bluuebunny/crossref_metadata_2025 huggingface dataset:
Radial Data Mining to Identify Density–Dose Interactions That Predict Distant Failure Following SABR
Authors: Davey Angela , van Herk Marcel , Faivre-Finn Corinne , McWilliam Alan
Published: March 2022

Purpose

Lower dose outside the planned treatment area in lung stereotactic radiotherapy has been linked to increased risk of distant metastasis (DM) possibly due to underdosage of microscopic disease (MDE). Independently, tumour density on pretreatment computed tomography (CT) has been linked to risk of MDE. No studies have investigated the interaction between imaging biomarkers andincidentaldose. The interaction would showcase whether the impact of dose on outcome is dependent on imaging and, hence, if imaging could inform which patients require dose escalation outside the gross tumour volume (GTV). We propose an image-based data mining methodology to investigate density–dose interactions radially from the GTV to predict DM with noa prioriassumption on location.

Methods

Dose and density were quantified in 1-mm annuli around the GTV for 199 patients with early-stage lung cancer treated with 60 Gy in 5 fractions. Each annulus was summarised by three density and three dose parameters. For parameter combinations, Cox regressions were performed including adose–densityinteraction in independent annuli. Heatmaps were created that described improvement in DM prediction due to the interaction. Regions of significant improvement were identified and studied in overall outcome models.

Results

Dose–density interactions were identified that significantly improved prediction for over 50% of bootstrap resamples. Dose and density parameters werenotsignificant when the interaction was omitted. Tumour density variance and high peritumour density were associated with DM for patients with more cold spots (less than 30-Gy EQD2) and non-uniform dose about 3 cm outside of the GTV. Associations identified were independent of the mean GTV dose.

Conclusions

Patients with high tumour variance and peritumour density have increased risk of DM if there is a low and non-uniform dose outside the GTV. The dose regions are independent of tumour dose, suggesting thatincidentaldose may play an important role in controlling occult disease. Understanding such interactions is key to identifying patients who will benefit from dose-escalation. The methodology presented allowed spatial dose–density interactions to be studied at the exploratory stage for the first time. This could accelerate the clinical implementation of imaging biomarkers by demonstrating the impact ofincidentaldose for tumours of varying characteristics in routine data.
Elucidating the Synergistic Effect of Multiple Chinese Herbal Prescriptions in the Treatment of Post-stroke Neurological Damage
Authors: Xu Anqi , Wen Zhuo-Hua , Su Shi-Xing , Chen Yu-Peng , Liu Wen-Chao , Guo Shen-Quan , Li Xi-Feng , Zhang Xin , Li Ran , Xu Ning-Bo , Wang Ke-Xin , Li Wen-Xing , Guan Dao-Gang , Duan Chuan-Zhi
Published: March 2022

Background: Traditional Chinese medicine (TCM) has been widely used in the treatment of human diseases. However, the synergistic effects of multiple TCM prescriptions in the treatment of stroke have not been thoroughly studied.

Objective of the study: This study aimed to reveal the mechanisms underlying the synergistic effects of these TCM prescriptions in stroke treatment and identify the active compounds.

Methods: Herbs and compounds in the Di-Tan Decoction (DTD), Xue-Fu Zhu-Yu Decoction (XFZYD), and Xiao-Xu-Ming Decoction (XXMD) were acquired from the TCMSP database. SEA, HitPick, and TargetNet web servers were used for target prediction. The compound-target (C-T) networks of three prescriptions were constructed and then filtered using the collaborative filtering algorithm. We combined KEGG enrichment analysis, molecular docking, and network analysis approaches to identify active compounds, followed by verification of these compounds with an oxygen-glucose deprivation and reoxygenation (OGD/R) model.

Results: The filtered DTD network contained 39 compounds and 534 targets, the filtered XFZYD network contained 40 compounds and 508 targets, and the filtered XXMD network contained 55 compounds and 599 targets. The filtered C-T networks retained approximately 80% of the biological functions of the original networks. Based on the enriched pathways, molecular docking, and network analysis results, we constructed a complex network containing 3 prescriptions, 14 botanical drugs, 26 compounds, 13 targets, and 5 pathways. By calculating the synergy score, we identified the top 5 candidate compounds. The experimental results showed that quercetin, baicalin, and ginsenoside Rg1 independently and synergistically increased cell viability.

Conclusion: By integrating pharmacological and chemoinformatic approaches, our study provides a new method for identifying the effective synergistic compounds of TCM prescriptions. The filtered compounds and their synergistic effects on stroke require further research.
Diabetes, Metformin and the Clinical Course of Covid-19: Outcomes, Mechanisms and Suggestions on the Therapeutic Use of Metformin
Authors: Bailey Clifford J. , Gwilt Mike
Published: March 2022

Objectives: Pre-existing or new diabetes confers an adverse prognosis in people with Covid-19. We reviewed the clinical literature on clinical outcomes in metformin-treated subjects presenting with Covid-19.

Methods: Structured PubMed search: metformin AND [covid (ti) OR covid-19 (ti) OR covid19 (ti) OR coronavirus (ti) OR SARS-Cov2 (ti)], supplemented with another PubMed search: “diabetes AND [covid OR covid-19 OR covid19 OR coronavirus (i) OR SARS-Cov2 (ti)]” (limited to “Clinical Study”, “Clinical Trial”, “Controlled Clinical Trial”, “Meta-Analysis”, “Observational Study”, “Randomized Controlled Trial”, “Systematic Review”).

