bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Pathobiology of the Cerebrovasculature in Aging and in Alzheimers Disease Cases With Cerebral Amyloid Angiopathy
Authors: Ojo Joseph O. , Reed Jon M. , Crynen Gogce , Vallabhaneni Prashanthi , Evans James , Shackleton Benjamin , Eisenbaum Maximillian , Ringland Charis , Edsell Anastasia , Mullan Michael , Crawford Fiona , Bachmeier Corbin
Published: May 2021

Cerebrovascular dysfunction and cerebral amyloid angiopathy (CAA) are hallmark features of Alzheimer's disease (AD). Molecular damage to cerebrovessels in AD may result in alterations in vascular clearance mechanisms leading to amyloid deposition around blood vessels and diminished neurovascular-coupling. The sequelae of molecular events leading to these early pathogenic changes remains elusive. To address this, we conducted a comprehensive in-depth molecular characterization of the proteomic changes in enriched cerebrovessel fractions isolated from the inferior frontal gyrus of autopsy AD cases with low (85.5 ± 2.9 yrs) vs. high (81 ± 4.4 yrs) CAA score, aged-matched control (87.4 ± 1.5 yrs) and young healthy control (47 ± 3.3 yrs) cases. We employed a 10-plex tandem isobaric mass tag approach in combination with our ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method. Enriched cerebrovascular fractions showed very high expression levels of proteins specific to endothelial cells, mural cells (pericytes and smooth muscle cells), and astrocytes. We observed 150 significantly regulated proteins in young vs. aged control cerebrovessels. The top pathways significantly modulated with aging included chemokine, reelin, HIF1α and synaptogenesis signaling pathways. There were 213 proteins significantly regulated in aged-matched control vs. high CAA cerebrovessels. The top three pathways significantly altered from this comparison were oxidative phosphorylation, Sirtuin signaling pathway and TCA cycle II. Comparison between low vs. high CAA cerebrovessels identified 84 significantly regulated proteins. Top three pathways significantly altered between low vs. high CAA cerebrovessels included TCA Cycle II, Oxidative phosphorylation and mitochondrial dysfunction. Notably, high CAA cases included more advanced AD pathology thus cerebrovascular effects may be driven by the severity of amyloid and Tangle pathology. These descriptive proteomic changes provide novel insights to explain the age-related and AD-related cerebrovascular changes contributing to AD pathogenesis. Particularly, disturbances in energy bioenergetics and mitochondrial biology rank among the top AD pathways altered in cerebrovessels. Targeting these failed mechanisms in endothelia and mural cells may provide novel disease modifying targets for developing therapeutic strategies against cerebrovascular deterioration and promoting cerebral perfusion in AD. Our future work will focus on interrogating and validating these novel targets and pathways and their functional significance.
Clinical Significance of Ultrasound-Based Hemodynamic Assessment of Extracranial Internal Carotid Artery and Posterior Cerebral Artery in Symptomatic and Angiographic Evolution of Moyamoya Disease: A Preliminary Study
Authors: Zheng Shuai , Ge Peicong , Shi Zhiyong , Wang Jingzhe , Li Yi , Yu Tengfei , Zhang Jinghan , Zhang Hongxia , Zhang Dong , He Wen
Published: May 2021

Objective: To investigate the hemodynamic changes using ultrasound according to digital subtraction angiography (DSA) findings and explore the association between ultrasound parameters and clinical symptoms of moyamoya disease (MMD).

Methods: Hemodynamic parameters of extracranial internal carotid artery (EICA) and posterior cerebral artery (PCA) were evaluated by ultrasound. According to DSA findings, EICA parameters among Suzuki stages (stage I-II, III-IV, and V-VI), and PCA parameters among leptomeningeal system scores (score 0–2, 3–4, and 5–6) were compared, respectively. ROC analysis was performed based on the ultrasound parameters to distinguish stroke from non-stroke patients.

Results: Forty patients with MMD were included in our study (16 men; median age, 37 years). The diameter (D), peak systolic velocity (PSV), end diastolic velocity (EDV) and flow volume (FV) of EICA decreased as the Suzuki stage advanced (D: P < 0.001; PSV: P < 0.001; EDV: P < 0.001; FV: P < 0.001). The PSV and EDV of PCA increased as the leptomeningeal system scores advanced (PSV: P < 0.001; EDV: P < 0.001). ROC analysis showed that the area under the curves (AUCs) based on the D and FV of EICA, the PSV and EDV of PCA and their combination were 0.688, 0.670, 0.727, 0.684, and 0.772, respectively, to distinguish stroke from non-stroke patients.

