bluuebunny/crossref_metadata_2025 huggingface dataset:
Translational Studies on Anti-Atrial Fibrillatory Action of Oseltamivir by its in vivo and in vitro Electropharmacological Analyses
Authors: Kambayashi Ryuichi , Izumi-Nakaseko Hiroko , Goto Ai , Tsurudome Kazuya , Ohshiro Hironori , Izumi Taku , Hagiwara-Nagasawa Mihoko , Chiba Koki , Nishiyama Ryota , Oyama Satomi , Nunoi Yoshio , Takei Yoshinori , Matsumoto Akio , Sugiyama Atsushi
Published: April 2021

Oseltamivir has been shown to prolong the atrial conduction time and effective refractory period, and to suppress the onset of burst pacing-induced atrial fibrillation in vitro. To better predict its potential clinical benefit as an anti-atrial fibrillatory drug, we performed translational studies by assessing in vivo anti-atrial fibrillatory effect along with in vivo and in vitro electropharmacological analyses. Oseltamivir in intravenous doses of 3 (n = 6) and 30 mg/kg (n = 7) was administered in conscious state to the persistent atrial fibrillation model dogs to confirm its anti-atrial fibrillatory action. The model was prepared by tachypacing to the atria of chronic atrioventricular block dogs for > 6 weeks. Next, oseltamivir in doses of 0.3, 3 and 30 mg/kg was intravenously administered to the halothane-anesthetized intact dogs to analyze its in vivo electrophysiological actions (n = 4). Finally, its in vitro effects of 10–1,000 μM on IK,ACh, IKur, IKr, INa and ICaL were analyzed by using cell lines stably expressing Kir3.1/3.4, KV1.5, hERG, NaV1.5 or CaV1.2, respectively (n = 3 for IK,ACh and IKr or n = 6 for IKr, INa and ICaL). Oseltamivir in doses of 3 and 30 mg/kg terminated the atrial fibrillation in 1 out of 6 and in 6 out of 7 atrial fibrillation model dogs, respectively without inducing any lethal ventricular arrhythmia. Its 3 and 30 mg/kg delayed inter-atrial conduction in a frequency-dependent manner, whereas they prolonged atrial effective refractory period in a reverse frequency-dependent manner in the intact dogs. The current assay indicated that IC50 values for IK,ACh and IKr were 160 and 231 μM, respectively, but 1,000 µM inhibited INa, ICaL and IKur by 22, 19 and 13%, respectively. The extent of INa blockade was enhanced at faster beating rate and more depolarized resting membrane potential. Oseltamivir effectively terminated the persistent atrial fibrillation, which may be largely due to the prolongation of the atrial effective refractory period and inter-atrial conduction time induced by IK,ACh and IKr inhibitions along with INa suppression. Thus, oseltamivir can exert a powerful anti-atrial fibrillatory action through its ideal multi-channel blocking property; and oseltamivir would become a promising seed compound for developing efficacious and safe anti-atrial fibrillatory drugs.
Cannabidiol and Amisulpride Improve Cognition in Acute Schizophrenia in an Explorative, Double-Blind, Active-Controlled, Randomized Clinical Trial
Authors: Leweke F. Markus , Rohleder Cathrin , Gerth Christoph W. , Hellmich Martin , Pukrop Ralf , Koethe Dagmar
Published: April 2021

Cannabidiol (CBD), a principal phytocannabinoid constituent, has demonstrated antipsychotic properties in recent clinical trials. While it has also been suggested a promising candidate for the treatment of neurodegenerative disorders, it failed to demonstrate efficacy in cognitive impairments associated with schizophrenia as an add-on treatment (600 mg/day for 6 weeks) in 18 chronically ill patients co-treated with a variety of psychopharmacologic drugs. Here, we report on the results of parallel-group, active-controlled, mono-therapeutic, double-blind, randomized clinical trial (CBD-CT1; ClinicalTrials.gov identifier: NCT00628290) in 42 acute paranoid schizophrenic patients receiving either CBD (up to 800 mg/day) or amisulpride (AMI, up to 800 mg/day) for four weeks in an inpatient setting with neurocognition as a secondary objective. Twentynine patients (15 and 14 in the CBD and AMI group, respectively) completed two cognitive assessments at baseline and the end of the treatment period. We investigated the following cognitive domains: pattern recognition, attention, working memory, verbal and visual memory and learning, processing speed, and verbal executive functions. When applying the Bonferroni correction for multiple testing, p < 0.0004 would indicate statistical significance. There was no relevant difference in neurocognitive performance between the CBD and the AMI group at baseline, and we observed no post-treatment differences between both groups. However, we observed improvements within both groups from pre-to post-treatment (standardized differences reported as Cohen’s d) in visual memory (CBD: 0.49, p = 0.015 vs. AMI: 0.63, p = 0.018) and processing speed (CBD: 0.41, p = 0.004 vs. AMI: 0.57, p = 0.023). Furthermore, CBD improved sustained attention (CBD: 0.47, p = 0.013, vs. AMI: 0.52, p = 0.085), and visuomotor coordination (CBD: 0.32, p = 0.010 vs. AMI: 0.63, p = 0.088) while AMI led to enhanced working memory performance in two different paradigms (Subject Ordered Pointing Task–AMI: 0.53, p = 0.043 vs. CBD: 0.03, p = 0.932 and Letter Number Sequencing–AMI: 0.67, p = 0.017 vs. CBD: 0.08 p = 0.755). There was no relevant correlation between changes in neurocognitive parameters and psychotic symptoms or anandamide serum levels. This study shows that both CBD and AMI improve neurocognitive functioning with comparable efficacy in young and acutely ill schizophrenia patients via an anandamide-independent mechanism.
Chemical Composition, Antioxidant Potential, and Blood Glucose Lowering Effect of Aqueous Extract and Essential Oil of Thymus Serrulatus Hochst. Ex Benth
Authors: Haile Tesfay , Cardoso Susana M. , de Oliveira Raphaelli Chirle , Pereira Olívia R. , Pereira Elisa dos Santos , Vizzotto Márcia , Nora Leonardo , Asfaw Adissu Alemayehu , Periasamy Gomathi , Karim Aman
Published: April 2021