Results: The effects of metformin on the clinical course of Covid-19 were evaluated in retrospective analyses: most noted improved clinical outcomes amongst type 2 diabetes patients treated with metformin at the time of hospitalisation with Covid-19 infection. These outcomes include reduced admission into intensive care and reduced mortality in subgroups with versus without metformin treatment.

Conclusion: The pleiotropic actions of metformin associated with lower background cardiovascular risk may mediate some of these effects, for example reductions of insulin resistance, systemic inflammation and hypercoagulability. Modulation by metformin of the cell-surface ACE2 protein (a key binding target for SARS-CoV 2 spike protein) via the AMP kinase pathway may be involved. While pre-existing metformin treatment offers potentially beneficial effects and can be continued when Covid-19 infection is not severe, reports of increased acidosis and lactic acidosis in patients with more severe Covid-19 disease remind that metformin should be withdrawn in patients with hypoxaemia or acute renal disease. Prospective study of the clinical and metabolic effects of metformin in Covid-19 is warranted.
Spectrum-Effect Relationship Analysis of Bioactive Compounds in Zanthoxylum nitidum (Roxb.) DC. by Ultra-High Performance Liquid Chromatography Mass Spectrometry Coupled With Comprehensive Filtering Approaches
Authors: Rao Si-wei , Duan Yuan-yuan , Pang Han-qing , Xu Shao-hua , Hu Shou-qian , Cheng Ke-guang , Liang Dong , Shi Wei
Published: March 2022

Zanthoxylum nitidum(Roxb.) DC. (ZN), with strong effects of anti-inflammation and antioxidant activities is treated as a core herb in traditional Chinese medicine (TCM) preparation for treating stomachache, toothache, and rheumatoid arthritis. However, the active ingredients of ZN are not fully clarified due to its chemical complexity. In the present study, a double spectrum–effect analysis strategy was developed and applied to explore the bioactive components in herbs, and ZN was used as an example. Here, the chemical components in ZN were rapidly and comprehensively profiled based on the mass defect filtering-based structure classification (MDFSC) and diagnostic fragment-ion-based extension approaches. Furthermore, the fingerprints of 20 batches of ZN samples were analyzed by high-performance liquid chromatography, and the anti-inflammatory and antioxidant activities of the 20 batches of ZN samples were studied. Finally, the partial least squares regression (PLSR), gray relational analysis models, and Spearman’s rank correlation coefficient (SRCC) were applied to discover the bioactive compounds in ZN. As a result, a total of 48 compounds were identified or tentatively characterized in ZN, including 35 alkaloids, seven coumarins, three phenolic acids, two flavonoids, and one lignan. The results achieved by three prediction models indicated that peaks4,12, and17were the potential anti-inflammatory compounds in ZN, whereas peaks3,5,7,12, and13were involved in the antioxidant activity. Among them, peaks4,5,7, and12were identified as nitidine, chelerythrine, hesperidin, and oxynitidine by comparison with the standards and other references. The data in the current study achieved by double spectrum–effect analysis strategy had great importance to improve the quality standardization of ZN, and the method might be an efficiency tool for the discovery of active components in a complex system, such as TCMs.
Evaluation and Application of Population Pharmacokinetic Models for Identifying Delayed Methotrexate Elimination in Patients With Primary Central Nervous System Lymphoma
Authors: Mao Junjun , Li Qing , Li Pei , Qin Weiwei , Chen Bobin , Zhong Mingkang
Published: March 2022

Objective: Several population pharmacokinetic (popPK) models have been developed to determine the sources of methotrexate (MTX) PK variability. It remains unknown if these published models are precise enough for use or if a new model needs to be built. The aims of this study were to 1) assess the predictability of published models and 2) analyze the potential risk factors for delayed MTX elimination.

Methods: A total of 1458 MTX plasma concentrations, including 377 courses (1–17 per patient), were collected from 77 patients who were receiving high-dose MTX for the treatment of primary central nervous system lymphoma in Huashan Hospital. PopPK analysis was performed using the NONMEM® software package. Previously published popPK models were selected and rebuilt. A new popPK model was then constructed to screen potential covariates using a stepwise approach. The covariates were included based on the combination of theoretical mechanisms and data properties. Goodness-of-fit plots, bootstrap, and prediction- and simulation-based diagnostics were used to determine the stability and predictive performance of both the published and newly built models. Monte Carlo simulations were conducted to qualify the influence of risk factors on the incidence of delayed elimination.

Results: Among the eight evaluated published models, none presented acceptable values of bias or inaccuracy. A two-compartment model was employed in the newly built model to describe the PK of MTX. The estimated mean clearance (CL/F) was 4.91 L h−1 (relative standard error: 3.7%). Creatinine clearance, albumin, and age were identified as covariates of MTX CL/F. The median and median absolute prediction errors of the final model were -10.2 and 36.4%, respectively. Results of goodness-of-fit plots, bootstrap, and prediction-corrected visual predictive checks indicated the high predictability of the final model.

