bluuebunny/crossref_metadata_2025_split huggingface dataset:
Canagliflozin Alleviates Diabetic Cardiovascular Disease via Lipid Lowering, Mitochondrial Homeostasis, and Gut Microbiota Regulation
Authors: Wang Xueliang , Wang Zhe , Liu Di , Jiang Hao , Cai Chao , Li Guoyun , Yu Guangli 
Published: August 2021

Abstract
Background: Type 2 diabetes mellitus (T2DM) is associated with cardiovascular disease (CVD). Sodium glucose cotransporter 2 inhibitors (SGLT2i) represent the most effective oral drugs for the treatment of T2DM, and have been shown to improve generalized vascular dysfunction. However, it’s effect on improving diabetic CVD and the possible action mechanism are currently unclear.Methods: T2DM was induced by feeding a high-fat diet (HFD) to male C57BL/6J mice for 24 weeks. Afterthat, HFD-fed mice were treated with Cana (50 mg/kg/d) or positive drug metformin (225 mg/kg/d) by oral gavage for 6 weeks. Myocardial mitochondrial morphology and cardiovascular abnormalities were assessed by transmission electron microscope and histological staining; lipids proﬁle and oxidative stress state were assessed by corresponding biochemical assay kits and histological staining; myocardial injury was characterized by H&E staining, TUNEL, and ELISA assays; colonic gut microbiota was assessed by 16S rDNA high-throughput sequencing.Results: Cana reduced the lipid (such as TG, TC, and LDL-C) accumulation in serum, thus decreased atherogenic index of plasma and arteriosclerosis index values. And, Cana reduced the circulating markers of inflammation (such as TNFα, MCP-1, and IL-6). More importantly, Cana improved cardiac mitochondrial homeostasis and relieved oxidative stress. Myocardial injury was alleviated after Cana treatment with decreasing levels of serous cTn I and sCD40L. Thus, cardiovascular abnormality was relieved by elevating the CD31 expression level, and suppressing ﬁbrosis and basement membrane thickening in T2DM mice. Interestingly, Cana administration increased the ratio of Firmicutes/Bacteroidetes and the relative abundance of Olsenella, Alistipes, and Alloprevotella, while decreased the abundance of Proteobacteria, Helicobacter and Mucispirillum at various taxonomic levels.Conclusions: Cana treatment improved CVD by decreasing the risk of atherosclerosis, maintaining a relatively normal haemogram, and reducing the thickness of vascular basement membrane and myocardial injury. Importantly, Cana treatment significantly elevated myocardial mitochondria homeostasis, thus ameliorated the oxidative stress and inflammatory states. Moreover, Cana subtly altered microbiota composition in T2DM mice with CVD, which contributed to the improvement of CVD. Collectively, the improvements of myocardial mitochondrial and gut microbiota homeostasis, may represent an important mechanism underlying the cardiovascular benefits of Cana treatment.
Machine Learning Aided Construction of the Quorum Sensing Communication Network for Human Gut Microbiota
Authors: Wu Shengbo , Feng Jie , Liu Chunjiang , Wu Hao , Qiu Zekai , Ge Jianjun , Sun Shuyang , Hong Xia , Li Yukun , Wang Xiaona , Yang Aidong , Guo Fei , Qiao Jianjun 
Published: August 2021

Abstract
Quorum sensing (QS) is a cell-cell communication mechanism that connects members in various microbial systems. Conventionally, limited QS entries were collected for specific microbes, which is far from being able to fully depict QS-based complex microbial interactions in human gut microbiota. In this study, we proposed a systematic workflow including three modules and the use of machine learning-based ensemble classifiers to collect reported QS entries, expand the QS repository, and mine new potential QS proteins. Furthermore, we developed the Quorum Sensing of Human Gut Microbes (QSHGM) database (http://www.qshgm.lbci.net/) including 28,567 redundancy removal QS entries, to bridge the gap between QS repositories and human gut microbiota. With the help of QSHGM, various QS-based microbial interactions could be predicted and a comprehensive QS communication network was further constructed and analysed for 818 human gut microbes. This work contributes to the establishment of the QS communication network which may form one of the key knowledge maps of the human gut microbiota, supporting future applications such as potential therapies to gut diseases.
Evaluation the Serum Level of Sex Hormones in Patients With Trigeminal Neuralgia
Authors: Lavaee Fatemeh , Zahed Parisa Mohaghegh , Zarei Fateme , Sardo Maryam Shahrokhi 
Published: August 2021