Thymus serrulatus, an endemic plant of Ethiopia, is traditionally used to cure various diseases and as a food ingredient. In the Ethiopian folk medicine, the decoction is orally taken as a remedy to treat diabetes and high blood pressure. The purpose of the present study was to evaluate the antioxidant and antihyperglycemic effects of the aqueous extract and of the essential oil of Thymus serrulatus. The chemical composition of the aqueous extract was determined by LC-MS and the essential oil was characterized by GC-MS analysis. Radical scavenging assays, namely scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH•), hydroxyl (•OH), and nitric oxide (•NO), were used as a first approach to screen the potential antioxidant abilities of the samples. Alpha-amylase and α-glucosidase inhibitory studies were also employed to evaluate the in vitro antihyperglycemic potential of the plant. The in vivo blood glucose lowering effect of the extracts was assessed using hypoglycemic activity and the oral glucose tolerance test in normal and in streptozotocin induced diabetic mice. When compared to the aqueous extract, the essential oil showed superior radical scavenging activity, particularly for •NO, as well as greater inhibitory potency against α-amylase and α-glucosidase (IC50 = 0.01 mg/ml and 0.11 mg/ml, respectively). Both tested samples showed a statistically significant antihyperglycemic effect. The aqueous extract at 600 mg/kg exerted maximum antihyperglycemic activity (44.14%), followed by the essential oil (30.82%). Body weight and glucose tolerance parameters were also improved by the samples both in normal and diabetic mice. The findings of this study support the hypothesis that aqueous extract and essential oil of T. serrulatus are promising therapeutic agents.
Pharmacokinetic Profile and Oral Bioavailability of Diosgenin, Charantin, and Hydroxychalcone From a Polyherbal Formulation
Authors: Salunkhe Ruchira , Gadgoli Chhaya , Naik Archana , Patil Nikita
Published: April 2021

Background: Diosgenin, charantin, and hydroxychalcone are utilized for standardization of popular antidiabetic herbal drugs Trigonella foenum-graecum L. belonging to family Fabaceae, Momordica charantia L. belonging to family Cucurbitaceae, and Cinnamomum verum J. Presl belonging to family Lauraceae. However, no reports on the bioavailability of these markers were available. The present study was undertaken to determine the bioavailability and pharmacokinetic profile of the markers and formulations containing the herbs.

Methods: The pharmacokinetic profile and absolute bioavailability of the pure active markers were determined in male Wistar rats by administrating individually the doses of 1.5 mg/kg i.v. and 15 mg/kg p.o., followed by estimation of serum levels of the markers at 0, 10, 30, 60, 120, and 240 mins till 24 h time points by a validated bioanalytical HPTLC method. Two standardized antidiabetic capsule formulations containing spray dried hydroalcoholic extracts of seeds of Trigonella foenum-graecum L. (42.8 mg equivalent to 0.95%w/w of diosgenin), fresh fruits of Momordica charantia L. (21.4 mg equivalent to 0.4% w/w of charantin), and bark of Cinnamomum verum J. Presl (10.71 mg equivalent to 0.079 %w/w hydroxychalcone) were prepared. In one formulation, piperine 1.5 mg was added along with the other herbal extracts mentioned. Bioavailability and pharmacokinetic profile of these two formulations were determined in male Wistar rats through estimating serum levels of active markers diosgenin, charantin, and hydroxychalcone at 0, 10, 30, 60, 120, and 240 mins till 24 h later oral administration of the formulations (Formulation without piperine F1 and formulation with Piperine F2).

Results: Plasma concentrations were found to decline mono-exponentially following intravenous administration, and the mean elimination half-life (t1/2) was observed to be 7.93, 8.21, and 4.66 h, respectively. The absolute oral bioavailability of pure markers was observed to be 9.0 ± 0.2%, 8.18 ± 0.36%, and 10.54 ± 0.52% by the dose normalization method. The oral bioavailabilities of the formulations with respect to diosgenin, charantin, and hydroxychalcone were found to be 9.78, 10.743, and 8.07%, respectively. The formulation containing piperine indicated a significant (p < 0.01) increase in the bioavailabilities of all the marker compounds.

