bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-Wide Identification of MATE Gene Family in Potato (Solanum tuberosum L.) and Expression Analysis in Heavy Metal Stress
Authors: Huang Yun , He Guandi , Tian Weijun , Li Dandan , Meng Lulu , Wu Danxia , He Tengbing
Published: May 2021

A genome-wide identification and expression analysis of multidrug and toxic compound extrusion (MATE) gene family in potato was carried out to explore the response of MATE proteins to heavy meta stress. In this study, we identified 64 MATE genes from potato genome, which are located on 12 chromosomes, and are divided into I–IV subfamilies based on phylogenetic analysis. According to their order of appearance on the chromosomes, they were named fromStMATE1–64. Subcellular location prediction showed that 98% of them are located on the plasma membrane as transporters. Synteny analysis showed that five pairs of collinearity gene pairs belonged to members of subfamily I and subfamily II had two pairs indicating that the duplication is of great significance to the evolution of genes in subfamilies I and II. Gene exon–intron structures and motif composition are more similar in the same subfamily. Every StMATE gene contained at least onecis-acting element associated with regulation of hormone transport. The relative expression levels of eight StMATE genes were significantly upregulated under Cu2+stress compared with the non-stress condition (0 h). After Cd2+stress for 24 h, the expression levels ofStMATE33in leaf tissue were significantly increased, indicating its crucial role in the process of Cd2+stress. Additionally,StMATE18/60/40/33/5were significantly induced by Cu2+stress, whileStMATE59(II) was significantly induced by Ni2+stress. Our study initially explores the biological functions of StMATE genes in the regulation of heavy metal stress, further providing a theoretical basis for studying the subsequent molecular mechanisms in detail.
Small Intestinal Tuft Cell Activity Associates With Energy Metabolism in Diet-Induced Obesity
Authors: Arora Pankaj , Andersen Daniel , Moll Janne Marie , Danneskiold-Samsøe Niels Banhos , Xu Liqin , Zhou Biaofeng , Kladis Georgios , Rausch Philipp , Workman Christopher T. , Kristiansen Karsten , Brix Susanne
Published: May 2021

Little is known about the involvement of type 2 immune response-promoting intestinal tuft cells in metabolic regulation. We here examined the temporal changes in small intestinal tuft cell number and activity in response to high-fat diet-induced obesity in mice and investigated the relation to whole-body energy metabolism and the immune phenotype of the small intestine and epididymal white adipose tissue. Intake of high fat diet resulted in a reduction in overall numbers of small intestinal epithelial and tuft cells and reduced expression of the intestinal type 2 tuft cell markers Il25 and Tslp. Amongst >1,700 diet-regulated transcripts in tuft cells, we observed an early association between body mass expansion and increased expression of the gene encoding the serine protease inhibitor neuroserpin. By contrast, tuft cell expression of genes encoding gamma aminobutyric acid (GABA)-receptors was coupled to Tslp and Il25 and reduced body mass gain. Combined, our results point to a possible role for small intestinal tuft cells in energy metabolism via coupled regulation of tuft cell type 2 markers and GABA signaling receptors, while being independent of type 2 immune cell involvement. These results pave the way for further studies into interventions that elicit anti-obesogenic circuits via small intestinal tuft cells.
Deconvoluting the T Cell Response to SARS-CoV-2: Specificity Versus Chance and Cognate Cross-Reactivity
Authors: Lehmann Alexander A. , Kirchenbaum Greg A. , Zhang Ting , Reche Pedro A. , Lehmann Paul V.
Published: May 2021

SARS-CoV-2 infection takes a mild or clinically inapparent course in the majority of humans who contract this virus. After such individuals have cleared the virus, only the detection of SARS-CoV-2-specific immunological memory can reveal the exposure, and hopefully the establishment of immune protection. With most viral infections, the presence of specific serum antibodies has provided a reliable biomarker for the exposure to the virus of interest. SARS-CoV-2 infection, however, does not reliably induce a durable antibody response, especially in sub-clinically infected individuals. Consequently, it is plausible for a recently infected individual to yield a false negative result within only a few months after exposure. Immunodiagnostic attention has therefore shifted to studies of specific T cell memory to SARS-CoV-2. Most reports published so far agree that a T cell response is engaged during SARS-CoV-2 infection, but they also state that in 20-81% of SARS-CoV-2-unexposed individuals, T cells respond to SARS-CoV-2 antigens (mega peptide pools), allegedly due to T cell cross-reactivity with Common Cold coronaviruses (CCC), or other antigens. Here we show that, by introducing irrelevant mega peptide pools as negative controls to account for chance cross-reactivity, and by establishing the antigen dose-response characteristic of the T cells, one can clearly discern between cognate T cell memory induced by SARS-CoV-2 infection vs. cross-reactive T cell responses in individuals who have not been infected with SARS-CoV-2.
Suppression of Endoplasmic Reticulum Stress by 4-PBA Protects Against Hyperoxia-Induced Acute Lung Injury via Up-Regulating Claudin-4 Expression
Authors: Pao Hsin-Ping , Liao Wen-I. , Tang Shih-En , Wu Shu-Yu , Huang Kun-Lun , Chu Shi-Jye
Published: May 2021