Abstract
Background and Aim: In this study FSH, LH, Testosterone, Estrogen, Progesterone serum levels in women affected by trigeminal neuralgia have been evaluated.Materials and Methods: This study is a cross sectional study during 2017-2018 in which FSH, LH, Testosterone, Estrogen, Progesterone serum levels in women affected by trigeminal neuralgia, who had referred to Emam Reza clinic and Oral and Maxillofacial Disease Department of Shiraz Dental Faculty, have been evaluated. Twenty-six women with trigeminal neuralgia were recruited in trigeminal neuralgia(TN) group and 26 healthy women whom their age were matched with TN group were enrolled in the healthy control group. Data was analyzed by SPSS version 18.Results: Sex hormone serum level was not significantly different between patients with TN and healthy control group (P value ≥0.05). In spite of this finding, the serum level of FSH in non-menopausal (P value=0.002) participants and progesterone in menopausal (P value=0.016) participants of TN and healthy control group, were significantly different. The serum level for both of these hormones were higher in patients with TN. In contrast to healthy control group, the sex hormone profiles of patients with TN, except LH did not follow the natural pattern changes based on menopausal status. Conclusion: In spite of no significant differences in sex hormonal profile of patients with TN and healthy controls, some hormonal disturbance in FSH and progesterone have been detected in TN patients in comparison between non-menopause and menopausal sex hormones profile.
“Prostaglandin E2 Sensitizes the Cough Reflex Centrally via EP3 Receptor-dependent Activation of NaV 1.8 Channels”
Authors: Al-Kandery Al-Shaimaa , Rao Muddana , EL-Hashim Ahmed 
Published: August 2021

Abstract
Background
Cough hypersensitivity is a major characteristic feature associated with several types of cough, including chronic cough, but its underlying mechanisms remain to be fully understood. Inflammatory mediators, such as prostaglandin E2 (PGE2), have been implicated in peripheral induction/sensitization of the cough reflex. In this study, using a conscious guinea pig model of cough, we investigated whether PGE2 can sensitize the cough reflex via central actions and, if so, via which mechanisms.
Methods
All drugs were administered by intracerebroventricular (i.c.v.) route and whole-body plethysmograph set-up was used for both induction, using aerosolized citric acid (0.2 M), and recording of cough. Immunohistochemistry was performed to confirm the expression of NaV 1.8 channels in the nucleus tractus solitarius (nTS).
Results
We show that both PGE2 and the non-selective EP1/EP3 agonist, sulprostone, dose-dependently enhanced the citric acid-induced cough (P ≤ 0.001, P ≤ 0.01, respectively). Pretreatment with the EP1 antagonist, ONO-8130, did not affect the sulprostone-induced cough sensitization, whilst the EP3 antagonist, L-798,106, dose-dependently inhibited this effect (P ≤ 0.05). Furthermore, treatment with either the EP2 agonist, butaprost or the EP4 agonist, L-902,688, had no effect on cough sensitization. Additionally, pretreatment with either the TRPV1 antagonist, JNJ-17203212 or the TRPA1 antagonist, HC-030031, alone or in combination, nor with the NaV 1.1, 1.2, 1.3, 1.4, 1.6 and 1.7 channel blocker, tetrodotoxin, had any effect on the cough. In contrast, pretreatment with the NaV 1.8 antagonist, A-803467, dose-dependently inhibited this effect (P ≤ 0.05). Furthermore, NaV 1.8 channels were shown to be expressed in the nTS.
Conclusion
Collectively, our findings show that PGE2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 but independently of TRPV1/TRPA1 and TTX-sensitive sodium channel activation. These results indicate that PGE2 plays an important role in central sensitization of the cough reflex and suggest that central EP3 receptors and/or Nav 1.8 channels may represent novel antitussive molecular targets.
Tissue- and Salinity-specific Na–Cl Cotransporter (NCC) Orthologues Involved in the Sea lamprey (Petromyzon Marinus) Adaptive Osmoregulation
Authors: Barany A. , Shaughnessy C. A. , Pelis R. M. , Fuentes J. , Mancera J. M. , McCormick S. D. 
Published: August 2021