Conclusion: In conclusion, diosgenin and charantin have low bioavailabilities as compared to hydroxychalcone. The bioavailabilities of all the three marker compounds can be increased exponentially with the addition of piperine.
Relationship Between the Free and Total Methotrexate Plasma Concentration in Children and Application to Predict the Toxicity of HD-MTX
Authors: Dong Wei-Chong , Guo Jia-Liang , Wu Xi-Kun , Zhao Meng-Qiang , Li Hao-Ran , Zhang Zhi-Qing , Jiang Ye
Published: April 2021

High-dose methotrexate (HD-MTX) can be highly effective as well as extremely toxic. Many drug molecules can bind to plasma proteins to different extents in vivo, whereas only the free drug can reach the site of action to exert a pharmacological effect and cause toxicity. However, free MTX concentrations in plasma have not been reported. Traditional analyses of free drugs are both cumbersome and inaccurate. We collected 92 plasma samples from 52 children diagnosed with ALL or NHL or other lymphomas that were treated with HD-MTX. The hollow fiber centrifugal ultrafiltration (HFCF-UF) was used to prepare plasma samples for analysis of the free MTX concentration. Protein precipitation was employed to measure the total MTX concentration. The HFCF-UF is a simple method involving a step of ordinary centrifugation; the validation parameters for the methodological results were satisfactory and fell within the acceptance criteria. A linearity coefficient r2 of 0.910 was obtained for the correlation between the free and total MTX plasma concentrations in 92 plasma samples. However, the free and total MTX concentrations was only weakly correlated in 16 clinical plasma specimens with total MTX concentrations >2 μmol L−1 (r2 = 0.760). Both the free and total MTX concentrations at 42 h were negatively correlated with the creatinine clearance (CCr) level (P = 0.023, r = −0.236 for total MTX and P = 0.020, r = −0.241for free MTX, respectively). The free MTX concentration could not be accurately estimated from the total MTX concentration for patients with high MTX levels which are conditions under which toxic reactions are more likely to occur. High plasma MTX levels could become a predictor of the occurrence of MTX nephrotoxicity to draw people's attention. The proposed HFCF-UF method is a simple and accurate way to evaluate efficacy and toxicity in clinical therapeutic drug monitoring.
Identification of a RAD52 Inhibitor Inducing Synthetic Lethality in BRCA2-Deficient Cancer Cells
Authors: Yang Qianye , Li Yu , Sun Rong , Li Jian
Published: April 2021

The breast cancer susceptibility gene 1/2 (BRCA1/2) is frequently mutated in many malignant tumors, such as breast cancer and ovarian cancer. Studies have demonstrated that inhibition of RAD52 gene function in BRCA2-deficient cancer causes synthetic lethality, suggesting a potential application of RAD52 in cancer-targeted therapy. In this study, we have performed a virtual screening by targeting the self-association domain (residues 85–159) of RAD52 with a library of 66,608 compounds and found one compound, C791-0064, that specifically inhibited the proliferation of BRCA2-deficient cancer cells. Our biochemical and cell-based experimental data suggested that C791-0064 specifically bound to RAD52 and disrupted the single-strand annealing activity of RAD52. Taken together, C791-0064 is a promising leading compound worthy of further exploitation in the context of BRCA-deficient targeted cancer therapy.
Comparison of the Efficacy of Danhong Injections at Different Time-points During the Perioperative Period of Acute Myocardial Infarction: A Systematic Review and Meta-analysis of Randomized Controlled Trials
Authors: He Qing-Ying , Yu Xin-Yu , Xiao Zheng , Sun Xin , Zhu Wei-Feng , Yi Xing-Qian , Chen Qian , Zhang Jia-Hui , Chen Shu-Xian , Zhou Xu , Nie He-Yun , Shang Hong-Cai , Chen Xiao-Fan
Published: April 2021

Objectives: Danhong injections (DHI) are widely used in the treatment of acute myocardial infarction (AMI). As there are no guidelines for the timing of DHI in the peri-percutaneous coronary intervention (PCI) period for AMI, we investigated the effects of DHI timing.

Methods: We reviewed reports published before September 30, 2020 in PubMed, embase, the Cochrane Central Register of Controlled Trials, the Chinese BioMedical database, Chinese VIP database, Wanfang database, and Chinese National Knowledge Infrastructure database. Only randomized controlled trials of DHI with percutaneous coronary intervention for AMI were included. Methodological quality was assessed using the Cochrane evaluation manual 5.3.3 criteria. A meta-analysis was performed, and forest plots were drawn.

Results: We included 23 studies which all revealed that patients in DHI groups had better efficacy than control groups. Subgroup analysis revealed that DHI administered intraoperatively and continued postoperatively was more effective in increasing left ventricular ejection fraction when compared to other time-points (p < 0.001). The pre- and intraoperative use of DHI could improve reflow more effectively than conventional treatment, while the effect was not significant in the postoperative intervention study (p = 0.654). The 16 postoperative interventions revealed that the effect of DHI at 14 days was better than that at 7 and 10 days for hs-CRP (p = 0.013), the 10-days treatment produced better results for CK-MB than for the other treatments (p < 0.001) and a dosage of 30 ml proved most effective for IL-6 (p < 0.001).

Conclusion: DHI proved to be superior to conventional Western medicine in reducing the incidence of adverse cardiac events, promoting reperfusion, improving cardiac function, reducing inflammatory factors, and protecting the myocardium. DHI should be administered early in the perioperative period and continued postoperatively because of its ability to improve cardiac function. Furthermore, in the PCI postoperative, 30 ml is recommended to inhibit IL-6 levels, for patients with high hs-CRP, a course of 14 days is most effective, for patients with obvious abnormalities of CK-MB, a 10-days course of treatment is recommended. However, due to the limited number and quality of the original randomized controlled trials, our conclusions need large, multi-centre RCTs to validation.
P2X7 Receptor–Mediated Inflammation in Cardiovascular Disease
Authors: Zhou Junteng , Zhou Zhichao , Liu Xiaojing , Yin Hai-Yan , Tang Yong , Cao Xin
Published: April 2021