Endoplasmic reticulum (ER) stress that disrupts ER function can occur in response to a wide variety of cellular stress factors leads to the accumulation of unfolded and misfolded proteins in the ER. Many studies have shown that ER stress amplified inflammatory reactions and was involved in various inflammatory diseases. However, little is known regarding the role of ER stress in hyperoxia-induced acute lung injury (HALI). This study investigated the influence of ER stress inhibitor, 4-phenyl butyric acid (4-PBA), in mice with HALI. Treatment with 4-PBA in the hyperoxia groups significantly prolonged the survival, decreased lung edema, and reduced the levels of inflammatory mediators, lactate dehydrogenase, and protein in bronchoalveolar lavage fluid, and increased claudin-4 protein expression in lung tissue. Moreover, 4-PBA reduced the ER stress-related protein expression, NF-κB activation, and apoptosis in the lung tissue. In in vitro study, 4-PBA also exerted a similar effect in hyperoxia-exposed mouse lung epithelial cells (MLE-12). However, when claudin-4 siRNA was administrated in mice and MLE-12 cells, the protective effect of 4-PBA was abrogated. These results suggested that 4-PBA protected against hyperoxia-induced ALI via enhancing claudin-4 expression.
AIRE Gene Mutation Presenting at Age 2 Years With Autoimmune Retinopathy and Steroid-Responsive Acute Liver Failure: A Case Report and Literature Review
Authors: Sakaguchi Hirotaka , Mizuochi Tatsuki , Haruta Masatoshi , Takase Ryuta , Yoshida Shigeo , Yamashita Yushiro , Nishikomori Ryuta
Published: May 2021

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare monogenic autosomal recessive disorder caused by mutation in the autoimmune regulator (AIRE) gene. Patients usually are diagnosed at ages between 5 and 15 years when they show 3 or more manifestations, most typically mucocutaneous candidiasis, Addison’s disease, and hypoparathyroidism. APECED-associated hepatitis (APAH) develops in only 10% to 40% of patients, with severity varying from subclinical chronic active hepatitis to potentially fatal acute liver failure (ALF). Ocular abnormalities are fairly common, most often keratopathy but sometimes retinopathy. Here we report a 2-year-old Japanese girl with an AIRE gene mutation who developed APAH with ALF, preceded by autoimmune retinopathy associated with anti-recoverin antibody before major symptoms suggested a diagnosis of APECED. Intravenous pulse methylprednisolone therapy followed by a corticosteroid combined with azathioprine treatment resolved ALF and achieved control of APAH. To our knowledge, our patient is the youngest reported to have ALF resulting from an AIRE gene mutation. Pulse methylprednisolone induction therapy followed by treatment with corticosteroid plus azathioprine may well be effective in other children with APAH and AIRE gene mutations.
Interaction Between the Intestinal Microbial Community and Transcriptome Profile in Common Carp (Cyprinus carpio L.)
Authors: Su Shengyan , Jing Xiaojun , Zhang Chengfeng , Hou Yiran , Li Zhixun , Yang Xingli , Zhou Xiaolin , Xu Pao , Tang Yongkai , Zhu Jian
Published: May 2021

In a previous study, we found that the growth performance of the new strain of Huanghe carp is related to gene expression and bacterial community in the gut. In order to better understand the relationship between the gene expression level and bacterial abundance in the gut, we studied the growth performance, gut bacterial structure, and transcriptome profile in the 4th generation of the new carp strain (selection group) at harvesting time, and compared them with the control line (traditional Huanghe carp). Body weight, depth, width, and length increased 14.58, 7.14, 5.04, and 5.07%, respectively. The gut microbiome of the selection group also exhibited significantly higher species diversity parameters (Shannon, Simpson, and chao1). Both PCA and phylogenetic analyses divided all gut samples into two parts: control and selection group. Aeromonas was the dominant taxon in the control group, followed by Firmicutes and Roseomonas; in the selection group, Roseomonas was the dominant taxon, followed by Firmicutes and then Aeromonas. Among the 249 significantly differentially expressed genes, 194 were downregulated and 55 were upregulated. Functional GO annotation produced 13 terms in the biological process, 8 in the cellular component, and 7 in the molecular function categories. KEGG annotation indicated that most of these genes were associated with the immune-related pathways. A total of 2,892 pairs of genes (245) and baceterial genera (256) were analyzed using Pearson’s correlation analysis. Most of the identified associations were mapped to the immune system, bacterial community, and cell differentiation categories. The top-10 bacterial genera identified by these analyses were Methylocystis, Ohtaekwangia, Roseomonas, Shewanella, Lutispora, GpVI, Desulfovibrio, Candidatus_Berkiella, Bordetella, and Azorhizobium. Genes paired with bacteria flora were divided into four functional categories: immune, growth, adipocyte differentiation, and nerve regulation. These genes may be related to the comparatively fast growth and high muscle polyunsaturated fatty acid content of the Huanghe carp new strain. Meanwhile, nerve regulation-related genes may be a reflection of the microbiota-gut-brain axis. These results illustrate that gut bacterial community structure is associated with the growth performance and gene expression in the Huanghe carp new strain.
The Formation of Two Hybrid Plasmids Mediated by IS26 and Tn6952 in Salmonella enterica Serotype Enteritidis
Authors: Liu Ying-ying , He Dan-dan , Zhang Meng-ke , Pan Yu-shan , Wu Hua , Yuan Li , Liu Jian-hua , Hu Gong-zheng
Published: May 2021