Abstract
The authors have requested that this preprint be removed from Research Square.
De novo human brain enhancers created by single nucleotide mutations
Authors: Li Shan , Hannenhalli Sridhar , Ovcharenko Ivan 
Published: August 2021

Abstract
Advanced human cognition is attributed to increased neocortex size and complexity, but the underlying gene regulatory mechanisms are unknown. Using deep learning model of embryonic neocortical enhancers, and human and macaque embryonic neocortex H3K27ac data, we identified ~4000 enhancers gained in the human, largely attributable to single-nucleotide essential mutations. The genes near gained enhancers exhibit increased expression in human embryonic neocortex, and are involved in critical neural developmental processes, and are expressed specifically in the progenitor cells and interneurons. The gained enhancers, especially the essential mutations, are associated with central nervous system disorders/traits. The essential mutations establish enhancer activities through affecting binding of key transcription factors of embryonic neocortex. Overall, our results suggest that non-coding mutations have led to de novo enhancer gains in the embryonic human neocortex, that orchestrate the expression of genes involved in critical developmental processes associated with human cognition.
Metabolic Regulation of SARS-CoV-2 Infection
Authors: Nahmias Yaakov , Ehrlich Avner , Ioannidis Konstantinos , Nasar Makram , Alkian Ismaeel Abu , Hofree Matan , Tikva Sigal Shafran , Rainy Nir , Houri Inbal , Cicero Arrigo , Pavanello Chiara , Sirtori Cesare , Cohen Jordana , Chirinos Julio , Deutsch Lisa , Gottlieb Amichai , Shibolet Oren , Maayan Shlomo 
Published: August 2021

Abstract
Viruses are efficient metabolic engineers that actively rewire host metabolic pathways to support their lifecycle, presenting attractive metabolic targets for intervention. Here we chart the metabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples. Bulk and single-cell analyses show that viral replication induces endoplasmic stress and lipid accumulation. Protein expression screen suggests a role for viral proteins in mediating this metabolic response even in the absence of replication. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication. Analysis of 3,233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lower markers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A subsequent prospective interventional open-label study was carried out in 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate (TriCor®) in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to control patients admitted during the same period and treated with the standard-of-care. Taken together, our data show that elevated lipid metabolism underlies critical aspects of COVID-19 pathogenesis, suggesting that pharmacological modulation of lipid metabolism should be strongly considered for the treatment of coronavirus infection.
Weathering Features of A Five-Story Stone Pagoda Compared To Its Quarrying Site In Geumgolsan Mountain, Korea
Authors: Jo Young Hoon , Lee Chan Hee 
Published: August 2021

Abstract
Understanding the long- and short-term weathering features according to rock type is very important for maintaining the original form of stone heritages. In this study, the material characteristics of a deteriorated five-story stone pagoda were compared with those of fresh rocks from its quarrying site at nearby Geumgolsan Mountain, Korea to diagnose the degree of damage and develop a comprehensive interpretation of the weathering mechanism. The stone pagoda was built from lithic tuff comprising pumice and phenocrysts such as quartz, K-feldspar, plagioclase, and mica based on plagioclase substrates; the mineralogical and geochemical characteristics are similar to those of the fresh rocks. The lithic tuff of the stone pagoda demonstrated a low ultrasonic velocity of 2863 m/s and a high water absorption rate and porosity of 9.5% and 19.2%, respectively, which are poorer than the physical properties of the fresh rocks (i.e., ultrasonic velocity of 3336 m/s, water absorption rate of 8.65%, and porosity of 17.83%). The lithological characteristics and physical properties demonstrated a considerable influence on the weathering and stability of the stone pagoda. In particular, fragments of relatively weak pumice detached from the original rock to form cavities of various sizes. These cavities introduced moisture within the rock, which produced oxides and hydroxides of iron and manganese. In addition, contaminants such as dust, salt crystals, clay minerals, and microorganisms adhering to the surface of the stone pagoda accelerated its physical, chemical, and biological weathering. The results of this study will be important for realizing the stable and long-term conservation of the five-story stone pagoda at Geumgolsan Mountain.
The Additional Effects of Clarithromycin And Pranlukast On The Cytokine Suppression By Corticosteroids Using Murine Allergic Bronchopulmonary Aspergillosis Model
Authors: Fukushima Chizu , Obase Yasushi , Fukahori Susumu , Yamaguchi Hiroyuki , Sakamoto Noriho , Matsuse Hiroto , Mukae Hiroshi 
Published: August 2021