Conclusions: Current published models are not sufficiently reliable for cross-center use. The elderly patients and those with renal dysfunction, hypoalbuminemia are at higher risk of delayed elimination.
Dec1 Deficiency Ameliorates Pulmonary Fibrosis Through the PI3K/AKT/GSK-3β/β-Catenin Integrated Signaling Pathway
Authors: Hu Xingxing , Zou Menglin , Ni Lan , Zhang Mingyang , Zheng Weishuai , Liu Bing , Cheng Zhenshun
Published: March 2022

Tissue remodeling/fibrosis is a main feature of idiopathic pulmonary fibrosis (IPF), which results in the replacement of normal lung parenchyma with a collagen-rich extracellular matrix produced by fibroblasts and myofibroblasts. Epithelial-mesenchymal transition (EMT) in type 2 lung epithelial cells is a key process in IPF, which leads to fibroblasts and myofibroblasts accumulation and excessive collagen deposition. DEC1, a structurally distinct class of basic helix-loop-helix proteins, is associated with EMT in cancer. However, the functional role of DEC1 in pulmonary fibrosis (PF) remains elusive. Herein, we aimed to explore DEC1 expression in IPF and bleomycin (BLM)-induced PF in mice and the mechanisms underlying the fibrogenic effect of DEC1 in PF in vivo and in vitro by Dec1-knockout (Dec1−/−) mice, knockdown and overexpression of DEC1 in alveolar epithelial cells (A549 cells). We found that the expression of DEC1 was increased in IPF and BLM-injured mice. More importantly, Dec1−/− mice had reduced PF after BLM challenge. Additionally, DEC1 deficiency relieved EMT development and repressed the PI3K/AKT/GSK-3β/β-catenin integrated signaling pathway in mice and in A549 cells, whereas DEC1 overexpression in vitro had converse effects. Moreover, the PI3K/AKT and Wnt/β-catenin signaling inhibitors, LY294002 and XAV-939, ameliorated BLM-meditated PF in vivo and relieved EMT in vivo and in vitro. These pathways are interconnected by the GSK-3β phosphorylation status. Our findings indicated that during PF progression, DEC1 played a key role in EMT via the PI3K/AKT/GSK-3β/β-catenin integrated signaling pathway. Consequently, targeting DEC1 may be a potential novel therapeutic approach for IPF.
ACPA Alleviates Bleomycin-Induced Pulmonary Fibrosis by Inhibiting TGF-β-Smad2/3 Signaling-Mediated Lung Fibroblast Activation
Authors: Chen Dongxin , Tang Huirong , Jiang Hongchao , Sun Lei , Zhao Wenjuan , Qian Feng
Published: March 2022

Pulmonary fibrosis is a group of life-threatening diseases with limited therapeutic options. The involvement of cannabinoid type 1 receptors (CB1R) has been indicated in fibrotic diseases, but whether or not the activation of CB1R can be a benefit for fibrosis treatment is controversial. In this study, we investigated the effects of arachidonoylcyclopropylamide (ACPA), as a selective CB1R agonist, on bleomycin (BLM)-induced pulmonary fibrosis. We showed that ACPA treatment significantly improved the survival rate of BLM-treated mice, alleviated BLM-induced pulmonary fibrosis, and inhibited the expressions of extracellular matrix (ECM) markers, such as collagen, fibronectin, and α-SMA. The enhanced expressions of ECM markers in transforming growth factor-beta (TGF-β)-challenged primary lung fibroblasts isolated from mouse lung tissues were inhibited by ACPA treatment in a dose-dependent manner, and the fibroblast migration triggered by TGF-β was dose-dependently diminished after ACPA administration. Moreover, the increased mRNA levels of CB1R were observed in both lung fibroblasts of BLM-induced fibrotic mice in vivo and TGF-β-challenged primary lung fibroblasts in vitro. CB1R-specific agonist ACPA significantly diminished the activation of TGF-β–Smad2/3 signaling, i.e., the levels of p-Smad2 and p-Smad3, and decreased the expressions of downstream effector proteins including slug and snail, which regulate ECM production, in TGF-β-challenged primary lung fibroblasts. Collectively, these findings demonstrated that CB1R-specific agonist ACPA exhibited antifibrotic efficacy in both in vitro and in vivo models of pulmonary fibrosis, revealing a novel anti-fibrosis approach to fibroblast-selective inhibition of TGF-β-Smad2/3 signaling by targeting CB1R.
Psilocybin-Induced Mystical-Type Experiences are Related to Persisting Positive Effects: A Quantitative and Qualitative Report
Authors: McCulloch Drummond E-Wen , Grzywacz Maria Zofia , Madsen Martin Korsbak , Jensen Peter Steen , Ozenne Brice , Armand Sophia , Knudsen Gitte Moos , Fisher Patrick MacDonald , Stenbæk Dea Siggaard
Published: March 2022

Psychedelic drugs such as psilocybin have shown substantial promise for the treatment of several psychiatric conditions including mood and addictive disorders. They also have the remarkable property of producing persisting positive psychological changes in healthy volunteers for at least several months. In this study (NCT03289949), 35 medium-high doses of psilocybin were administered to 28 healthy volunteers (12 females). By the end of the dosing day, participants reported the intensity of their acute experience using the 30-item Mystical Experience Questionnaire (MEQ) and an open-form qualitative report from home. Persisting psychological effects attributed to the psilocybin experience were measured using the Persisting Effects Questionnaire (PEQ) 3-months after administration. Using a linear latent-variable model we show that the MEQ total score is positively associated with the later emergence of positive PEQ effects (p = 3 × 10−5). Moreover, the MEQ subscales “Positive Mood” (pcorr = 4.1 × 10−4) and “Mysticality” (pcorr = 2.0 × 10−4) are associated with positive PEQ whereas the subscales “Transcendence of Time and Space” (pcorr = 0.38) and “Ineffability” (pcorr = 0.45) are not. Using natural language pre-processing, we provide the first qualitative descriptions of the “Complete Mystical Experience” induced by orally administered psilocybin in healthy volunteers, revealing themes such as a sense of connection with the Universe, familial love, and the experience of profound beauty. Combining qualitative and quantitative methods, this paper expands understanding of the acute psilocybin induced experience in healthy volunteers and suggests an importance of the type of experience in predicting lasting positive effects.
Subchronic Oral Toxicity of Sodium p-Hydroxybenzoate in Sprague-Dawley Rats
Authors: Fan Xiaoli , Song Hengzhi , Xu Xiaotian , Lu Xi , Wang Yuhui , Duan Xiaoqun
Published: March 2022