Conclusions: Ultrasound parameters were related to Suzuki stages and leptomeningeal system scores. Ultrasound may be useful in predicting the occurrence of stroke in patients with MMD. Future prospective studies with large sample sizes and long-term follow-up are needed to confirm our preliminary findings.
Case Report: An MRI Traumatic Brain Injury Longitudinal Case Study at 7 Tesla: Pre- and Post-injury Structural Network and Volumetric Reorganization and Recovery
Authors: Brown Stephanie S. G. , Dams-O'Connor Kristen , Watson Eric , Balchandani Priti , Feldman Rebecca E.
Published: May 2021

Importance: A significant limitation of many neuroimaging studies examining mild traumatic brain injury (mTBI) is the unavailability of pre-injury data.

Objective: We therefore aimed to utilize pre-injury ultra-high field brain MRI and compare a collection of neuroimaging metrics pre- and post-injury to determine mTBI related changes and evaluate the enhanced sensitivity of high-resolution MRI.

Design: In the present case study, we leveraged multi-modal 7 Tesla MRI data acquired at two timepoints prior to mTBI (23 and 12 months prior to injury), and at two timepoints post-injury (2 weeks and 8 months after injury) to examine how a right parietal bone impact affects gross brain structure, subcortical volumetrics, microstructural order, and connectivity.

Setting: This research was carried out as a case investigation at a single primary care site.

Participants: The case participant was a 38-year-old female selected for inclusion based on a mTBI where a right parietal impact was sustained.

Main outcomes: The main outcome measurements of this investigation were high spatial resolution structural brain metrics including volumetric assessment and connection density of the white matter connectome.

Results: At the first scan timepoint post-injury, the cortical gray matter and cerebral white matter in both hemispheres appeared to be volumetrically reduced compared to the pre-injury and subsequent post-injury scans. Connectomes produced from whole-brain diffusion-weighted probabilistic tractography showed a widespread decrease in connectivity after trauma when comparing mean post-injury and mean pre-injury connection densities. Findings of reduced fractional anisotropy in the cerebral white matter of both hemispheres at post-injury time point 1 supports reduced connection density at a microstructural level. Trauma-related alterations to whole-brain connection density were markedly reduced at the final scan timepoint, consistent with symptom resolution.

Conclusions and Relevance: This case study investigates the structural effects of traumatic brain injury for the first time using pre-injury and post-injury 7 Tesla MRI longitudinal data. We report findings of initial volumetric changes, decreased structural connectivity and reduced microstructural order that appear to return to baseline 8 months post-injury, demonstrating in-depth metrics of physiological recovery. Default mode, salience, occipital, and executive function network alterations reflect patient-reported hypersomnolence, reduced cognitive processing speed and dizziness.
Photoacoustic Mouse Brain Imaging Using an Optical Fabry-Pérot Interferometric Ultrasound Sensor
Authors: Chen Yuwen , Chen Buhua , Yu Tengfei , Yin Lu , Sun Mingjian , He Wen , Ma Cheng
Published: May 2021

Photoacoustic (PA, or optoacoustic, OA) mesoscopy is a powerful tool for mouse cerebral imaging, which offers high resolution three-dimensional (3D) images with optical absorption contrast inside the optically turbid brain. The image quality of a PA mesoscope relies on the ultrasonic transducer which detects the PA signals. An all-optical ultrasound sensor based on a Fabry-Pérot (FP) polymer cavity has the following advantages: broadband frequency response, wide angular coverage and small footprint. Here, we present 3D PA mesoscope for mouse brain imaging using such an optical sensor. A heating laser was used to stabilize the sensor’s cavity length during the imaging process. To acquire data for a 3D angiogram of the mouse brain, the sensor was mounted on a translation stage and raster scanned. 3D images of the mouse brain vasculature were reconstructed which showed cerebrovascular structure up to a depth of 8 mm with high quality. Imaging segmentation and dual wavelength imaging were performed to demonstrate the potential of the system in preclinical brain research.
Genetic Variants of DNA Repair Genes as Predictors of Radiation-Induced Subcutaneous Fibrosis in Oropharyngeal Carcinoma
Authors: Gupta Ankita , Mathew Don , Bhat Shabir Ahmad , Ghoshal Sushmita , Pal Arnab
Published: May 2021

Purpose

To investigate the impact of genetic variants of DNA repair and pro-fibrotic pathway genes on the severity of radiation-induced subcutaneous fibrosis in patients of oropharyngeal carcinoma treated with radical radiotherapy.