Abstract
Few medicines other than oral corticosteroids and anti-fungal medicines are currently known as reliable treatments for allergic bronchopulmonary aspergillosis (ABPA). The efficacies of macrolide or leukotriene receptor antagonist (LTRA) with or without corticosteroid on ABPA are unknown. Mice were sensitized to Dermatophagoides farinae (Df) allergen intranasally and infected with Aspergillus fumigatus (Af). After Af infection, corticosteroid (Dexamethasone; Dex) was administered for five days in DfAf/Dex group. The effects of macrolide (clarithromycin; CAM) or LTRA (pranlukast; PRN) with or without Dex were also evaluated. Pathologically, the combined treatment with Dex and CAM decreased the airway inflammation. The interleukin (IL)-5, IL-13 and macrophage inflammatory protein (MIP)-2 concentrations in homogenized lungs were significantly elevated in DfAf mice compared to control mice (p < 0.05, each). CAM significantly decreased the elevations of MIP-2 of DfAf mice (p < 0.05). The addition of CAM on Dex suppressed both of the MIP-2 and IL-5 elevation (p < 0.05, each, DfAf/Dex vs DfAf/Dex/CAM group), but the addition of PRN on Dex did not. It was suggested that combination of CAM and corticosteroid enhanced the suppressing effect of both eosinophilic and neutrophilic airway inflammations. This finding will give a new hope for the treatment of severe fungus-related asthma.
Human Rhinoviruses Prevailed Among Children in the Setting of Wearing Face Masks in Shanghai, 2020
Authors: Jia Ran , Lu Lijuan , Li Shu , Liu Pengcheng , Xu Menghua , Cao Lingfeng , Su Liyun , Xu Jin 
Published: August 2021

Abstract
Background Human rhinovirus (HRV) is the predominant etiological agent of the common cold in children and adults. A recent study showed that the inhibitory effect of face masks on viral shedding of HRV was less prominent than that on other respiratory viruses. Considering that most Chinese people have worn face masks in public area since the outbreak of coronavirus disease 2019, we aimed to find out whether HRV prevailed among children in 2020 and demonstrate the details of the epidemiological features of HRV under such a special circumstance. Methods We summarized the incidences of various respiratory virus infections in patients who visited the Children’s Hospital of Fudan University during 2018~2020, and genotyped HRV positive nasopharyngeal specimens collected from 316 inpatients and 72 outpatients that visited the hospital in 2020. Results There was a major prevalence of HRV among children in the latter half of 2020, with a clear seasonality that HRV-As prevailed in summer while HRV-Cs in autumn. HRV-As were more prone to cause severe lower respiratory tract infections (LRTI), while HRV-Cs were closely associated with childhood wheezing. The predominant genotypes were A11, A28, A47, A82, A101, C40 and C43. Notably, A21, A82 and A101 took up larger proportions in severe cases than in non-severe cases. Conclusions Our findings described a major prevalence of HRVs among children in 2020, which highlight the unique transmitting pattern of HRV and help to narrow the targets for antiviral strategies.
Combined Therapy of Platelet-Rich Plasma and Basic Fibroblast Growth Factor Using Gelatin-Hydrogel Sheet for Rotator Cuff Healing in Rat Models
Authors: Kataoka Takeshi , Mifune Yutaka , Inui Atsuyuki , Nishimoto Hanako , Kurosawa Takashi , Yamaura Kohei , Mukohara Shintaro , Matsushita Takehiko , Niikura Takahiro , Tabata Yasuhiko , Kuroda Ryosuke 
Published: August 2021