p-Hydroxybenzoic acid (p-HBA), which exists extensively in plants, is well known for its anti-inflammatory effects, but various adverse side effects have also been reported. Previous research has found that acid translated to its sodium salt improves the safety profile of compounds. Therefore, we hypothesized that p-HBA translated to sodium p-hydroxybenzoate would improve its safety profile. In the present study, we evaluated the toxicity of sodium p-hydroxybenzoate after 90 days of repeated oral toxicity experiments according to OECD guidelines in male and female Sprague–Dawley rats. Sodium p-hydroxybenzoate was administered orally to SD rats at doses of 0, 125, 250, and 500 mg/kg body weight (BW)/day for 90 days. All animals survived to the end of the study, and no sodium p-hydroxybenzoate treatment-associated mortality or clinical changes were observed during the study period. Sodium p-hydroxybenzoate did not promote any clinical signs of toxicologically relevant effects, including changes in body weight, food intake and urinalysis parameters, in male or female SD rats. Dose-related alterations in hematological parameters, organ weights and histopathological findings in hepatic tissue were examined in animals of both sexes in the 500 mg/kg BW/day group. Based on the study, the no-observed-adverse-effect level (NOAEL) for sodium p-hydroxybenzoate was determined to be 250 mg/kg BW/day in both male and female rats.
Low FODMAP Diet and Probiotics in Irritable Bowel Syndrome: A Systematic Review With Network Meta-analysis
Authors: Xie Chao-Rong , Tang Bin , Shi Yun-Zhou , Peng Wen-Yan , Ye Kun , Tao Qing-Feng , Yu Shu-Guang , Zheng Hui , Chen Min
Published: March 2022

Background: Probiotic and low fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) diet are two commonly used management approaches for patients with irritable bowel syndrome (IBS). We aimed to evaluate the most effective combinations and components among different probiotics or low FODMAP diet through component network meta-analysis (NMA).

Methods: We searched Embase, Ovid Medline, and Web of Science from inception to 21 January 2021. Randomized controlled trials (RCTs) examining the efficacy of probiotics and low FODMAP diet for IBS were included, with placebo, sham diet, or conventional treatments as controls. Binary outcomes were compared among treatments using the relative ratio (RR). A minimally contextualized framework recommended by the GRADE group was used to evaluate the certainty of evidence. The primary efficacy outcome was the relief of global IBS symptoms, and the secondary efficacy outcome was the reduction in IBS symptom scores or abdominal pain scores.

Key Results: We included 76 RCTs (n = 8058) after screening 1940 articles. Eight RCTs were classified as low risk of bias. Standard network meta-analysis (NMA) showed that Lactobacillus (RR 1.74, 95% CI 1.22–2.48) and Bifidobacterium (RR 1.76, 95% CI 1.01–3.07) were the most effective for the primary efficacy outcome (high certainty evidence); component NMA showed that Bacillus (RR 5.67, 95% CI 1.88 to 17.08, p = 0.002) and Lactobacillus (RR 1.42, 95% CI 1.07 to 1.91, p = 0.017) were among the most effective components. The results of standard NMA and CNMA analysis of the improvement of overall IBS symptom scores or abdominal pain scores were consistent with this finding.

Conclusion:Lactobacillus was the most effective component for the relief of IBS symptoms; Bifidobacterium and Bacillus were possibly effective and need further verification.

Systematic Review Registration: website, identifier registration number.
An Effective Sodium-Dependent Glucose Transporter 2 Inhibition, Canagliflozin, Prevents Development of Hypertensive Heart Failure in Dahl Salt-Sensitive Rats
Authors: He Lili , Ma Sai , Zuo Qingjuan , Zhang Guorui , Wang Zhongli , Zhang Tingting , Zhai Jianlong , Guo Yifang
Published: March 2022

Background: The aim of the study was to investigate the protective effect of canagliflozin (CANA) on myocardial metabolism and heart under stress overload and to further explore its possible molecular mechanism.

Methods: High-salt diet was used to induce heart failure with preserved ejection fraction (HFpEF), and then, the physical and physiological indicators were measured. The cardiac function was evaluated by echocardiography and related indicators. Masson trichrome staining, wheat germ agglutinin, and immunohistochemical staining were conducted for histology analysis. Meanwhile, oxidative stress and cardiac ATP production were also determined. PCR and Western blotting were used for quantitative detection of related genes and proteins. Comprehensive metabolomics and proteomics were employed for metabolic analysis and protein expression analysis.