Materials and Methods

Patients of newly diagnosed squamous cell carcinoma of oropharynx being treated with two-dimensional radical radiotherapy were enrolled in the study. Patients who had undergone surgery or were receiving concurrent chemotherapy were excluded. Patients were followed up at 6 weeks post completion of radiotherapy and every 3 months thereafter for a median of 16 months. Subcutaneous fibrosis was graded according to the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) grading system and the maximum grade was recorded over the length of the patient’s follow-up. Patients with severe fibrosis (≥G3), were compared to patients with minor (≤G2) fibrotic reactions. Eight single nucleotide polymorphisms of 7 DNA repair genes and 2 polymorphisms of a single pro-fibrotic pathway gene were analyzed by Polymerase Chain Reaction and Restriction Fragment Length Polymorphism and were correlated with the severity of subcutaneous fibrosis.

Results

179 patients were included in the analysis. Subcutaneous fibrosis was seen in 168 (93.9%) patients. 36 (20.1%) patients had severe (grade 3) fibrosis. On multivariate logistic regression analysis, Homozygous CC genotype of XRCC3 (722C>T, rs861539) (p=0.013*, OR 2.350, 95% CI 1.089-5.382), Homozygous AA genotype of ERCC4 Ex8 (1244G>A, rs1800067) (p=0.001**, OR 11.626, 95% CI 2.490-275.901) and Homozygous TT genotype of XRCC5 (1401G>T, rs828907) (p=0.020*, OR 2.188, 95% CI 1.652-7.334) were found to be predictive of severe subcutaneous fibrosis. On haplotype analysis, the cumulative risk of developing severe fibrosis was observed in patients carrying both haplotypes of variant Homozygous AA genotype of ERCC4 Ex8 (1244G>A, rs1800067) and Homozygous TT genotype of XRCC5 (1401 G>T, rs828907) (p=0.010*, OR 26.340, 95% CI 4.014-76.568).

Conclusion

We demonstrated significant associations between single nucleotide polymorphisms of DNA repair genes and radiation-induced subcutaneous fibrosis in patients of oropharyngeal carcinoma treated with radiotherapy. We propose to incorporate these genetic markers into predictive models for identifying patients genetically predisposed to the development of radiation-induced fibrosis, thus guiding personalized treatment protocols.
Rac1, A Potential Target for Tumor Therapy
Authors: Liang Jiaxin , Oyang Linda , Rao Shan , Han Yaqian , Luo Xia , Yi Pin , Lin Jinguan , Xia Longzheng , Hu Jiaqi , Tan Shiming , Tang Lu , Pan Qing , Tang Yanyan , Zhou Yujuan , Liao Qianjin
Published: May 2021

RAS-related C3 botulinum toxin substrate 1 (Rac.1) is one of the important members of Rho GTPases. It is well known that Rac1 is a cytoskeleton regulation protein that regulates cell adhesion, morphology, and movement. Rac1 is highly expressed in different types of tumors, which is related to poor prognosis. Studies have shown that Rac1 not only participates in the tumor cell cycle, apoptosis, proliferation, invasion, migration and angiogenesis, but also participates in the regulation of tumor stem cell, thus promoting the occurrence of tumors. Rac1 also plays a key role in anti-tumor therapy and participates in immune escape mediated by the tumor microenvironment. In addition, the good prospects of Rac1 inhibitors in cancer prevention and treatment are exciting. Therefore, Rac1 is considered as a potential target for the prevention and treatment of cancer. The necessity and importance of Rac1 are obvious, but it still needs further study.
Has COVID-19 Affected Cancer Screening Programs? A Systematic Review
Authors: Alkatout Ibrahim , Biebl Matthias , Momenimovahed Zohre , Giovannucci Edward , Hadavandsiri Fatemeh , Salehiniya Hamid , Allahqoli Leila
Published: May 2021

Background

Health care services across the world have been enormously affected by the onset of the coronavirus disease 2019 (COVID-19). Services in oncology have been curtailed because medical services have been focused on preventing the spread of the virus and maximizing the number of available hospital beds. The present study was designed to investigate the impact of COVID-19 on cancer screening.