Purinergic P2X7 receptor, a nonselective cation channel, is highly expressed in immune cells as well as cardiac smooth muscle cells and endothelial cells. Its activation exhibits to mediate nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome activation, resulting in the release of interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), and pyroptosis, thus triggering inflammatory response. These pathological mechanisms lead to the deterioration of various cardiovascular diseases, including atherosclerosis, arrhythmia, myocardial infarction, pulmonary vascular remodeling, and cardiac fibrosis. All these worsening cardiac phenotypes are proven to be attenuated after the P2X7 receptor inhibition in experimental studies. The present review aimed to summarize key aspects of P2X7 receptor–mediated inflammation and pyroptosis in cardiovascular diseases. The main focus is on the evidence addressing the involvement of the P2X7 receptor in the inflammatory responses to the occurrence and development of cardiovascular disease and therapeutic interventions.
Metabolic Changes Induced by Purinergic Signaling: Role in Food Intake
Authors: Caruso Vanni , Zuccarini Mariachiara , Di Iorio Patrizia , Muhammad Ishaq , Ronci Maurizio
Published: April 2021

The purinergic signalling has a well-established role in the regulation of energy homeostasis, but there is growing evidence of its implication in the control of food intake. In this review, we provide an integrative view of the molecular mechanisms leading to changes in feeding behaviour within hypothalamic neurons following purinergic receptor activation. We also highlight the importance of purinergic signalling in metabolic homeostasis and the possibility of targeting its receptors for therapeutic purposes.
Inadequate Dosage May Lead to the Recurrence of Postoperative Pulmonary Hypertension in Patients With Congenital Heart Disease
Authors: Li Xinmei , Li Te
Published: April 2021

Background: Pulmonary arterial hypertension (PAH) associated with congenital heart disease (PAH-CHD) occurs predominantly among patients with uncorrected congenital heart disease (CHD). It is an intractable problem to control PAH continuously and stably after an operation.

Methods: 1) OPLS-DA combined with S-plot was used to retrospectively analyze the results of preoperative and postoperative PAH and 39 biochemical indicators of 235 patients admitted to Fuwai Yunnan Cardiovascular Hospital from January 2019 to December 2020. 2) Combined with Meta-analysis, the recurrence in postoperative PAH was analyzed in terms of operation factors, doses administered, and age factors.

Results: 1) 4 indicators (PAH, RBC, HGB, and CO2) that reflect the prognosis of patients had been found by OPLS-DA combined with S-plot. 2) The recurrence rate of postoperative PAH was 37.02%. The comprehensive therapeutic effect of interventional closure was better than that of surgical operation. PAH was not significantly higher again in patients who received either the instruction dose or the literature dose. Postoperative combination therapy (bosentan and sildenafil) was more effective than bosentan alone. Recovery after treatment was better in infants than in the other four age groups.

Conclusion: OPLS-DA combined with S-plot was used for the first time to analyze clinical examination data. In this study, this method proved to be a feasible method for analyzing clinical data We recommend interventional closure as the first choice for patients with PAH-CHD. For postoperative oral therapy, we recommend the combination therapy (bosentan with sildenafil). To prevent the recurrence, the dose should be strictly prescribed according to the instructions, literature, or body surface area converted. Moreover, we recommend treatment at a young age in these patients.
AKT Inhibitors: New Weapons in the Fight Against Breast Cancer?
Authors: Martorana Federica , Motta Gianmarco , Pavone Giuliana , Motta Lucia , Stella Stefania , Vitale Silvia Rita , Manzella Livia , Vigneri Paolo
Published: April 2021

The serine/threonine kinase AKT is a key component of the PI3K/AKT/mTOR signaling pathway as it exerts a pivotal role in cell growth, proliferation, survival, and metabolism. Deregulation of this pathway is a common event in breast cancer including hormone receptor-positive (HR+) disease, HER2-amplified, and triple negative tumors. Hence, targeting AKT represents an attractive treatment option for many breast cancer subtypes, especially those resistant to conventional treatments. Several AKT inhibitors have been recently developed and two ATP-competitive compounds, capivasertib and ipatasertib, have been extensively tested in phase I and II clinical trials either alone, with chemotherapy, or with hormonal agents. Additionally, phase III trials of capivasertib and ipatasertib are already under way in HR+ and triple-negative breast cancer. While the identification of predictive biomarkers of response and resistance to AKT inhibition represents an unmet need, new combination strategies are under investigation aiming to boost the therapeutic efficacy of these drugs. As such, trials combining capivasertib and ipatasertib with CDK4/6 inhibitors, immune checkpoint inhibitors, and PARP inhibitors are currently ongoing. This review summarizes the available evidence on AKT inhibition in breast cancer, reporting both efficacy and toxicity data from clinical trials along with the available translational correlates and then focusing on the potential use of these drugs in new combination strategies.
Inhibition of the Proliferation of Human Lung Fibroblasts by Prostacyclin Receptor Agonists is Linked to a Sustained cAMP Signal in the Nucleus
Authors: Roberts Maxine J. , May Lauren T. , Keen Alastair C. , Liu Bonan , Lam Terrance , Charlton Steven J. , Rosethorne Elizabeth M. , Halls Michelle L.
Published: April 2021