To characterize the formation mechanism and characteristics of two cointegrate plasmids in Salmonella enterica serotype Enteritidis strain S13, plasmids from strain S13 and three corresponding transconjugants were subjected to whole genome sequencing and analyzed using bioinformatics tools. The traits of two fusion plasmids in transconjugants were characterized by stability and conjugation experiments. Sequence analysis indicated that strain S13 contained four plasmids, including mcr-1-bearing pS13-1, blaCTX–M–55-carrying pS13-2, tet(M)-bearing pS13-3, and floR-carrying pS13-4. IncN1-F33:A–:B– plasmid pS13-2, respectively, fused with IncFI:A–:B– plasmid pS13-3 and IncX1 plasmid pS13-4, which generated two cointegrate plasmids, designated pS13D and pS13F, which involved in two intermolecular replicative mechanisms mediated by IS26 and the novel transposon Tn6952 (ΔTnAS3-IS26-ΔISEcp1-ramA-ΔIS26-ΔTnAS1), respectively. This is the first report of the fusion of the IncN1-F33:A–:B– plasmid and IncFI:A–:B– plasmid mediated by IS26, and with IncX1 plasmid mediated by Tn6952. The formation and evolution of cointegrate plasmids could expand the resistance and host spectrum of fusion plasmids.
Optimum Integration Procedure for Connectionist and Dynamic Field Equations
Authors: Rieznik Andrés , Di Tella Rocco , Schvartzman Lara , Babino Andrés
Published: May 2021

Connectionist and dynamic field models consist of a set of coupled first-order differential equations describing the evolution in time of different units. We compare three numerical methods for the integration of these equations: the Euler method, and two methods we have developed and present here: a modified version of the fourth-order Runge Kutta method, and one semi-analytical method. We apply them to solve a well-known nonlinear connectionist model of retrieval in single-digit multiplication, and show that, in many regimes, the semi-analytical and modified Runge Kutta methods outperform the Euler method, in some regimes by more than three orders of magnitude. Given the outstanding difference in execution time of the methods, and that the EM is widely used, we conclude that the researchers in the field can greatly benefit from our analysis and developed methods.
CoMB-Deep: Composite Deep Learning-Based Pipeline for Classifying Childhood Medulloblastoma and Its Classes
Authors: Attallah Omneya
Published: May 2021

Childhood medulloblastoma (MB) is a threatening malignant tumor affecting children all over the globe. It is believed to be the foremost common pediatric brain tumor causing death. Early and accurate classification of childhood MB and its classes are of great importance to help doctors choose the suitable treatment and observation plan, avoid tumor progression, and lower death rates. The current gold standard for diagnosing MB is the histopathology of biopsy samples. However, manual analysis of such images is complicated, costly, time-consuming, and highly dependent on the expertise and skills of pathologists, which might cause inaccurate results. This study aims to introduce a reliable computer-assisted pipeline called CoMB-Deep to automatically classify MB and its classes with high accuracy from histopathological images. This key challenge of the study is the lack of childhood MB datasets, especially its four categories (defined by the WHO) and the inadequate related studies. All relevant works were based on either deep learning (DL) or textural analysis feature extractions. Also, such studies employed distinct features to accomplish the classification procedure. Besides, most of them only extracted spatial features. Nevertheless, CoMB-Deep blends the advantages of textural analysis feature extraction techniques and DL approaches. The CoMB-Deep consists of a composite of DL techniques. Initially, it extracts deep spatial features from 10 convolutional neural networks (CNNs). It then performs a feature fusion step using discrete wavelet transform (DWT), a texture analysis method capable of reducing the dimension of fused features. Next, the CoMB-Deep explores the best combination of fused features, enhancing the performance of the classification process using two search strategies. Afterward, it employs two feature selection techniques on the fused feature sets selected in the previous step. A bi-directional long-short term memory (Bi-LSTM) network; a DL-based approach that is utilized for the classification phase. CoMB-Deep maintains two classification categories: binary category for distinguishing between the abnormal and normal cases and multi-class category to identify the subclasses of MB. The results of the CoMB-Deep for both classification categories prove that it is reliable. The results also indicate that the feature sets selected using both search strategies have enhanced the performance of Bi-LSTM compared to individual spatial deep features. CoMB-Deep is compared to related studies to verify its competitiveness, and this comparison confirmed its robustness and outperformance. Hence, CoMB-Deep can help pathologists perform accurate diagnoses, reduce misdiagnosis risks that could occur with manual diagnosis, accelerate the classification procedure, and decrease diagnosis costs.
Prognostic Value of Pre-Treatment CT Radiomics and Clinical Factors for the Overall Survival of Advanced (IIIB–IV) Lung Adenocarcinoma Patients
Authors: Hong Duo , Zhang Lina , Xu Ke , Wan Xiaoting , Guo Yan
Published: May 2021

Purpose

The purpose of this study was to investigate the prognostic value of pre-treatment CT radiomics and clinical factors for the overall survival (OS) of advanced (IIIB–IV) lung adenocarcinoma patients.

Methods

This study involved 165 patients with advanced lung adenocarcinoma. The Lasso–Cox regression model was used for feature selection and radiomics signature building. Then a clinical model was built based on clinical factors; a combined model in the form of nomogram was constructed with both clinical factors and the radiomics signature. Harrell’s concordance index (C-Index) and Receiver operating characteristic (ROC) curves at cut-off time points of 1-, 2-, and 3- year were used to estimate and compare the predictive ability of all three models. Finally, the discriminatory ability and calibration of the nomogram were analyzed.