Methods

Databases such as Medline, Web of Science Core Collection (Indexes = SCI-EXPANDED, SSCI, A & HCI Timespan) and Scopus were searched comprehensively for articles published until January 2021. The keywords used were COVID-19 and cancer screening, Articles dealing with cancer screening in the COVID-19 pandemic were included in the review.

Results

The review comprised 17 publications. The impact of COVID-19 was categorized into four dimensions: a significant decline in cancer screening and pathology samples, the cancer diagnosis rate, an increase in advanced cancers, mortality rate and years of life lost (YLLs).

Conclusion

Cancer screening programs have been clearly interrupted since the onset of the COVID-19 disease. The anticipated outcomes include delayed diagnosis and marked increases in the numbers of avoidable cancer deaths. Urgent policy interventions are needed to handle the backlog of routine diagnostic services and minimize the harmful effects of the COVID-19 pandemic on cancer patients.
Surgery Plus Chemotherapy Versus Surgery Alone for Limited-Stage Small-Cell Lung Cancer: A Population-Based Survival Outcome Analysis
Authors: Ye Pingting , Guo Zhuolin , Zhang Yanfei , Dong Chunyan , Li Ming
Published: May 2021

Introduction

For patients with limited-stage small-cell lung cancer (LS-SCLC), effective treatment methods still remain a clinical challenge. The aim of this study is to evaluate the survival outcome of surgery plus chemotherapy vs. surgery alone in patients with LS-SCLC.

Methods

LS-SCLC patients selected from the Surveillance, Epidemiology and End Results (SEER) database diagnosed between January 1, 2004, and December 31, 2015. Comparison of overall survival (OS) and cancer-specific survival (CSS) between two groups performed propensity score matching (PSM), inverse probability of treatment weight (IPTW), and overlap weighting analysis.

Results

Of the 477 LS-SCLC patients identified from the SEER database between 2004 and 2015, 262 (54.9%) received surgery-plus-chemotherapy treatment and the others received surgery-alone treatment. Univariate and multivariate analyses showed that treatment option (P< 0.001), tumor location (P= 0.02) and AJCC stage (P< 0.001) were independent prognostic predictors of OS in LS-SCLC patients. Median OS was 35 months in surgery-plus-chemotherapy group vs. 23 months in surgery-alone group. Survival analysis showed that surgery plus chemotherapy offered significantly improved OS as compared with surgery-alone treatment before and after IPTW, PSM and overlap weighting method (all P< 0.05). According to AJCC stage stratification, OS of the unmatched patients with stage I (P= 0.049) and II (P= 0.001) SCLC who received surgery-plus-chemotherapy treatment was significantly better than that of surgery-alone patients.

Conclusions

This cohort study showed that surgery plus chemotherapy was associated with longer survival time than surgery alone in LS-SCLC patients, especially in those with stage I and II SCLC. Further prospective studies are required to confirm our conclusions.
Transcriptional Regulation of Drug Metabolizing CYP Enzymes by Proinflammatory Wnt5A Signaling in Human Coronary Artery Endothelial Cells
Authors: Skaria Tom , Bachli Esther , Schoedon Gabriele
Published: May 2021

Downregulation of drug metabolizing enzymes and transporters by proinflammatory mediators in hepatocytes, enterocytes and renal tubular epithelium is an established mechanism affecting pharmacokinetics. Emerging evidences indicate that vascular endothelial cell expression of drug metabolizing enzymes and transporters may regulate pharmacokinetic pathways in heart to modulate local drug bioavailability and toxicity. However, whether inflammation regulates pharmacokinetic pathways in human cardiac vascular endothelial cells remains largely unknown. The lipid modified protein Wnt5A is emerging as a critical mediator of proinflammatory responses and disease severity in sepsis, hypertension and COVID-19. In the present study, we employed transcriptome profiling and gene ontology analyses to investigate the regulation of expression of drug metabolizing enzymes and transporters by Wnt5A in human coronary artery endothelial cells. Our study shows for the first time that Wnt5A induces the gene expression of CYP1A1 and CYP1B1 enzymes involved in phase I metabolism of a broad spectrum of drugs including chloroquine (the controversial drug for COVID-19) that is known to cause toxicity in myocardium. Further, the upregulation of CYP1A1 and CYP1B1 expression is preserved even during inflammatory crosstalk between Wnt5A and the prototypic proinflammatory IL-1β in human coronary artery endothelial cells. These findings stimulate further studies to test the critical roles of vascular endothelial cell CYP1A1 and CYP1B1, and the potential of vascular-targeted therapy with CYP1A1/CYP1B1 inhibitors in modulating myocardial pharmacokinetics in Wnt5A-associated inflammatory and cardiovascular diseases.
Polypharmacy to Mitigate Acute and Delayed Radiation Syndromes
Authors: Gasperetti Tracy , Miller Tessa , Gao Feng , Narayanan Jayashree , Jacobs Elizabeth R. , Szabo Aniko , Cox George N. , Orschell Christie M. , Fish Brian L. , Medhora Meetha
Published: May 2021