Idiopathic pulmonary fibrosis is a chronic and progressive fibrotic lung disease, and current treatments are limited by their side effects. Proliferation of human lung fibroblasts in the pulmonary interstitial tissue is a hallmark of this disease and is driven by prolonged ERK signalling in the nucleus in response to growth factors such as platelet-derived growth factor (PDGF). Agents that increase cAMP have been suggested as alternative therapies, as this second messenger can inhibit the ERK cascade. We previously examined a panel of eight Gαs-cAMP-coupled G protein-coupled receptors (GPCRs) endogenously expressed in human lung fibroblasts. Although the cAMP response was important for the anti-fibrotic effects of GPCR agonists, the magnitude of the acute cAMP response was not predictive of anti-fibrotic efficacy. Here we examined the reason for this apparent disconnect by stimulating the Gαs-coupled prostacyclin receptor and measuring downstream signalling at a sub-cellular level. MRE-269 and treprostinil caused sustained cAMP signalling in the nucleus and complete inhibition of PDGF-induced nuclear ERK and fibroblast proliferation. In contrast, iloprost caused a transient increase in nuclear cAMP, there was no effect of iloprost on PDGF-induced ERK in the nucleus, and this agonist was much less effective at reversing PDGF-induced proliferation. This suggests that sustained elevation of cAMP in the nucleus is necessary for efficient inhibition of PDGF-induced nuclear ERK and fibroblast proliferation. This is an important first step towards understanding of the signalling events that drive GPCR inhibition of fibrosis.
Multifunctional Metasurface Lens With Tunable Focus Based on Phase Transition Material
Authors: Song Yongkang , Liu Weici , Wang Xiaolei , Wang Faqiang , Wei Zhongchao , Meng Hongyun , Lin Ning , Zhang Hongqiang
Published: April 2021

Metasurfaces have powerful light field manipulation capabilities, which have been extensively studied in the past few years and have developed rapidly in various fields. At present, the focus of metasurface research has shifted to the tunable functionality. In this paper, a temperature-controllable multifunctional metasurface lens based on phase transition material is designed. First of all, by controlling the temperature of the desired working area and the polarization of the incident light, switching among multiple focus, single focus, and no focus at any position can be achieved, and the intensity and helicity of the output light can be adjusted. In addition, a polarization-sensitive intensity-tunable metalens based on the P-B phase principle is designed, when the incident light is linearly polarized light, left-handed circularly polarized light, or right-handed circularly polarized light, it has the same focal point but with different light field intensities. Therefore, the focused intensity can be tunable by the polarization state of the incident light.
Long Non-coding RNA MEG3 Promotes Renal Tubular Epithelial Cell Pyroptosis by Regulating the miR-18a-3p/GSDMD Pathway in Lipopolysaccharide-Induced Acute Kidney Injury
Authors: Deng Junhui , Tan Wei , Luo Qinglin , Lin Lirong , Zheng Luquan , Yang Jurong
Published: April 2021

Background and Objective: Acute kidney injury (AKI) is a complication of sepsis. Pyroptosis of gasdermin D (GSDMD)-mediated tubular epithelial cells (TECs) play important roles in pathogenesis of sepsis-associated AKI. Long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3), an imprinted gene involved in tumorigenesis, is implicated in pyroptosis occurring in multiple organs. Herein, we investigated the role and mechanisms of MEG3 in regulation of TEC pyroptosis in lipopolysaccharide (LPS)-induced AKI.

Materials and Methods: Male C57BL/6 mice and primary human TECs were treated with LPS for 24 h to establish the animal and cell models, respectively, of sepsis-induced AKI. Renal function was assessed by evaluation of serum creatinine and urea levels. Renal tubule injury score was assessed by Periodic acid-Schiff staining. Renal pyroptosis was assessed by evaluating expression of caspase-1, GSDMD, and inflammatory factors IL-1β and IL-18. Cellular pyroptosis was assessed by analyzing the release rate of LDH, expression of IL-1β, IL-18, caspase-1, and GSDMD, and using EtBr and EthD2 staining. MEG3 expression in renal tissues and cells was detected using RT-qPCR. The molecular mechanisms of MEG3 in LPS-induced AKI were assessed through bioinformatics analysis, RNA-binding protein immunoprecipitation, dual luciferase reporter gene assays, and a rescue experiment.

Results: Pyroptosis was detected in both LPS-induced animal and cell models, and the expression of MEG3 in these models was significantly up-regulated. MEG3-knockdown TECs treated with LPS showed a decreased number of pyroptotic cells, down-regulated secretion of LDH, IL-1β, and IL-18, and decreased expression of GSDMD, compared with those of controls; however, there was no difference in the expression of caspase-1 between MEG3 knockdown cells and controls. Bioinformatics analysis screened out miR-18a-3P, and further experiments demonstrated that MEG3 controls GSDMD expression by acting as a ceRNA for miR-18a-3P to promote TECs pyroptosis.

Conclusion: Our study demonstrates that lncRNA MEG3 promoted renal tubular epithelial pyroptosis by regulating the miR-18a-3p/GSDMD pathway in LPS-induced AKI.
Supplemental LED Lighting Effectively Enhances the Yield and Quality of Greenhouse Truss Tomato Production: Results of a Meta-Analysis
Authors: Appolloni Elisa , Orsini Francesco , Pennisi Giuseppina , Gabarrell Durany Xavier , Paucek Ivan , Gianquinto Giorgio
Published: April 2021