Results: In this study, CANA showed diuretic, hypotensive, weight loss, and increased intake of food and water. Dahl salt-sensitive (DSS) rats fed with a diet containing 8% NaCl AIN-76A developed left ventricular remodeling and diastolic dysfunction caused by hypertension. After CANA treatment, cardiac hypertrophy and fibrosis were reduced, and the left ventricular diastolic function was improved. Metabolomics and proteomics data confirmed that CANA reduced myocardial glucose metabolism and increased fatty acid metabolism and ketogenesis in DSS rats, normalizing myocardial metabolism and reducing the myocardial oxidative stress. Mechanistically, CANA upregulated p-adenosine 5′-monophosphate-activated protein kinase (p-AMPK) and sirtuin 1 (SIRT1) and significantly induced the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a).

Conclusion: CANA can improve myocardial hypertrophy, fibrosis, and left ventricular diastolic dysfunction induced by hypertension in DSS rats, possibly through the activation of the AMPK/SIRT1/PGC-1a pathway to regulate energy metabolism and oxidative stress.
Effect of Dietary Ramie Powder (Boehmeria nivea) at Various Levels on Growth Performance, Carcass and Meat Qualities, Biochemical Indices, and Antioxidative Capacity of Linwu Ducks
Authors: Lin Qian , Liu Yang , Wang Xin , Wang Yan-Zhou , Huang Peng , Liu Chun-Jie , Liao Li-Ping , Li Ying-Hui , Fan Zhi-Yong , Zeng Jian-Guo , Zhu Si-Yuan , Qiu Hua-Jiao
Published: March 2022

Current experiment was designed to check the effect of dietary supplementation of ramie powder on the growth performance, carcass and meat qualities and antioxidative capacity of Linwu ducks. A total of 312 ducks at 21-day-age were equally divided into 4 groups, fed with control diet, control diet supplemented of 3, 6, or 12% ramie powder, respectively. The results showed that dietary supplementation of 6 and 12% ramie powder increased the final weight and daily body weight gain (P < 0.05), and dietary supplementation of 6% ramie improved the cooking loss of the leg meat 45-mins-postmortem compared with the control group (P < 0.05). Moreover, dietary supplementation of 6% ramie powder promoted the antioxidative capacity of the ducks by increasing the serum activities of superoxide dismutase and glutathione (P < 0.05), as well as the mRNA expressions of glutathione peroxidase 1 in the breast meat and superoxide dismutase 1 in the leg meat (P < 0.05). This experiment demonstrated that dietary supplementation of ramie powder showed beneficial efficacy on the growth performance of Linwu ducks. It corroborated the potential of dietary ramie being used as poultry feed ingredient and suggested that 6% was the proper supplementation rate of ramie powder in Linwu ducks’ feed.
Regional Differences in Mucociliary Clearance in the Upper and Lower Airways
Authors: Rogers Troy D. , Button Brian , Kelada Samir N. P. , Ostrowski Lawrence E. , Livraghi-Butrico Alessandra , Gutay Mark I. , Esther Charles R. , Grubb Barbara R.
Published: March 2022

As the nasal cavity is the portal of entry for inspired air in mammals, this region is exposed to the highest concentration of inhaled particulate matter and pathogens, which must be removed to keep the lower airways sterile. Thus, one might expect vigorous removal of these substances via mucociliary clearance (MCC) in this region. We have investigated the rate of MCC in the murine nasal cavity compared to the more distal airways (trachea). The rate of MCC in the nasal cavity (posterior nasopharynx, PNP) was ∼3–4× greater than on the tracheal wall. This appeared to be due to a more abundant population of ciliated cells in the nasal cavity (∼80%) compared to the more sparsely ciliated trachea (∼40%). Interestingly, the tracheal ventral wall exhibited a significantly lower rate of MCC than the tracheal posterior membrane. The trachealis muscle underlying the ciliated epithelium on the posterior membrane appeared to control the surface architecture and likely in part the rate of MCC in this tracheal region. In one of our mouse models (Bpifb1 KO) exhibiting a 3-fold increase in MUC5B protein in lavage fluid, MCC particle transport on the tracheal walls was severely compromised, yet normal MCC occurred on the tracheal posterior membrane. While a blanket of mucus covered the surface of both the PNP and trachea, this mucus appeared to be transported as a blanket by MCC only in the PNP. In contrast, particles appeared to be transported as discrete patches or streams of mucus in the trachea. In addition, particle transport in the PNP was fairly linear, in contrast transport of particles in the trachea often followed a more non-linear route. The thick, viscoelastic mucus blanket that covered the PNP, which exhibited ∼10-fold greater mass of mucus than did the blanket covering the surface of the trachea, could be transported over large areas completely devoid of cells (made by a breach in the epithelial layer). In contrast, particles could not be transported over even a small epithelial breach in the trachea. The thick mucus blanket in the PNP likely aids in particle transport over the non-ciliated olfactory cells in the nasal cavity and likely contributes to humidification and more efficient particle trapping in this upper airway region.
Age-Related Unstructured Spike Patterns and Molecular Localization in Drosophila Circadian Neurons
Authors: Nguyen Dieu Linh , Hutson Anelise N. , Zhang Yutian , Daniels Skylar D. , Peard Aidan R. , Tabuchi Masashi
Published: March 2022