There is a need for countermeasures to mitigate lethal acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE). In WAG/RijCmcr rats, ARS occurs by 30-days following total body irradiation (TBI), and manifests as potentially lethal gastrointestinal (GI) and hematopoietic (H-ARS) toxicities after >12.5 and >7 Gy, respectively. DEARE, which includes potentially lethal lung and kidney injuries, is observed after partial body irradiation >12.5 Gy, with one hind limb shielded (leg-out PBI). The goal of this study is to enhance survival from ARS and DEARE by polypharmacy, since no monotherapy has demonstrated efficacy to mitigate both sets of injuries. For mitigation of ARS following 7.5 Gy TBI, a combination of three hematopoietic growth factors (polyethylene glycol (PEG) human granulocyte colony-stimulating factor (hG-CSF), PEG murine granulocyte-macrophage-CSF (mGM-CSF), and PEG human Interleukin (hIL)-11), which have shown survival efficacy in murine models of H-ARS were tested. This triple combination (TC) enhanced survival by 30-days from ∼25% to >60%. The TC was then combined with proven medical countermeasures for GI-ARS and DEARE, namely enrofloxacin, saline and the angiotensin converting enzyme inhibitor, lisinopril. This combination of ARS and DEARE mitigators improved survival from GI-ARS, H-ARS, and DEARE after 7.5 Gy TBI or 13 Gy PBI. Circulating blood cell recovery as well as lung and kidney function were also improved by TC + lisinopril. Taken together these results demonstrate an efficacious polypharmacy to mitigate radiation-induced ARS and DEARE in rats.
Fecal Microbiota Transplantation is a Promising Switch Therapy for Patients with Prior Failure of Infliximab in Crohn’s Disease
Authors: Li Qianqian , Ding Xiao , Liu Yujie , Marcella Cicilia , Dai Min , Zhang Ting , Bai Jianling , Xiang Liyuan , Wen Quan , Cui Bota , Zhang Faming
Published: May 2021

Background: How to handle patients with anti-tumor necrosis factor (anti-TNF) failure was a common challenge to clinicians in Crohn’s disease (CD). The present study is dedicated to clarifying whether fecal microbiota transplantation (FMT) could be a switch therapy for patients with prior failure of infiiximab (IFX) in CD in a long-term observation.

Methods: Thirty-six patients with CD who had prior failure of IFX were recruited from January 2013 to December 2019. The “one-hour FMT protocol” was followed in all patients. All patients received the first course of FMT through gastroscopy or mid-gut transendoscopic enteral tubing. After April 2014, the methodology of FMT was coined as washed microbiota transplantation (WMT), substituting for the manual methods, which is dependent on the automatic microbiota purification system and the washing process. The primary endpoint of this study was the clinical remission at one month and one year after FMT. The secondary endpoint was the safety of FMT in the short and long term, and clinical factors as predictors for long-term efficacy of FMT. Clinical factors as independent predictors of efficacy from FMT were isolated using univariable and multivariable logistic regression analysis.

Results: There was no significant difference in the rates of clinical response and remission between IFX treatment stage and FMT treatment stage (at one month, three months and six months after administration) (p > 0.05). Compared with those of 19 patients who achieved clinical remission at one month after FMT, the rates of clinical relapse were significantly higher in 18 patients who achieved clinical remission at one month after IFX [log-rank test p = 0.0009 HR = 3.081 (95% CI 1.43–6.639)]. Multivariate analysis revealed that the gender of donor (95% CI: 0.001–0.72; p = 0.031) was an independent predictor of efficacy at one year after FMT. No serious adverse events (AEs) associated with FMT were observed during and after FMT. The rate of AEs was significantly lower in group FMT than that in group IFX (p = 0.002).

Conclusion: The present findings first time provided the evidence for clinicians to consider FMT into practice as an alternative switch therapy for patients with prior loss of response or intolerance to IFX in CD.