Intensive growing systems used for greenhouse tomato production, together with light interception by cladding materials or other devices, may induce intracanopy mutual shading and create suboptimal environmental conditions for plant growth. There are a large number of published peer-reviewed studies assessing the effects of supplemental light-emitting diode (LED) lighting on improving light distribution in plant canopies, increasing crop yields and producing qualitative traits. However, the research results are often contradictory, as the lighting parameters (e.g., photoperiod, intensity, and quality) and environmental conditions vary among conducted experiments. This research presents a global overview of supplemental LED lighting applications for greenhouse tomato production deepened by a meta-analysis aimed at answering the following research question: does supplemental LED lighting enhance the yield and qualitative traits of greenhouse truss tomato production? The meta-analysis was based on the differences among independent groups by comparing a control value (featuring either background solar light or solar + HPS light) with a treatment value (solar + supplemental LED light or solar + HPS + supplemental LED light, respectively) and included 31 published papers and 100 total observations. The meta-analysis results revealed the statistically significant positive effects (p-value < 0.001) of supplemental LED lighting on enhancing the yield (+40%), soluble solid (+6%) and ascorbic acid (+11%) contents, leaf chlorophyll content (+31%), photosynthetic capacity (+50%), and leaf area (+9%) compared to the control conditions. In contrast, supplemental LED lighting did not show a statistically significant effect on the leaf stomatal conductance (p-value = 0.171). In conclusion, in addition to some partial inconsistencies among the considered studies, the present research enables us to assert that supplemental LED lighting ameliorates the quantitative and qualitative aspects of greenhouse tomato production.
Developmental Analysis of the GATA Factor HANABA TARANU Mutants in Medicago truncatula Reveals Their Roles in Nodule Formation
Authors: Xu Yiteng , Wang Hongfeng , Lu Zhichao , Wen Lizhu , Gu Zhiqun , Zhang Xue , Yu Guangle , Wang Hailong , Zhou Chuanen , Han Lu
Published: April 2021

Formation of nodules on legume roots results from symbiosis with rhizobial bacteria. Here, we identified two GATA transcription factors, MtHAN1 and MtHAN2, in Medicago truncatula, which are the homologs of HANABA TARANU (HAN) and HANABA TARANU LIKE in Arabidopsis thaliana. Our analysis revealed that MtHAN1 and MtHAN2 are expressed in roots and shoots including the root tip and nodule apex. We further show that MtHAN1 and MtHAN2 localize to the nucleus where they interact and that single and double loss-of-function mutants of MtHAN1 and MtHAN2 did not show any obvious phenotype in flower development, suggesting their role is different than their closest Arabidopsis homologues. Investigation of their symbiotic phenotypes revealed that the mthan1 mthan2 double mutant develop twice as many nodules as wild type, revealing a novel biological role for GATA transcription factors. We found that HAN1/2 transcript levels respond to nitrate treatment like their Arabidopsis counterparts. Global gene transcriptional analysis by RNA sequencing revealed different expression genes enriched for several pathways important for nodule development including flavonoid biosynthesis and phytohormones. In addition, further studies suggest that MtHAN1 and MtHAN2 are required for the expression of several nodule-specific cysteine-rich genes, which they may activate directly, and many peptidase and peptidase inhibitor genes. This work expands our knowledge of the functions of MtHANs in plants by revealing an unexpected role in legume nodulation.
Cold Hardiness Dynamics and Spring Phenology: Climate-Driven Changes and New Molecular Insights Into Grapevine Adaptive Potential
Authors: De Rosa Valeria , Vizzotto Giannina , Falchi Rachele
Published: April 2021

Climate change has become a topic of increasing significance in viticulture, severely challenged by this issue. Average global temperatures are increasing, but frost events, with a large variability depending on geographical locations, have been predicted to be a potential risk for grapevine cultivation. Grape cold hardiness encompasses both midwinter and spring frost hardiness, whereas the avoidance of spring frost damage due to late budbreak is crucial in cold resilience. Cold hardiness kinetics and budbreak phenology are closely related and affected by bud’s dormancy state. On the other hand, budbreak progress is also affected by temperatures during both winter and spring. Genetic control of bud phenology in grapevine is still largely undiscovered, but several studies have recently aimed at identifying the molecular drivers of cold hardiness loss and the mechanisms that control deacclimation and budbreak. A review of these related traits and their variability in different genotypes is proposed, possibly contributing to develop the sustainability of grapevine production as climate-related challenges rise.
TALEN-Based HvMPK3 Knock-Out Attenuates Proteome and Root Hair Phenotypic Responses to flg22 in Barley
Authors: Takáč Tomáš , Křenek Pavel , Komis George , Vadovič Pavol , Ovečka Miroslav , Ohnoutková Ludmila , Pechan Tibor , Kašpárek Petr , Tichá Tereza , Basheer Jasim , Arick Mark , Šamaj Jozef
Published: April 2021

Mitogen activated protein kinases (MAPKs) integrate elicitor perception with both early and late responses associated with plant defense and innate immunity. Much of the existing knowledge on the role of plant MAPKs in defense mechanisms against microbes stems from extensive research in the model plant Arabidopsis thaliana. In the present study, we investigated the involvement of barley (Hordeum vulgare) MPK3 in response to flagellin peptide flg22, a well-known bacterial elicitor. Using differential proteomic analysis we show that TALEN-induced MPK3 knock-out lines of barley (HvMPK3 KO) exhibit constitutive downregulation of defense related proteins such as PR proteins belonging to thaumatin family and chitinases. Further analyses showed that the same protein families were less prone to flg22 elicitation in HvMPK3 KO plants compared to wild types. These results were supported and validated by chitinase activity analyses and immunoblotting for HSP70. In addition, differential proteomes correlated with root hair phenotypes and suggested tolerance of HvMPK3 KO lines to flg22. In conclusion, our study points to the specific role of HvMPK3 in molecular and root hair phenotypic responses of barley to flg22.
Delivering Clinically on Our Knowledge of Oxytocin and Sensory Stimulation: The Potential of Infant Carrying in Primary Prevention
Authors: Norholt Henrik
Published: April 2021

