomás de Albuquerque , Albuquerque Caio Coelho Silva
Published: June 2021

O presente artigo tem como objetivo a identificação dos valores patrimoniais do Parque dos Manguezais (Unidade de Conservação do Recife) que representam a significância natural do bem e que consiste na etapa inicial do processo de conservação patrimonial, de acordo com a Australian Natural Heritage Charter (IUCN, 2002). Para identificação dos valores, foram entrevistadas distintas categorias de atores (moradores do entorno, especialistas e agentes públicos), cujos depoimentos foram analisados com base no método Análise de Conteúdo. Como resultado, foram estabelecidas as dimensões patrimoniais relacionadas aos aspectos ecológicos e culturais da Unidade de Conservação, assim como foram levadas em consideração as inter-relações que tais atores mantêm com o ecossistema e que sinalizam as ações objetivas de conservação do Parque dos Manguezais.
Coronary Disease Association With ADAMTS7 Is Due to Protease Activity
Authors: Mizoguchi Taiji , MacDonald Bryan T. , Bhandary Bidur , Popp Nicholas R. , Laprise Dylan , Arduini Alessandro , Lai Daniel , Zhu Qiuyu Martin , Xing Yi , Kaushik Virendar K. , Kathiresan Sekar , Ellinor Patrick T.
Published: June 2021

Rationale:

Despite contemporary therapy, coronary artery disease (CAD) remains a leading cause of mortality. Genetic variants at
ADAMTS7
have been associated with CAD and the loss of ADAMTS7 (a disintegrin and metalloproteinase with thrombospondin motifs 7) is protective for atherosclerosis. ADAMTS7 is a secreted metalloproteinase and complex proteoglycan; yet, the mechanism linking ADAMTS7 to CAD risk remains unresolved.

Objective:

To investigate the role of ADAMTS7 catalytic function in vascular smooth muscle cellular migration and during atherosclerosis.

Methods and Results:

We established a new purification strategy for full-length mouse ADAMTS7 and demonstrated the loss of activity in the catalytic mutant form of ADAMTS7. To test if the enzymatic activity of ADAMTS7 mediates atherosclerosis, we generated a catalytically inactive mutant mouse allele and compared it to the
Adamts7
knockout. Using 2 models of atherosclerosis, we found that reducing either ADAMTS7 dosage or catalytic function decreased the burden of atherosclerosis. We demonstrate impaired vascular smooth muscle migration in both
Adamts7
catalytic mutant and null cells using a lateral migration wound healing assay. Expression of the wild-type allele rescued the migration phenotype in
Adamts7
null cells while expression of the catalytic mutant protein did not. We then characterized a human
ADAMTS7
coding variant rs3825807 (Ser214Pro) associated with reduced CAD risk. This variant had a hypomorphic effect on ADAMTS7 secretion and migration of vascular smooth muscle cells, findings consistent with our mouse studies.

Conclusions:

We demonstrated that loss of ADAMTS7 catalytic function protects against atherosclerosis via phenotype switch of vascular smooth muscle cells and that the atherosclerosis protective effects could be mediated by a loss-of-function coding variant associated with CAD risk. In aggregate, we provide compelling evidence that dosage of ADAMTS7 and catalytic function are responsible for the atherosclerotic phenotype, suggesting that the catalytic domain would be an attractive therapeutic target for CAD.
Predictors of the Pressor Response to the Norepinephrine Transporter Inhibitor, Atomoxetine, in Neurogenic Orthostatic Hypotension
Authors: Shibao Cyndya A. , Palma Jose-Alberto , Celedonio Jorge E. , Martinez Jose , Kaufmann Horacio , Biaggioni Italo
Published: June 2021