Aging decreases sleep quality by disrupting the molecular machinery that regulates the circadian rhythm. However, we do not fully understand the mechanism that underlies this process. In Drosophila, sleep quality is regulated by precisely timed patterns of spontaneous firing activity in posterior DN1 (DN1p) circadian clock neurons. How aging affects the physiological function of DN1p neurons is unknown. In this study, we found that aging altered functional parameters related to neural excitability and disrupted patterned spike sequences in DN1p neurons during nighttime. We also characterized age-associated changes in intrinsic membrane properties related to spike frequency adaptations and synaptic properties, which may account for the unstructured spike patterns in aged DN1p neurons. Because Slowpoke binding protein (SLOB) and the Na+/K+ ATPase β subunit (NaKβ) regulate clock-dependent spiking patterns in circadian networks, we compared the subcellular organization of these factors between young and aged DN1p neurons. Young DN1p neurons showed circadian cycling of HA-tagged SLOB and myc-tagged NaKβ targeting the plasma membrane, whereas aged DN1p neurons showed significantly disrupted subcellular localization patterns of both factors. The distribution of SLOB and NaKβ signals also showed greater variability in young vs. aged DN1p neurons, suggesting aging leads to a loss of actively formed heterogeneity for these factors. These findings showed that aging disrupts precisely structured molecular patterns that regulate structured neural activity in the circadian network, leading to age-associated declines in sleep quality. Thus, it is possible to speculate that a recovery of unstructured neural activity in aging clock neurons could help to rescue age-related poor sleep quality.
Antioxidant and Fatty Acid Changes in Pomegranate Peel With Induced Chilling Injury and Browning by Ethylene During Long Storage Times
Authors: Valdenegro Mónika , Fuentes Lida , Bernales Maricarmen , Huidobro Camila , Monsalve Liliam , Hernández Ignacia , Schelle Maximiliano , Simpson Ricardo
Published: March 2022

Pomegranate (Punica granatum) is a non-climacteric fruit with a high antioxidant content in arils and peels, of which 92% are anthocyanins and tannins. However, it is susceptible to chilling injury (CI), a physiological disorder concentrated in the peel, which can affect the organoleptic quality of the fruit. To understand the effects of modified atmosphere and ethylene in responses to stress on the antioxidant quality of the fruit and composition of fatty acids in the peel under CI conditions, the exogenous ethylene treatments (0.5, 1.0, and 1.5 μg L–1), 1-methylcyclopropene (1-MCP; 1 μl L–1), modified atmosphere packaging (MAP: XTend™ bags), combined strategy MAP/1-MCP, and package in macroperforated bags (MPB-control treatment) were evaluated. The assay was performed in cold conditions (2 ± 1°C; 85% RH) to stimulate damage and was sampled for 120 days (+3 days at 20°C). During cold storage, CI symptoms began at 20 days in MPB and at 60 days for all treatments with exogenous ethylene; CI symptoms were delayed up to 120 days in MAP, 1-MCP, and the combined MAP/1-MCP treatment. Damage was concentrated in the peel. Ethylene and MPB-control treatments induced significant electrolyte leakage, lipid peroxidation, and oxidative damage. In contrast, MAP alone or in combination with 1-MCP successfully delayed CI symptoms. However, no significant differences were observed between treatments in fatty acid content, e.g., in the peel, oleic acid, linoleic acid, palmitic acid, but a significant loss was noted after 60 days of storage. Cold storage caused an increase in anthocyanin concentration in the peel and arils, increasing up to 12 times in the peel of the fruit treated with ethylene at the final stage of storage (120 days + 3 days at 20°C), with non-significant differences in the tannin content in the peel. During long-term cold storage of pomegranate, MAP and 1-MCP treatments delay and reduce the appearance of CI symptoms. This long cold storage induces an important decrease in the unsaturated/saturated fatty acid ratio, which is not reversed by any postharvest treatment. A higher unsaturated/saturated fatty acid ratio after 1-MCP treatments showed a protective effect in peel tissues. In addition, it was possible to increase the concentration of anthocyanins in the peel of cold-storage pomegranates treated with ethylene.
A Comprehensive Analysis of Calmodulin-Like Proteins of Glycine max Indicates Their Role in Calcium Signaling and Plant Defense Against Insect Attack
Authors: Yadav Manisha , Pandey Jyotsna , Chakraborty Amrita , Hassan Md. Imtaiyaz , Kundu Jiban Kumar , Roy Amit , Singh Indrakant Kumar , Singh Archana
Published: March 2022

The calcium (Ca2+) signaling is a crucial event during plant-herbivore interaction, which involves a transient change in cytosolic Ca2+ concentration, which is sensed by Ca2+-sensors, and the received message is transduced to downstream target proteins leading to appropriate defense response. Calmodulin-like proteins (CMLs) are calcium-sensing plant-specific proteins. Although CMLs have been identified in a few plants, they remained uncharacterized in leguminous crop plants. Therefore, a wide-range analysis of CMLs of soybean was performed, which identified 41 true CMLs with greater than 50% similarity with Arabidopsis CMLs. The phylogenetic study revealed their evolutionary relatedness with known CMLs. Further, the identification of conserved motifs, gene structure analysis, and identification of cis-acting elements strongly supported their identity as members of this family and their involvement in stress responses. Only a few Glycine max CMLs (GmCMLs) exhibited differential expression in different tissue types, and rest of them had minimal expression. Additionally, differential expression patterns of GmCMLs were observed during Spodoptera litura-feeding, wounding, and signaling compound treatments, indicating their role in plant defense. The three-dimensional structure prediction, identification of interactive domains, and docking with Ca2+ ions of S. litura-inducible GmCMLs, indicated their identity as calcium sensors. This study on the characterization of GmCMLs provided insights into their roles in calcium signaling and plant defense during herbivory.
Effect of Methyl Jasmonate in Gene Expression, and in Hormonal and Phenolic Profiles of Holm Oak Embryogenic Lines Before and After Infection With Phytophthora cinnamomi
Authors: Morcillo Marian , Sales Ester , Corredoira Elena , Martínez María Teresa , Segura Juan , Arrillaga Isabel
Published: March 2022