Results

Thirteen significant features were selected to build the radiomics signature whose C-indexes were 0.746 (95% CI, 0.699 to 0.792) in the training cohort and 0.677 (95% CI, 0.597 to 0.766) in the validation cohort. The C-indexes of combined model achieved 0.799 (95% CI, 0.757 to 0.84) in the training cohort and 0.733 (95% CI, 0.656 to 0.81) in the validation cohort, which outperformed the clinical model and radiomics signature. Moreover, the areas under the curve (AUCs) of the radiomic signature for 2-year prediction was superior to that of the clinical model. The combined model had the best AUCs for 2- and 3-year predictions.

Conclusions

Radiomic signatures and clinical factors have prognostic value for OS in advanced (IIIB–IV) lung adenocarcinoma patients. The optimal model should be selected according to different cut-off time points in clinical application.
Identifying Periampullary Regions in MRI Images Using Deep Learning
Authors: Tang Yong , Zheng Yingjun , Chen Xinpei , Wang Weijia , Guo Qingxi , Shu Jian , Wu Jiali , Su Song
Published: May 2021

Background

Development and validation of a deep learning method to automatically segment the peri-ampullary (PA) region in magnetic resonance imaging (MRI) images.

Methods

A group of patients with or without periampullary carcinoma (PAC) was included. The PA regions were manually annotated in MRI images by experts. Patients were randomly divided into one training set, one validation set, and one test set. Deep learning methods were developed to automatically segment the PA region in MRI images. The segmentation performance of the methods was compared in the validation set. The model with the highest intersection over union (IoU) was evaluated in the test set.

Results

The deep learning algorithm achieved optimal accuracies in the segmentation of the PA regions in both T1 and T2 MRI images. The value of the IoU was 0.68, 0.68, and 0.64 for T1, T2, and combination of T1 and T2 images, respectively.

Conclusions

Deep learning algorithm is promising with accuracies of concordance with manual human assessment in segmentation of the PA region in MRI images. This automated non-invasive method helps clinicians to identify and locate the PA region using preoperative MRI scanning.
The Application of the Lymphoma International Prognostic Index to Predict Venous Thromboembolic Events in Diffuse Large B-Cell Lymphoma Patients
Authors: Abdel-Razeq Hikmat , Ma’koseh Mohammad , Abdel-Razeq Rashid , Amarin Rula , Abufara Alaa , Mansour Razan , Manasrah Mohammad , Al-Rwashdeh Mohammad , Bater Rayan
Published: May 2021

Background

Venous thromboembolic events (VTE) are commonly encountered in patients with lymphoma. Several risk assessments models (RAM) had attempted to identify higher risk patients with varying success. The International Prognostic Index (IPI) is a clinicopathological tool developed to help predict both response to treatment and prognosis of patients with diffuse large B-cell lymphoma (DLBCL).

Objective

In this study, we utilize the IPI index to identify group of patients with DLBCL at higher risk for VTE.

Patients/Methods

Patients with pathologically-confirmed diagnosis of DLBCL and with image-confirmed VTE, treated and followed at our institution were included. Rates of VTE was calculated for each risk category.

Results

A total of 373 patients, median age 49 (range: 18-90) years were included. VTE were reported in 56 (15.0%) patients; 51 (91.1%) had active disease while 29 (51.8%) were ambulatory at time of VTE diagnosis. VTE rates were particularly high among patients with poor performance status (26.2%, P=0.028) and high LDH (19.0%, P=0.023). Applying the age-adjusted IPI separated patients into two risk categories; VTE were diagnosed in 9.7% in patients with “low and low-intermediate” scores compared to 19.8% in patients with “high and high-intermediate” scores, P=0.020.

Conclusions

The original IPI and its modified versions, routinely used at diagnosis as a prognostic and predictive tool for patients with DLBCL, can also be utilized to define high risk patients for VTE; the risk of whom might be high enough to recommend thromboprophylaxis even in the ambulatory settings. More work is needed to refine and improve currently available RAMs.
Approach to Identifying Causative Pathogens of Community-Acquired Pneumonia in Children Using Culture, Molecular, and Serology Tests
Authors: Mardian Yan , Menur Naysilla Adhella , Lokida Dewi , Farida Helmia , Aman Abu Tholib , Karyana Muhammad , Lukman Nurhayati , Kosasih Herman , Kline Ahnika , Lau Chuen-Yen
Published: May 2021

Determining the causative pathogen(s) of community-acquired pneumonia (CAP) in children remains a challenge despite advances in diagnostic methods. Currently available guidelines generally recommend empiric antimicrobial therapy when the specific etiology is unknown. However, shifts in epidemiology, emergence of new pathogens, and increasing antimicrobial resistance underscore the importance of identifying causative pathogen(s). Although viral CAP among children is increasingly recognized, distinguishing viral from bacterial etiologies remains difficult. Obtaining high quality samples from infected lung tissue is typically the limiting factor. Additionally, interpretation of results from routinely collected specimens (blood, sputum, and nasopharyngeal swabs) is complicated by bacterial colonization and prolonged shedding of incidental respiratory viruses. Using current literature on assessment of CAP causes in children, we developed an approach for identifying the most likely causative pathogen(s) using blood and sputum culture, polymerase chain reaction (PCR), and paired serology. Our proposed rules do not rely on carriage prevalence data from controls. We herein share our perspective in order to help clinicians and researchers classify and manage childhood pneumonia.
The Optimal Adjuvant Strategy of Aidi Injection With Gemcitabine and Cisplatin in Advanced Non–small Cell Lung Cancer: A Meta-analysis of 70 Randomized Controlled Trials
Authors: Wang Cheng-Qiong , Zheng Xiao-Tian , Chen Xiao-Fan , Jiang Hong , Huang Jun , Jiang Yuan , Hu Shan-Shan , Huang Xiao-Rong , Liu Shi-Yu , Gong Qi-Hai , Feng Ji-Hong , Xiao Xue , Li Xiao-Fei , Xiao Zheng
Published: May 2021

Introduction: Aidi injection (Aidi) is composed of cantharidin, astragaloside, ginsenoside, and elentheroside E. As an important adjuvant therapy, Aidi in combination with gemcitabine and cisplatin (GP) is often used in the treatment of non-small cell lung cancer (NSCLC).