We previously reported that the norepinephrine transporter inhibitor, atomoxetine, improved standing blood pressure and lightheadedness in patients with neurogenic orthostatic hypotension (nOH). The purpose of the present study was to determine the predictors of the pressor response to atomoxetine. Patients with nOH who participated in the clinical trials (
https://www.clinicaltrials.gov
; Unique identifiers: NCT00223691 and NCT01316666) were included in this retrospective analysis. All subjects underwent autonomic function testing, plasma norepinephrine, systolic, diastolic blood pressure, and symptoms assessments, whereas seated and standing, before, and 60 minutes after a single dose of atomoxetine 18 mg. A subset of 25 patients underwent iodine-123–labeled metaiodobenzylguanidine scanning to estimate the degree of cardiac sympathetic denervation. A total of 99 subjects with nOH (67±9 years old, 40 women) participated in the study, 35 with multiple system atrophy, 52 with pure autonomic failure, and 12 with Parkinson disease. The average orthostatic decrease in their systolic blood pressure/diastolic blood pressure was −52±26/−22±15 mm Hg. Supine plasma norepinephrine levels predicted the standing systolic blood pressure (adjusted R
2
was 0.12, F [3,80]=4.66,
P
=0.007) and diastolic blood pressure (adjusted R
2
was 0.18, F [3, 80]=7.04,
P
=0.001) in response to atomoxetine. The increase in systolic blood pressure after atomoxetine was associated with the decrease in nOH-related symptoms (
R
2
=0.14, F [1,44]=8.16
P
=0.007). In conclusion, plasma norepinephrine was modestly associated with the pressor response to atomoxetine in patients with nOH. Additionally, the improvement in nOH-related symptoms was associated with the increase in the pressor response to atomoxetine.
Targeting MicroRNA-192-5p, a Downstream Effector of NOXs (NADPH Oxidases), Reverses Endothelial DHFR (Dihydrofolate Reductase) Deficiency to Attenuate Abdominal Aortic Aneurysm Formation
Authors: Huang Kai , Narumi Taro , Zhang Yixuan , Li Qiang , Murugesan Priya , Wu Yusi , Liu Norika Mengchia , Cai Hua
Published: June 2021

We have shown that endothelial-specific DHFR (dihydrofolate reductase) deficiency underlies eNOS (endothelial NO synthase) uncoupling and formation of abdominal aortic aneurysm (AAA). Here, we examined a novel role of microRNA-192-5p in mediating NOX (NADPH oxidase)-dependent DHFR deficiency and AAA formation. microRNA-192-5p is predicted to target DHFR. Intriguingly, homo sapiens–microRNA-192-5p expression was substantially upregulated in human patients with AAA. In human aortic endothelial cells exposed to hydrogen peroxide (H
2
O
2
), homo sapiens–microRNA-192-5p expression was significantly upregulated. This was accompanied by a marked downregulation in DHFR mRNA and protein expression, which was restored by homo sapiens–microRNA-192-5p–specific inhibitor. Of note, microRNA-192-5p expression was markedly upregulated in Ang II (angiotensin II)–infused hph-1 (hyperphenylalaninemia 1) mice, which was attenuated in hph-1–NOX1, hph-1–NOX2, hph-1–neutrophil cytosol factor 1, and hph-1–NOX4 double mutant mice where AAA incidence was also abrogated, indicating a downstream effector role of microRNA-192-5p following NOX activation. In vivo treatment with mus musculus–microRNA-192-5p inhibitor attenuated expansion of abdominal aortas in Ang II–infused hph-1 mice as defined by ultrasound and postmortem inspection. It also reversed features of vascular remodeling including matrix degradation, adventitial hypertrophy, and formation of intraluminal thrombi. These animals had restored DHFR mRNA and protein expression, attenuated superoxide production, recoupled eNOS, and preserved NO bioavailability. In conclusion, our data for the first time demonstrate a critical role of microRNA-192-5p in mediating NOX-dependent DHFR deficiency and AAA formation, inhibition of which is robustly effective in attenuating development of AAA. Since the mouse and human microRNA-192-5p sequences are identical, the microRNA-192-5p inhibitors may be readily translatable into novel therapeutics for the treatment of AAA.
Mesenchymal Stem/Stromal Cell–Derived Extracellular Vesicles for Chronic Kidney Disease: Are We There Yet?
Authors: Eirin Alfonso , Lerman Lilach O.
Published: June 2021