Oxytocin (OT) is one of the most intensively researched neuropeptides during the three past decades. In benign social contexts, OT exerts a range of desirable socioemotional, stress-reducing, and immunoregulatory effects in mammals and humans and influences mammalian parenting. Consequentially, research in potential pharmacological applications of OT toward human social deficits/disorders and physical illness has increased substantially. Regrettably, the results from the administration of exogenous OT are still relatively inconclusive. Research in rodent maternal developmental programming has demonstrated the susceptibility of offspring endogenous OT systems to maternal somatosensory stimulation, with consequences for behavioral, epigenetic, cognitive, and neurological outcomes. A translation of this animal research into practically feasible human parenting recommendations has yet to happen, despite the significant prevention potential implied by the maternal developmental programming research. Extended physical contact with full-term healthy infants in the months following birth (infant carrying) might constitute the human equivalent of those specific rodent maternal behaviors, found to positively influence emerging OT systems. Findings from both OT and maternal programming research parallel those found for infants exposed to such extended parental physical contact, whether through skin-to-skin contact or infant carrying. Clinical support of parents to engage in extended physical contact represents a feasible intervention to create optimum conditions for the development of infant OT systems, with potential beneficial long-term health effects.
Exploratory Study of the Relationship Between Happiness and the Rise of Media Consumption During COVID-19 Confinement
Authors: Muñiz-Velázquez José Antonio , Gómez-Baya Diego , Lozano Delmar Javier
Published: April 2021

The confinement of the population into their homes as a result of COVID-19 has entailed a notable increase in the consumption of diverse media. This exploratory study aimed to examine how the increase in media consumption was related to subjective happiness and psychological well-being. For this purpose, a questionnaire was administered to a sample of Spanish adults (n = 249; 53.8% women; aged between 18 and 75, Mage = 42.06, SD = 12.37) to assess their consumption of different media before and during confinement. Moreover, participants were evaluated for hedonic, eudaimonic, social, and experienced happiness by using the Pemberton Happiness Index (PHI). The results underlined the great increase in the consumption of TV for entertainment and social networking sites (SNS) during confinement. Furthermore, it was found that higher consumption was negatively correlated with the level of happiness, so that, people who reported greater well-being, both subjective and psychological, spent less time watching TV and using SNS. In contrast, no association was found between the level of happiness and the consumption of news (regardless of the media) and radio. Therefore, it seems that far from cultivating greater happiness, those who engaged in heavy consumption of TV entertainment and SNS during confinement were less happy than those who did so more moderately and spent more time using other media or performing other activities.
Athlete Experiences of Shame and Guilt: Initial Psychometric Properties of the Athletic Perceptions of Performance Scale Within Junior Elite Cricketers
Authors: Rice Simon M. , Treeby Matt S. , Olive Lisa , Saw Anna E. , Kountouris Alex , Lloyd Michael , Macleod Greg , Orchard John W. , Clarke Peter , Gwyther Kate , Purcell Rosemary
Published: April 2021

Guilt and shame are self-conscious emotions with implications for mental health, social and occupational functioning, and the effectiveness of sports practice. To date, the assessment and role of athlete-specific guilt and shame has been under-researched. Reporting data from 174 junior elite cricketers (M = 17.34 years; females n = 85), the present study utilized exploratory factor analysis in validating the Athletic Perceptions of Performance Scale (APPS), assessing three distinct and statistically reliable factors: athletic shame-proneness, guilt-proneness, and no-concern. Conditional process analysis indicated that APPS shame-proneness mediated the relationship between general and athlete-specific distress (p < 0.01), with this pathway non-contingent on sex or past 12-month help-seeking for mental health concerns (p's > 0.05). While APPS domains of guilt-proneness and no-concern were not significant mediators, they exhibited correlations in the expected direction with indices of psychological distress and well-being. The APPS may assist coaches and support staff identify players who may benefit from targeted interventions to reduce the likelihood of experiencing shame-prone states.
From Which Direction Does the Empire Strike (Back)?
Authors: Halicki Katharina Theresa , Ingendahl Moritz , Mayer Maren , John Melvin , Schreiner Marcel Raphael , Wänke Michaela
Published: April 2021

In cultures with left-right-script, agentic behavior is mentally represented as following a left-to-right trajectory, an effect referred to as the Spatial Agency Bias (SAB, Suitner and Maass, 2016). In this research, we investigated whether spatial representations of activities are universal across activities by analyzing the opposite concepts of “attack” and “defense”. Both behaviors involve similar actions (e.g., fighting) but may differ in perceived agency. Moreover “defense” is necessarily always a response to an attack and may therefore be represented by a trajectory in the opposite direction. Two studies found the classic SAB for activities representing attacking but a reduction (Study 1) and reversal (Study 2) for activities involving defense. Although the spatial representation of defense on the right was much weaker and less unequivocal than that of attack on the left, the results suggest that the spatial representations of defense and attack are located in different positions. Apparently not all actors and all activities are spatially represented on the left with a left-to-right trajectory but position and direction depend on the perceived agency. Directions for future research and applications of our findings are discussed.
The Role of Iconic Gestures in Speech Comprehension: An Overview of Various Methodologies
Authors: Kandana Arachchige Kendra G. , Simoes Loureiro Isabelle , Blekic Wivine , Rossignol Mandy , Lefebvre Laurent
Published: April 2021