Objectives: We performed a new evaluation to demonstrate the clinical efficacy and safety of the Aidi and GP combination and further explored an optimal strategy for achieving an ideal response and safety level in advanced NSCLC.

Methodology: We collected all the related trials from Chinese and English-language databases, analyzed their methodological bias risk using the Cochrane evaluation Handbook for Systematic Reviews of Interventions Version 5.1.0, extracted all the data using a predefined data extraction form, pooled the data using a series of meta-analyses, and finally summarized the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

Results: We included 70 trials with 5,509 patients. Compared with GP alone, the Aidi and GP combination showed a significant improvement in the objective response rate (ORR) [1.82 (1.62–2.04)], disease control rate (DCR) [2.29 (1.97–2.67)], and quality of life (QOL) [3.03 (2.55–3.60)] and a low incidence of hematotoxicity and gastrointestinal and hepatorenal toxicity. Aidi might be more suitable for patients who are first-treated, elderly, or patients with a Karnofsky Performance Status (KPS) score ≥ 60 or anticipated survival time (AST) ≥3 months. An Aidi (50 ml/day, 7–14 days/cycle for one to two cycles), gemcitabine (1000 mg/m2), and cisplatin (20–30 mg/m2, 40–50 mg/m2, or 60–80 mg/m2) might be an optimal regimen for realizing an ideal response and safety level. Most results were robust and of moderate quality.

Conclusion: Current evidence indicates that Aidi's value in adjuvant chemotherapy may be broad-spectrum, not just for some regimens. The Aidi and GP combination may show a good short-term response, antitumor immunity, and safety level in patients with NSCLC. Aidi (50 ml/day, 7–14 days/cycle for one and two cycles) with GEM (1000 mg/m2) and DDP (20–30 mg/m2 or 40–50 mg/m2) may be an optimal regimen for realizing an ideal goal in patients who are first-treatment, elderly, or have a KPS score ≥ 60 or AST≥3 months.
Amazonian Medicine and the Psychedelic Revival: Considering the “Dieta”
Authors: O’Shaughnessy David M. , Berlowitz Ilana
Published: May 2021

Background: In Peruvian Amazonian medicine, plant diets (dietas) are a fundamental and highly flexible technique with a variety of uses: from treating and preventing illness, to increasing strength and resilience, to rites of passage, to learning even medicine itself. Many of the plants used in diets are psychoactive; for example, one now well-known plant that can be dieted is Banisteriopsis caapi—the vine also used in the psychoactive brew ayahuasca. The use of ayahuasca has attracted increasing clinical attention towards Amazonian medicine in recent decades, and much work has focused on the potent DMT-containing ayahuasca brew, thus placing the tradition within the purview of psychedelic science.

Aims: In comparison to ayahuasca, the properties of diets have been studied less often. Our work draws on data from Amazonian healers to examine plant diets as medical practices, while also considering their fit within the “set and setting framework” that is central to psychedelic research. We argue that the framework is not sufficiently broad for understanding diets, and thus the investigation aimed to expand the conceptual field of Amazonian medicine, particularly in the context of a renewed psychedelic science and its theoretical concepts.

Design: We used qualitative data from interviews with Amazonian healers, applying a thematic analysis and contrasting findings with the available literature.

Setting: Interviews were conducted in various locations in the San Martín province of Peru between 2015 and 2017.

Participants: We selected and interviewed eight healers who had been extensively trained in traditional Amazonian medicine.

Measures: Semi-structured interviews were used to gain insight into the healers’ personal experiences with plant diets.

Conclusions: Diets are complex but understudied medical practices that should not be explained by reference to pharmacology or psychology only. Intercultural and interdisciplinary research programmes are called for in order to not only better understand plant diets, but traditional Amazonian medicine on the whole.
Benzaldehyde, A New Absorption Promoter, Accelerating Absorption on Low Bioavailability Drugs Through Membrane Permeability
Authors: Wen Wen , Luo Jie , Li Ping , Huang Wenge , Wang Ping , Xu Shijun
Published: May 2021

Styrax, one of the most famous folk medicines, is a necessary medicine in formulas to help other drugs reach the focal zone and maximize the effectiveness, the mechanism that promotes absorption is not clear yet. This study was carried out to investigate the absorption-promoting effects and the mechanism of benzaldehyde, a key active compound of styrax, on the diffusion rates of drugs with different oral bioavailability. Caco-2 transport experiments were used to investigate the transport rate. Molecular Dynamics Simulation analysis and fluorescence-anisotropy measurements were used to explore the underlying mechanism of absorption-promoting. Validation test in vivo was carried out to reveal the absorption-promoting effects of benzaldehyde on high hydrophilicity drugs. Our data indicated that benzaldehyde(50 μM) elevated the cumulative quantity of passively diffusion drugs with high hydrophilicity such as acyclovir and hydrochlorothiazide. MD and membrane fluidity data explained that benzaldehyde can loosen the structure of the lipid bilayer. The validation tests showed that benzaldehyde (140 mg/kg) remarkably increased the Cmax and AUC0-6 of acyclovir and hydrochlorothiazide in vivo. These present studies suggested that benzaldehyde can promote the absorption of drugs with a lower oral bioavailability through disturbing the integrity of lipid bilayer enhanced membrane permeability.
Leveraging the Variability of Pharmacovigilance Disproportionality Analyses to Improve Signal Detection Performances
Authors: Khouri Charles , Nguyen Thuy , Revol Bruno , Lepelley Marion , Pariente Antoine , Roustit Matthieu , Cracowski Jean-Luc
Published: May 2021