The dieback syndrome affecting Quercus ilex and other oak species impels the search for tolerant plant genotypes, as well as methods of plant immunization against such infections. Elicitation treatments can be an effective strategy to activate plant defense response and embryogenic lines represent a promising tool to generate new tolerant genotypes and also to study early markers involved in defense response. The aim of the presented work was to investigate changes in gene expression, and in hormonal and phenolic profiles induced in three holm oak embryogenic lines (ELs) elicited with methyl jasmonate (MeJA) before and after infection with the oomycete Phytophthora cinnamomi, which is the main biotic agent involved in this pathogenic process. The three ELs, derived from three genotypes, showed different basal profiles in all tested parameters, noting that the VA5 naïve genotype from a scape tree was characterized by a basal higher expression in NADPH-dependent cinnamyl alcohol dehydrogenase (CAD) and chalcone synthase (CHS) genes and also by higher caffeic acid content. Our work also identifies changes triggered by MeJA elicitation in holm oak embryogenic lines, such as increases in ABA and JA contents, as well as in levels of most of the determined phenolic compounds, especially in caffeic acid in Q8 and E00 ELs, but not in their biosynthesis genes. Irrespective of the EL, the response to oomycete infection in holm oak elicited plant material was characterized by a further increase in JA. Since JA and phenols have been described as a part of the Q. ilex defense response against P. cinnamomi, we propose that MeJA may act as an induced resistance (IR) stimulus and that in our embryogenic material induced both direct (detected prior to any challenge) and primed (detected after subsequent challenge) defense responses.
Improving Soil Resource Uptake by Plants Through Capitalizing on Synergies Between Root Architecture and Anatomy and Root-Associated Microorganisms
Authors: Galindo-Castañeda Tania , Lynch Jonathan P. , Six Johan , Hartmann Martin
Published: March 2022

Root architectural and anatomical phenotypes are highly diverse. Specific root phenotypes can be associated with better plant growth under low nutrient and water availability. Therefore, root ideotypes have been proposed as breeding targets for more stress-resilient and resource-efficient crops. For example, root phenotypes that correspond to the Topsoil Foraging ideotype are associated with better plant growth under suboptimal phosphorus availability, and root phenotypes that correspond to the Steep, Cheap and Deep ideotype are linked to better performance under suboptimal availability of nitrogen and water. We propose that natural variation in root phenotypes translates into a diversity of different niches for microbial associations in the rhizosphere, rhizoplane and root cortex, and that microbial traits could have synergistic effects with the beneficial effect of specific root phenotypes. Oxygen and water content, carbon rhizodeposition, nutrient availability, and root surface area are all factors that are modified by root anatomy and architecture and determine the structure and function of the associated microbial communities. Recent research results indicate that root characteristics that may modify microbial communities associated with maize include aerenchyma, rooting angle, root hairs, and lateral root branching density. Therefore, the selection of root phenotypes linked to better plant growth under specific edaphic conditions should be accompanied by investigating and selecting microbial partners better adapted to each set of conditions created by the corresponding root phenotype. Microbial traits such as nitrogen transformation, phosphorus solubilization, and water retention could have synergistic effects when correctly matched with promising plant root ideotypes for improved nutrient and water capture. We propose that elucidation of the interactive effects of root phenotypes and microbial functions on plant nutrient and water uptake offers new opportunities to increase crop yields and agroecosystem sustainability.
Innovation and Emerging Roles of Populus trichocarpa TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR Transcription Factors in Abiotic Stresses by Whole-Genome Duplication
Authors: Wang Shuo , Shen Yirong , Guo Liangyu , Tan Lingling , Ye Xiaoxue , Yang Yanmei , Zhao Xijuan , Nie Yuqi , Deng Deyin , Liu Shenkui , Wu Wenwu
Published: March 2022

The TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR (TCP) family proteins are plant-specific transcription factors that have been well-acknowledged for designing the architectures of plant branch, shoot, and inflorescence. However, evidence for their innovation and emerging role in abiotic stress has been lacking. In this study, we identified a total of 36 TCP genes in Populus trichocarpa, 50% more than that in Arabidopsis (i.e., 24). Comparative intra-genomes showed that such significant innovation was mainly due to the most recent whole genome duplication (rWGD) in Populus lineage around Cretaceous-Paleogene (K-Pg) boundary after the divergence from Arabidopsis. Transcriptome analysis showed that the expressions of PtrTCP genes varied among leaf, stem, and root, and they could also be elaborately regulated by abiotic stresses (e.g., cold and salt). Moreover, co-expression network identified a cold-associated regulatory module including PtrTCP31, PtrTCP10, and PtrTCP36. Of them, PtrTCP10 was rWGD-duplicated from PtrTCP31 and evolved a strong capability of cold induction, which might suggest a neofunctionalization of PtrTCP genes and contribute to the adaptation of Populus lineage during the Cenozoic global cooling. Evidentially, overexpression of PtrTCP10 into Arabidopsis increased freezing tolerance and salt susceptibility. Integrating co-expression network and cis-regulatory element analysis confirmed that PtrTCP10 can regulate the well-known cold- and salt-relevant genes (e.g., ZAT10, GolS2, and SOS1), proving that PtrTCP10 is an evolutionary innovation in P. trichocarpa response to environmental changes. Altogether, our results provide evidence of the rWGD in P. trichocarpa responsible for the innovation of PtrTCP genes and their emerging roles in environmental stresses.
Leader Humility and Machiavellianism: Investigating the Effects on Followers’ Self-Interested and Prosocial Behaviors
Authors: Chen Shu-Chen , Zou Wen-Qian , Liu Na-Ting
Published: March 2022