Abstract
Introduction: Excellent outcomes of arthroscopic rotator cuff repair for small and medium tears have been recently reported. However, re-tears after surgery have been a common complication after surgical repair of large and massive rotator cuff tears andoften occur in early postoperative phase. It was previously reported that basic fibroblastgrowth factor and platelet-rich plasma enhanced rotator cuff tear healing. Wehypothesized that this combined therapy could enhance rotator cuff healing after rotatorcuff repair in a rat model. This study aimed to evaluate the efficacy of combined therapyof platelet-rich plasma and basic fibroblast growth factor with gelatin-hydrogel sheet.Methods: To create a rotator cuff defect, the infraspinatus tendon of Sprague Dawley ratwas resected from the greater tuberosity. The infraspinatus tendons were repaired andcovered with gelatin-hydrogel sheet impregnated with PBS (control group), basicfibroblast growth factor (bFGF group), platelet-rich plasma (PRP group), or both basicfibroblast growth factor and platelet-rich plasma (combined group). Histologicalexaminations were conducted using hematoxylin and eosin, safranin O, andimmunofluorescence staining such as Isolectin B4, type II collagen. For mechanicalanalysis, ultimate failure load of the tendon-humeral head complex was evaluated at41 weeks postoperatively.Results: In the hematoxylin and eosin staining, the tendon maturing score of the combined group was higher than that of the control group postoperativeat 2 weeks. Inthe safranin O staining, stronger proteoglycan staining was observed in the combinedgroup compared with the other groups at postoperative 2 weeks. Vascular staining withisolectin B4 in 3 treatment groups was significantly higher than that in the control group.Type II collagen expression in the combined group was significantly higher than those inthe other groups. The ultimate failure load of the combined group was significantly higherthan that of the control group.Conclusion: Combined therapy of basic fibroblast growth factor and platelet-rich plasmapromoted angiogenesis; tendon maturing and fibrocartilage regeneration at the enthesis,which could be enhance the mechanical strength. It was suggested that basic fibroblastgrowth factor and platelet-rich plasma enhance both tendon and bone-tendon junctionhealing, and basic fibroblast growth factor and platelet-rich plasma were synergistic.
The Association of Household Socioeconomic Status and Neighborhood Support System With Adherence to Cardiovascular Fitness Among Persons With Diabetes Mellitus in Ghana a Hospital-based Cross Sectional Study.
Authors: Doglikuu Be-Ikuu , Abubakari Abdulai , Yaseri Mehdi , Shakibazadeh Elham , Djazayery Abolghassem , Mirzaei Khadijeh 
Published: August 2021

Abstract
Background: Diabetes mellitus (DM) is an independent risk-factor for cardiovascular diseases. Physical activities (PAs) could reverse this risk factor. However some factors could influence adherence to PAs. Our study investigates the association of household socioeconomic status and neighborhood support system with adherence to cardiovascular fitness among persons with diabetes mellitus (DM) in Ghana.Methods: Facility-based cross-sectional-study was conducted among 530 T2DM patients in Ghana. Structured-questionnaires were used to collect demographic, anthropometric, and clinical variables. Household socioeconomic status (SES) was assessed using wealth-composite index and adherence to PAs measured using WHO PA-short form questionnaires. SPSS version-22 was used in data analysis.Results: There were significant mean difference in low (P = 0.010) and high (P = 0.0001) social/neighborhood supports according to place of residence. After adjusting for age and diabetes duration, high SES (quintile 3) Adjusted Odd Ratio (AOR) =0.68, 95% confidence interval (95%CI) (0.22, 0.07), moderate SES (quintile 3), AOR=3.16, 95%CI (1.01, 9.89) and high social support system (quintile 2) AOR =3.29, 95%CI (1.02, 10.58) were significant for adherence to cardiovascular fitness. Furthermore Low SES (quintile 3) AOR= 3.52, 95%CI (1.44, 8.59) and low social support system (quintile 1) AOR=1.05, 95%CI (1.05, 1.09) were significant for adherence to sedentary lifestyle among persons with diabetes mellitus. Conclusion: SES, and Social/neighborhood support systems are associated with adherence to cardiovascular fitness. Health care workers should prioritized these variables as modifiable factors in diseases preventions and health promotion