Background: A plethora of methods and models of disproportionality analyses for safety surveillance have been developed to date without consensus nor a gold standard, leading to methodological heterogeneity and substantial variability in results. We hypothesized that this variability is inversely correlated to the robustness of a signal of disproportionate reporting (SDR) and could be used to improve signal detection performances.

Methods: We used a validated reference set containing 399 true and false drug-event pairs and performed, with a frequentist and a Bayesian disproportionality method, seven types of analyses (model) for which the results were very unlikely to be related to actual differences in absolute risks of ADR. We calculated sensitivity, specificity and plotted ROC curves for each model. We then evaluated the predictive capacities of all models and assessed the impact of combining such models with the number of positive SDR for a given drug-event pair through binomial regression models.

Results: We found considerable variability in disproportionality analysis results, both positive and negative SDR could be generated for 60% of all drug-event pairs depending on the model used whatever their truthfulness. Furthermore, using the number of positive SDR for a given drug-event pair largely improved the signal detection performances of all models.

Conclusion: We therefore advocate for the pre-registration of protocols and the presentation of a set of secondary and sensitivity analyses instead of a unique result to avoid selective outcome reporting and because variability in the results may reflect the likelihood of a signal being a true adverse drug reaction.
Population Pharmacokinetics of Ropeginterferon Alfa-2b: A Comparison Between Healthy Caucasian and Chinese Subjects
Authors: Zhu Min , Wang Mei-xia , Li Zi-ran , Wang Wei , Su Xia , Jiao Zheng
Published: May 2021

Objective: To develop a population pharmacokinetic (PK) model for ropeginterferon alfa-2b and to compare its PK properties between Caucasian and Chinese populations.

Methods: A population PK model was developed based on data from two phase I clinical trials conducted in Caucasian and Chinese individuals, to evaluate the influence of ethnicity on the PKs of ropeginterferon alfa-2b.

Results: We included 456 observations from 30 healthy Caucasian subjects and 438 observations from 27 healthy Chinese subjects in the population PK analysis. The PKs of ropeginterferon alfa-2b were best described by a one-compartment quasi-equilibrium approximated target-mediated drug disposition model with first-order absorption and absorption lag times. The typical value (relative standard error%) of apparent clearance (CL/F) and volume of distribution of ropeginterferon alfa-2b in 70-kg subjects were 0.778 (12%) L/day and 2.32 (14%) L, respectively. Body weight was the only significant factor affecting the CL/F. There were no obvious differences in the PK properties of ropeginterferon alfa-2b, and predicted steady-state exposure was similar in the Chinese and Caucasian populations.

Conclusion: No significant ethnic differences in ropeginterferon alfa-2b PKs were observed between the Chinese and Caucasian populations.
Increased Endogenous Activity of the Renin-Angiotensin System Reduces Infarct Size in the Rats with Early Angiotensin II-dependent Hypertension which Survive the Acute Ischemia/Reperfusion Injury
Authors: Husková Zuzana , Kikerlová Soňa , Sadowski Janusz , Alánová Petra , Sedláková Lenka , Papoušek František , Neckář Jan
Published: May 2021

We investigated the role of the interaction between hypertension and the renin-angiotensin system in the pathophysiology of myocardial ischemia/reperfusion injury. We hypothesized that in the early phase of angiotensin II (ANG II)-dependent hypertension with developed left ventricular hypertrophy, cardioprotective mechanism(s) are fully activated. The experiments were performed in transgenic rats with inducible hypertension, noninduced rats served as controls. The early phase of ANG II-dependent hypertension was induced by five-days (5 days) dietary indole-3-carbinol administration. Cardiac hypertrophy, ANG II and ANG 1–7 levels, protein expression of their receptors and enzymes were determined. Separate groups were subjected to acute myocardial ischemia/reperfusion injury, and infarct size and ventricular arrhythmias were assessed. Induced rats developed marked cardiac hypertrophy accompanied by elevated ANG levels. Ischemia/reperfusion mortality was significantly higher in induced than noninduced rats (52.1 and 25%, respectively). The blockade of AT1 receptors with losartan significantly increased survival rate in both groups. Myocardial infarct size was significantly reduced after 5 days induction (by 11%), without changes after losartan treatment. In conclusion, we confirmed improved cardiac tolerance to ischemia/reperfusion injury in hypertensive cardiohypertrophied rats and found that activation of AT1 receptors by locally produced ANG II in the heart was not the mechanism underlying infarct size reduction.
Triazine Derivative as Putative Candidate for the Reduction of Hormone-Positive Breast Tumor: In Silico, Pharmacological, and Toxicological Approach
Authors: Tayyab Imtiaz Muhammad , Anwar Fareeha , Saleem Uzma , Ahmad Bashir , Hira Sundas , Mehmood Yumna , Bashir Manal , Najam Saima , Ismail Tariq
Published: May 2021

Background and objectives: Breast cancer is a heterogeneous disease that poses the highest incidence of morbidity among women and presents many treatment challenges. In search of novel breast cancer therapies, several triazine derivatives have been developed for their potential chemotherapeutic activity. This study aims to evaluate the N-nitroso-N-methyl urea (NMU)–induced anti–mammary gland tumor activity of 2,4,6 (O-nitrophenyl amino) 1,3,5-triazine (O-NPAT).