Mesenchymal stem/stromal cells (MSCs) are the most utilized cell type for cellular therapy, partly due to their important proliferative potential and ability to differentiate into various cell types. MSCs produce large amounts of extracellular vesicles (EVs), which carry genetic and protein cargo to mediate MSC paracrine function. Recently, MSC-derived EVs have been successfully used in several preclinical models of chronic kidney disease. However, uncertainty remains regarding EV fate, safety, and long-term effects, which might impose important limitations on their path to clinical translation. This review discusses the therapeutic application of MSC-derived EV therapy for renal disease, with particular emphasis on potential mechanisms of kidney repair and major translational barriers. Emerging evidence indicates that the cargo of MSC-derived EVs is capable of modulating several pathways responsible for renal injury, including inflammation, oxidative stress, apoptosis, fibrosis, and microvascular remodeling. EV-induced modulation of these pathways has been associated with important renoprotective effects in experimental studies. However, scarce clinical data are available, and several challenges need to be addressed as we move toward clinical translation, including standardization of methods for EV isolation and characterization, EV fate, duration of EV effects, and effects of cardiovascular risk factors. MSC-derived EVs have the potential to preserve renal structure and function, but further experimental and clinical evidence is needed to confirm their protective effects in patients with chronic kidney disease.
Accurate Prediction of Total PlGF (Placental Growth Factor) From Free PlGF and sFlt-1 (Soluble Fms-Like Tyrosine Kinase-1): Evidence for Markedly Elevated PlGF Levels in Women With Acute Fatty Liver of Pregnancy
Authors: Neuman Rugina I. , Saleh Langeza , Verdonk Koen , van den Meiracker Anton H. , Russcher Henk , Metselaar Herold J. , Visser Willy , Danser A.H. Jan
Published: June 2021

Acute fatty liver of pregnancy (AFLP) is characterized by elevated circulating sFlt-1 (soluble Fms-like tyrosine kinase-1), although the free circulating levels of its ligand, PlGF (placental growth factor) are not decreased. Here, we hypothesized that women with AFLP exhibit elevated PlGF production in comparison to women with preeclampsia or hemolysis elevated liver enzymes and low platelet count syndrome. Making use of the well-known mathematical formulas describing drug-receptor interactions, we established that serum total PlGF could be accurately predicted from sFlt-1 and free PlGF levels (n=42; mean calculated K
D
of 50 pmol/L), yielding similar values as the previously published method of thermal dissociation of the sFlt-1-PlGF complexes (
r
=0.94,
P
<0.0001). We found that median levels of free PlGF were significantly lower in women with preeclampsia (n=13; 117pg/mL) or hemolysis elevated liver enzymes and low platelet count syndrome (n=12; 59 pg/mL) compared with women without preeclampsia (n=11; 349pg/mL,
P
<0.0001). In contrast, median total PlGF did not differ between women with no preeclampsia, preeclampsia, and hemolysis elevated liver enzymes and low platelet count syndrome (354 versus 435 versus 344pg/mL), whereas it was markedly elevated in AFLP compared with all groups (2054 pg/mL,
P
<0.0001). Furthermore, in AFLP, both sFlt-1 and total PlGF declined rapidly postdelivery, with significantly higher predelivery total PlGF (n=12; median, 2054 pg/mL) than postpartum levels (n=14; median, 163pg/mL,
P
<0.0001), suggesting that in AFLP, PlGF is largely placenta-derived. Collectively, our findings indicate that like sFlt-1, PlGF production is significantly upregulated in AFLP, mainly originating from the placenta. Importantly, total PlGF can now be easily calculated from already available free PlGF and sFlt-1 levels, allowing subsequent evaluation of other groups in whom PlGF is altered.
Kidney-Specific
Klotho
Gene Deletion Causes Aortic Aneurysm via Hyperphosphatemia
Authors: Wang Qiongxin , Wang Shirley , Sun Zhongjie
Published: June 2021