Existing research on leader humility primarily demonstrates its positive effects. This study challenges this view by proposing the potential negative effects of leader humility on followers’ behaviors. Furthermore, this paper employs the person-situation interactionist perspective to extend the research on integrating followers’ personality traits and leader humility. Specifically, this study proposed that leader humility triggers their followers’ sense of power; moreover, this study wagers that whether followers’ sense of power encourages self-interested or prosocial behavior in followers depends on their particular Machiavellian traits. The theoretical model was tested using the time-lagged supervisor–subordinate matched data obtained. Our findings revealed that follower Machiavellianism fosters the relationship between a sense of power and self-interested behavior but it weakens the relationship between a sense of power and prosocial behavior. Thus, this study provides a better understanding regarding the effect of follower personality and leader humility on follower behavioral reactions.
University Students and Their Ability to Perform Self-Regulated Online Learning Under the COVID-19 Pandemic
Authors: Klimova Blanka , Zamborova Katarina , Cierniak-Emerych Anna , Dziuba Szymon
Published: March 2022

The COVID-19 pandemic has affected all aspects of the educational system, including students’ learning styles, which are heavily dependent on self-regulated studying strategies and motivation. The purpose of this study was to discover whether Central European students, in this case the Slovak and Czech students, were able to perform self-regulated learning during online learning under the COVID-19 pandemic to achieve their learning goals and improve academic performance, as well as to propose a few practical recommendations how to develop and maintain students’ self-regulation learning in this new online environment. The methodology was based on a questionnaire survey conducted among 268 students at two Central European universities in February and March 2021. The findings indicate that Central European students seemed to be able to perform their online self-study, especially in regard to personal competencies, meaningfulness and motivation. They reported higher awareness of their strengths and weaknesses in learning, time management, and/or the usefulness of making an effort to study. However, the findings reveal an urgent need for more work to be done in the area of metacognitive strategies, such as reflective and critical thinking, analyzing and evaluating. In this respect, the teacher’s role is replaceable since s/he serves as a facilitator and promotes these metacognitive strategies by providing students with constructive feedback, monitoring their learning, reviewing their progress, and/or providing opportunities to reflect on their learning. There were not any striking differences between the Czech and Slovak students. Nevertheless, Slovak students (females in particular) seemed to be more self-disciplined and goal-oriented in their learning.
Historical Linguistics of Sign Languages: Progress and Problems
Authors: Power Justin M.
Published: March 2022

In contrast to scholars and signers in the nineteenth century, William Stokoe conceived of American Sign Language (ASL) as a unique linguistic tradition with roots in nineteenth-centurylangue des signes française, a conception that is apparent in his earliest scholarship on ASL. Stokoe thus contributed to the theoretical foundations upon which the field of sign language historical linguistics would later develop. This review focuses on the development of sign language historical linguistics since Stokoe, including the field's significant progress and the theoretical and methodological problems that it still faces. The review examines the field's development through the lens of two related problems pertaining to how we understand sign language relationships and to our understanding of cognacy, as the term pertains to signs. It is suggested that the theoretical notions underlying these terms do not straightforwardly map onto the historical development of many sign languages. Recent approaches in sign language historical linguistics are highlighted and future directions for research are suggested to address the problems discussed in this review.
Identification and Determination of Dimensions of Health-Related Quality of Life for Cancer Patients in Routine Care – A Qualitative Study
Authors: Schrage Theresa , Görlach Mirja , Schulz Holger , Bleich Christiane
Published: March 2022

Purpose

Continuous patient-reported outcomes (PROs) to identify and address patients’ needs represent an important addition to current routine care. The aim of this study was to identify and determine important dimensions of health-related quality of life (HrQoL) in routine oncological care.

Methods

In a cross-sectional qualitative study, interviews and focus groups were carried out and recorded. The interviewees were asked for their evaluation on HrQoL in general and specifically regarding cancer treatment. The material was transcribed and analyzed using qualitative content analysis based on Mayring. The results were reviewed in an expert discussion.

Results

Interviews with patients (N = 28) and clinicians (N = 4), as well as five focus groups with clinicians (N = 18) were conducted. Initially, nine deductive and two inductive categories on HrQoL were built. Four categories (partnership/sexuality, spirituality/religiousness, health perception, and overall health) were excluded following the qualitative content analysis because they were hardly or not at all mentioned by participants. Following on from the analysis of the expert discussion, one dimension was added (dignity), and two further categories were excluded (mobility and feeling of security in treatment). The resulting system consisted of six dimensions: emotional health, physical ailments, autonomy, social functionality, dignity, and resources.

Conclusion

The identified dimensions of HrQoL in routine oncological care were found to differ from those used in existing HrQoL measurements for (cancer) patients. Further research is needed to test and evaluate the presented structure in a larger sample of cancer patients to further assess its psychometric properties.