Methods: The in silico modeling and in vitro cytotoxicity assay were performed to strengthen the research hypothesis. For in vivo experimentation, 30 female rats were divided into five groups. Group I (normal control) received normal saline. Group II (disease control) received NMU (50 mg/kg). Group III (standard control) was treated with tamoxifen (5 mg/kg). Groups IV and V received O-NPAT at a dose level of 30 and 60 mg/kg, respectively. For tumor induction, 3 intraperitoneal doses of NMU were given at a 3-week interval, whereas all treatment compounds were administered orally for 14 consecutive days. Biochemical and oxidative stress markers were estimated for all experimental animals. DNA strand breakage alongside inflammatory markers was also measured for the analysis of inflammation. The hormonal profile of progesterone and estrogen was also estimated.

Results: The test compound presented a significant reduction in organ weight and restored the hepatic and renal enzymes. O-NPAT treatments enhanced the antioxidant enzyme level of catalase (CAT), superoxide dismutase (SOD), and total sulfhydryl (TSH), with a highly significant reduction in lactate dehydrogenase (LDH) and lipid peroxidation. Also, the decrease in fragmented DNA, hormonal levels (estradiol and progesterone), and inflammatory cytokines (IL-6 and TNF-α) justified the dosage efficacy further supported by histopathological findings.

Conclusion: All results indicated the anti–breast tumor activity of O-NPAT and presented its possibility of exploitation for beneficial effects in breast cancer treatment.
A Vector Series Solution for a Class of Hyperbolic System of Caputo Time-Fractional Partial Differential Equations With Variable Coefficients
Authors: El-Ajou Ahmad , Al-Zhour Zeyad
Published: May 2021

In this paper, we introduce a series solution to a class of hyperbolic system of time-fractional partial differential equations with variable coefficients. The fractional derivative has been considered by the concept of Caputo. Two expansions of matrix functions are proposed and used to create series solutions for the target problem. The first one is a fractional Laurent series, and the second is a fractional power series. A new approach, via the residual power series method and the Laplace transform, is also used to find the coefficients of the series solution. In order to test our proposed method, we discuss four interesting and important applications. Numerical results are given to authenticate the efficiency and accuracy of our method and to test the validity of our obtained results. Moreover, solution surface graphs are plotted to illustrate the effect of fractional derivative arrangement on the behavior of the solution.
Flexible Broadband Terahertz Modulation Based on Strain-Sensitive MXene Material
Authors: Liu Yangqi , Li Xiang , Yang Tingting , Liu Jingyu , Liu Bin , Shen Jingling , Zhang Bo , Wang Fuhe
Published: May 2021

A flexible broadband terahertz modulator based on a strain-sensitive MXene material is reported. MXene is shown to have high terahertz wave absorption through experimental testing of various substrate samples. Results show that the THz signal transmission increases with increasing stretching degree, which differs obviously from transmission through pure PVAc substrates. Analysis of the terahertz time-domain spectrum and electrical characterization indicate that the sample’s conductivity decreases with increasing stretching degree. The trend and magnitude of the electrical conductivity results are also very similar to those from the time-domain spectrum. MXene is shown to be a simple, efficient terahertz broadband spectrum modulator with transmittance that can be affected by applying external forces.
Effect of Aftershocks on Seismic Fragilities of Single-Story Masonry Structures
Authors: Zhang Hao , Sun Tong , Hou Shi-Wei , Gao Qing-Meng , Li Xi
Published: May 2021

The effect of aftershocks on the fragility of single-story masonry structures is investigated using probabilistic seismic demand analysis Finite element models of an unreinforced masonry (URM) structure and a confined masonry (CM) structure are established and their seismic response characteristics when subjected to mainshock, aftershock, and the mainshock-aftershock sequence are then comparatively investigated. The effects of aftershocks and the use of confining members on the seismic response are studied. Probabilistic seismic demand models of the structures are built, and fragility curves under various conditions are derived to investigate the effect of aftershocks on structural fragility. The maximum roof displacement and maximum inter-story drift ratio are lower in the confined masonry model than in the unreinforced masonry model; additionally, the probability of exceedance (PE) values of each damage limit state reduced, and those of the mainshock-damaged models subjected to aftershock significantly increase compared to those directly subjected to a same-intensity aftershock. The probability of severe damage or collapse compared with the mainshock-damaged CM model is greater than when each is subjected to a same intensity aftershock. The use of confining members benefits aftershock resistance and reduces the failure probability of the mainshock-damaged structure. The PE values significantly increase with the aftershock scaling factor δ. Therefore, the effect of aftershocks should be considered in the seismic design and analysis of masonry structures.
Voluntary Wheel Running Partially Attenuates Early Life Stress-Induced Neuroimmune Measures in the Dura and Evoked Migraine-Like Behaviors in Female Mice
Authors: Eller Olivia C. , Yang Xiaofang , Fuentes Isabella M. , Pierce Angela N. , Jones Brittni M. , Brake Aaron D. , Wang Ruipeng , Dussor Gregory , Christianson Julie A.
Published: May 2021