Iconic gesture-speech integration is a relatively recent field of investigation with numerous researchers studying its various aspects. The results obtained are just as diverse. The definition of iconic gestures is often overlooked in the interpretations of results. Furthermore, while most behavioral studies have demonstrated an advantage of bimodal presentation, brain activity studies show a diversity of results regarding the brain regions involved in the processing of this integration. Clinical studies also yield mixed results, some suggesting parallel processing channels, others a unique and integrated channel. This review aims to draw attention to the methodological variations in research on iconic gesture-speech integration and how they impact conclusions regarding the underlying phenomena. It will also attempt to draw together the findings from other relevant research and suggest potential areas for further investigation in order to better understand processes at play during speech integration process.
Does the Rural Environment Influence Symptomatology and Optimize the Effectiveness of Disease Acceptance? A Study Among Women With Fibromyalgia
Authors: Catalá Patricia , Blanco Sheila , Perez-Calvo Soledad , Luque-Reca Octavio , Bedmar Dolores , Peñacoba Cecilia
Published: April 2021

The present study aims to explore whether the symptoms associated with fibromyalgia are contextually influenced by the area of residence (rural/urban). Furthermore, it is analyzed whether the effect of the acceptance of the disease on the emotional, cognitive and physical symptoms is moderated by the patients’ place of residence. Using a cross-sectional design, a total of 234 women with fibromyalgia (mean age = 56.91 years; SD = 8.94) were surveyed, of which 55.13% resided in rural areas and 44.87% in urban areas. Self-reported questionnaires were used to assess pain severity, anxiety and depression, functional limitation, physical and mental fatigue and acceptance of the disease. The results show significant differences in acceptance (p = 0.040), pain (p < 0.001), and physical and mental fatigue (p = 0.003 and p = 0.004, respectively) between patients from rural and urban areas. The rural area patients presented higher levels of acceptance and pain and lesser levels of physical and mental fatigue compared to the urban area. The moderation analysis add that, only in patients from the rural area, the variables of physical symptoms (pain, functional limitation, and physical fatigue) were significantly and negatively associated with acceptance. This study addresses for the first time the role of the place of residence in suffering from fibromyalgia, suggesting that the rural or urban environment plays a relevant role in the severity and/or management of symptoms in fibromyalgia women. Limitations and practical implications are also discussed.
School Refusal Behavior and Aggression in Spanish Adolescents
Authors: Gonzálvez Carolina , Martín Miriam , Vicent María , Sanmartín Ricardo
Published: April 2021

In order to reduce school attendance problems and aggressive behavior, it is essential to determine the relationship between both variables. The aim of this study was twofold: (1) to examine the mean differences in scores on aggression, based on school refusal behavior, and (2) to analyze the predictive capacity of high scores on aggression, based on school refusal behavior factors. The sample consisted of 1455 Spanish secondary school students, aged 13–17 (M = 14.85; SD = 1.56). The School Refusal Assessment Scale-Revised (I. Avoidance of negative affectivity, II. Escape from aversive social and/or evaluative situations, III. Pursuit of attention from significant others, and IV. Pursuit of tangible reinforcement outside of school) and the Aggression Questionnaire (I. Physical Aggression, II. Verbal Aggression, III. Anger, and IV. Hostility) were used. Results indicated that students having high levels of Physical Aggression, Verbal Aggression, Anger, and Hostility received significantly higher scores on school refusal behavior. In most cases, school refusal behavior was found to be a positive and statistically significant predictor of aggression. Students that base their school refusal on the pursuit of tangible reinforcements outside of school earned higher scores, and other functional conditions underlying school refusal behavior were found to be associated with aggression issues. The role of aggression as a risk factor for school refusal behavior is discussed.
Mental Health Outcomes Among Civil Servants Aiding in Coronavirus Disease 2019 Control
Authors: Hu Qingqing , Hu Xiaochu , Zheng Beibei , Li Lanjuan
Published: April 2021

Objective: To assess the psychiatric status of Chinese civil servants aiding in coronavirus disease 2019 (COVID-19) control.

Background: During the COVID-19 pandemic, Chinese civil servants have faced high workloads that may contribute to mental disorders. We assessed the prevalence of both depression and anxiety symptoms among civil servants in Jiangsu and surrounding provinces using the Chinese versions of the 9-item Patient Health Questionnaire (PHQ-9) and the 7-item Generalized Anxiety Disorder (GAD-7) scale.

Methods: The PHQ-9 and GAD-7 were used to assess the severity of symptoms of depression and anxiety, respectively. Multivariable logistic regression analysis was performed to identify factors associated with mental health outcomes.

Results: In total, 867 Chinese civil servants aiding in COVID-19 control were included in our study. Overall, 37.25 and 38.06% of all respondents reported having symptoms of depression and anxiety, respectively. Respondents who were younger and more educated and those who had fewer years of work experience had higher scores for both depression and anxiety. Multivariable logistic regression analysis showed that being a woman, being younger, having more education and having fewer years of work experience were associated with a higher risk of symptoms of depression and anxiety. However, whether they had experience combating infectious diseases or worked in frontline, there was no significant difference between respondents with and without experience, as well as between frontline and non-frontline workers, in both symptoms of depression and anxiety.

Conclusions: The civil servants aiding in COVID-19 control reported suffering from varying degrees of mental disorders. Therefore, more attention should be devoted to the psychological distress of these civil servants.