Klotho
is an aging-suppressor gene. The purpose of this study was to determine whether deletion of the
klotho
gene in kidneys causes aortic aneurysm (AA) and investigate the underlying mechanisms. Klotho-floxed alleles and tamoxifen-inducible kidney-specific CreER
T2
mice were crossed to generate KL
flox/flox
(floxed Klotho); KspCadCreER
T2
mice. Tamoxifen injection induced kidney-specific deletion of
klotho
gene, which led to severe hyperphosphatemia and thoracic and abdominal AA formation in mice on a normal diet. The architectural destruction of the aortic wall in the first 7 days post-Klotho ablation was manifested by overwhelming aortic cell death and calcification, massive MMP (metalloproteinase) 2/9 secretion, elastin degradation, and limited collagen deposition, resulting in aortic wall thinning and AA formation. The adverse reparative remodeling of aortas in the following 7 days exhibited robust fibroblast proliferation and osteogenic differentiation and redundant collagen deposition, further promoting aortic wall thickening and AA progression. These changes were accompanied by aortic macrophage infiltration and osteoclast transition. Interestingly, low-phosphorus diet normalized serum phosphate levels, prevented vascular cell apoptosis and osteogenic differentiation, and consequently retained aortic structure in Klotho-deficient mice. Mechanistically, excessive inorganic phosphate and calcium promoted vascular cell death, osteogenic differentiation, and MMP2/9 secretion ex vivo and in vitro. We found that NF-κB (nuclear factor-kappa B) mediated phosphate-induced MMP2 generation in human aortic smooth muscle cells in vitro. These findings provide the first evidence for a causative role of Klotho deficiency–induced hyperphosphatemia in AA development. Interventional control of dietary phosphorus may be a new preventive and therapeutic strategy for AA.
Intensive Lifestyle Intervention Increases Plasma Midregional Proatrial Natriuretic Peptide Concentrations in Overweight Children
Authors: Thomsen Camilla F. , Goharian Tina S. , Larsen Kristian T. , Goetze Jens P. , Andersen Lars B. , Jeppesen Jørgen L.
Published: June 2021

Background

Overweight adults have low circulating concentrations of ANP (atrial natriuretic peptide) and proANP fragments. We tested the hypothesis that an intensive lifestyle intervention with an intended weight loss would increase plasma concentrations of a proANP fragment in overweight children.

Methods and Results

We measured MR‐proANP (midregional proANP) concentrations in plasma from overweight children who participated in the OOIS (Odense Overweight Intervention Study). OOIS randomized 115 overweight children (11–13 years, 55% girls) to an intensive day‐camp intervention arm with increased physical activity and healthy diet or to a less intensive standard intervention arm for 6 weeks. We used linear mixed‐effects modeling for repeated measures to estimate the difference in the mean change with 95% CIs in fasting plasma MR‐proANP concentrations between the 2 arms, and we used partial least squares regression analysis to identify candidate mediators. Differences in weight, fitness, and metabolic factors were also analyzed. At baseline, fasting plasma MR‐proANP concentrations were (median [interquartile range]) 35.0 pmol/L (26.8–42.0) in the day‐camp intervention arm and 37.2 pmol/L (31.7–44.7) in standard intervention arm participants, respectively. After 6 weeks intervention, children in the day‐camp intervention arm had increased their MR‐proANP (5.4 pmol/L [0.8–10.0],
P
=0.022) and their fitness (2.33 mL O
2
/min per kg [0.52–4.14],
P
=0.012) and they had deceased their body mass index (−2.12 kg/m
2
[−2.59 to −1.65],
P
<0.001) as compared with children in standard intervention arm. In the partial least squares analysis, decreases in fasting insulin and in estimated insulin resistance were associated with the observed increase in MR‐proANP concentrations.

Conclusions

An intensive lifestyle intervention increases plasma MR‐proANP among overweight children.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01574352.