Migraine is a complex neurological disorder that affects three times more women than men and can be triggered by endogenous and exogenous factors. Stress is a common migraine trigger and exposure to early life stress increases the likelihood of developing chronic pain disorders later in life. Here, we used our neonatal maternal separation (NMS) model of early life stress to investigate whether female NMS mice have an increased susceptibility to evoked migraine-like behaviors and the potential therapeutic effect of voluntary wheel running. NMS was performed for 3 h/day during the first 3 weeks of life and initial observations were made at 12 weeks of age after voluntary wheel running (Exercise, -Ex) or sedentary behavior (-Sed) for 4 weeks. Mast cell degranulation rates were significantly higher in dura mater from NMS-Sed mice, compared to either naïve-Sed or NMS-Ex mice. Protease activated receptor 2 (PAR2) protein levels in the dura were significantly increased in NMS mice and a significant interaction of NMS and exercise was observed for transient receptor potential ankyrin 1 (TRPA1) protein levels in the dura. Behavioral assessments were performed on adult (>8 weeks of age) naïve and NMS mice that received free access to a running wheel beginning at 4 weeks of age. Facial grimace, paw mechanical withdrawal threshold, and light aversion were measured following direct application of inflammatory soup (IS) onto the dura or intraperitoneal (IP) nitroglycerin (NTG) injection. Dural IS resulted in a significant decrease in forepaw withdrawal threshold in all groups of mice, while exercise significantly increased grimace score across all groups. NTG significantly increased grimace score, particularly in exercised mice. A significant effect of NMS and a significant interaction effect of exercise and NMS were observed on hindpaw sensitivity following NTG injection. Significant light aversion was observed in NMS mice, regardless of exercise, following NTG. Finally, exercise significantly reduced calcitonin gene-related peptide (CGRP) protein level in the dura of NMS and naïve mice. Taken together, these findings suggest that while voluntary wheel running improved some measures in NMS mice that have been associated with increased migraine susceptibility, behavioral outcomes were not impacted or even worsened by exercise.
Acoustic Vulnerability, Hydraulic Capacitance, and Xylem Anatomy Determine Drought Response of Small Grain Cereals
Authors: Degraeve Szanne , De Baerdemaeker Niels J. F. , Ameye Maarten , Leroux Olivier , Haesaert Geert Jozej Willem , Steppe Kathy
Published: May 2021

Selection of high-yielding traits in cereal plants led to a continuous increase in productivity. However, less effort was made to select on adaptive traits, favorable in adverse and harsh environments. Under current climate change conditions and the knowledge that cereals are staple foods for people worldwide, it is highly important to shift focus to the selection of traits related to drought tolerance, and to evaluate new tools for efficient selection. Here, we explore the possibility to use vulnerability to drought-induced xylem embolism of wheat cultivars Excalibur and Hartog (Triticum aestivum L.), rye cultivar Duiker Max (Secale cereale L.), and triticale cultivars Dublet and US2014 (x Triticosecale Wittmack) as a proxy for their drought tolerance. Multiple techniques were combined to underpin this hypothesis. During bench-top dehydration experiments, acoustic emissions (AEs) produced by formation of air emboli were detected, and hydraulic capacitances quantified. By only looking at the AE50 values, one would classify wheat cultivar Excalibur as most tolerant and triticale cultivar Dublet as most vulnerable to drought-induced xylem embolism, though Dublet had significantly higher hydraulic capacitances, which are essential in terms of internal water storage to temporarily buffer or delay water shortage. In addition, xylem anatomical traits revealed that both cultivars have a contrasting trade-off between hydraulic safety and efficiency. This paper emphasizes the importance of including a cultivar’s hydraulic capacitance when evaluating its drought response and vulnerability to drought-induced xylem embolism, instead of relying on the AE50 as the one parameter.
A Comparative Analysis of Transcription Networks Active in Juvenile and Mature Wood in Populus
Authors: Luo Laifu , Zhu Yingying , Gui Jinshan , Yin Tongmin , Luo Wenchun , Liu Jianquan , Li Laigeng
Published: May 2021

Juvenile wood (JW) and mature wood (MW) have distinct physical and chemical characters, resulting from wood formation at different development phases over tree lifespan. However, the regulatory mechanisms that distinguish or modulate the characteristics of JW and MW in relation to each other have not been mapped. In this study, by employing the Populus trees with an identical genetic background, we carried out RNA sequencing (RNA-seq) and whole genome bisulfite sequencing (WGBS) in JW and MW forming tissue and analyzed the transcriptional programs in association with the wood formation in different phrases. JW and MW of Populus displayed different wood properties, including higher content of cellulose and hemicelluloses, less lignin, and longer and larger fiber cells and vessel elements in MW as compared with JW. Significant differences in transcriptional programs and patterns of DNA methylation were detected between JW and MW. The differences were concentrated in gene networks involved in regulating hormonal signaling pathways responsible for auxin distribution and brassinosteroids biosynthesis as well as genes active in regulating cell expansion and secondary cell wall biosynthesis. An observed correlation between gene expression profiling and DNA methylation indicated that DNA methylation affected expression of the genes related to auxin distribution and brassinosteroids signal transduction, cell expansion in JW, and MW formation. The results suggest that auxin distribution, brassinosteroids biosynthesis, and signaling be the critical molecular modules in formation of JW and MW. DNA methylation plays a role in formatting the molecular modules which contribute to the transcriptional programs of wood formation in different development phases. The study sheds light into better understanding of the molecular networks underlying regulation of wood properties which would be informative for genetic manipulation for improvement of wood formation.