Clinical Trial Registration:https://clinicaltrials.gov, identifier NCT01793831
Association Between Chinese Herbal Medicine Therapy and the Risk of Chronic Kidney Disease in Gout Patients
Authors: Xiao Yan-Zhuan , Ye Zhi-Zhong , Liang Yuan-Tong , Chen Xin-Peng , Wang Yu-Hsun , Xu Qiang , Wei James Cheng-Chung
Published: May 2021

Background: Chinese herbal medicine (CHM) has been nationally and globally used in treating gout for over a millennium. The potential relationship between the incidence of chronic kidney disease (CKD) in gout patients and CHM therapy is unclear. Thus, this study aimed to provide some evidence regarding the relationship between CHM therapy and the occurrence of CKD in gout patients.

Methods: We used data from the National Health Insurance Research database (NHIRD) in Taiwan. In this population-based nested case-control study, all participants were identified by International Classification of Diseases, Ninth Revision (ICD-9). Conditional logistic regression was used to calculate the odds ratio (OR) of the risk of CKD in gout patients treated with CHM therapy.

Results: Data on 1718 gout patients with CKD and 1:1 matched 1718 gout patients without CKD were collected for analysis. The results showed that CHM therapy in gout patients did not increase the risk of developing CKD (adjusted OR = 1.01; 95% confidence interval [CI]: 0.86–1.18; p > 0.05). Moreover, CHM therapy in gout patients for >365 days did not increase the incidence of CKD (adjusted OR = 1.30; 95% CI: 0.90–1.88; p = 0.162).

Conclusion: Traditional CHM therapy does not increase the incidence of CKD in gout patients.
The Heat Sensing Trpv1 Receptor Is Not a Viable Anticonvulsant Drug Target in the Scn1a+/− Mouse Model of Dravet Syndrome
Authors: Satpute Janve Vaishali , Anderson Lyndsey L. , Bahceci Dilara , Hawkins Nicole A. , Kearney Jennifer A. , Arnold Jonathon C.
Published: May 2021

Cannabidiol has been approved for the treatment of drug-resistant childhood epilepsies including Dravet syndrome (DS). Although the mechanism of anticonvulsant action of cannabidiol is unknown, emerging data suggests involvement of the transient receptor potential cation channel subfamily V member 1 (Trpv1). Pharmacological and genetic studies in conventional seizure models suggest Trpv1 is a novel anticonvulsant target. However, whether targeting Trpv1 is anticonvulsant in animal models of drug-resistant epilepsies is not known. Thus, we examined whether Trpv1 affects the epilepsy phenotype of the F1.Scn1a+/−mouse model of DS. We found that corticalTrpv1mRNA expression was increased in seizure susceptible F1.Scn1a+/−mice with a hybrid genetic background compared to seizure resistant 129.Scn1a+/−mice isogenic on 129S6/SvEvTac background, suggestingTrpv1could be a genetic modifier. Previous studies show functional loss of Trpv1 is anticonvulsant. However, Trpv1 selective antagonist SB-705498 did not affect hyperthermia-induced seizure threshold, frequency of spontaneous seizures or survival of F1.Scn1a+/−mice. Surprisingly,Trpv1deletion had both pro- and anti-seizure effects.Trpv1deletion did not affect hyperthermia-induced seizure temperature thresholds of F1.Scn1a+/−;Trpv1+/−at P14-16 but was proconvulsant at P18 as it reduced seizure temperature thresholds. Conversely,Trpv1deletion did not alter the frequency of spontaneous seizures but reduced their severity. These results suggest thatTrpv1is a modest genetic modifier of spontaneous seizure severity in the F1.Scn1a+/−model of DS. However, the opposing pro- and anti-seizure effects ofTrpv1deletion and the lack of effects of Trpv1 inhibition suggest that Trpv1 is unlikely a viable anticonvulsant drug target in DS.
Identification of an Alternative Glycyrrhizin Metabolite Causing Liquorice-Induced Pseudohyperaldosteronism and the Development of ELISA System to Detect the Predictive Biomarker
Authors: Ishiuchi Kan'ichiro , Morinaga Osamu , Yoshino Tetsuhiro , Mitamura Miaki , Hirasawa Asuka , Maki Yasuhito , Tashita Yuuna , Kondo Tsubasa , Ogawa Kakuyou , Lian Fangyi , Ogawa-Ochiai Keiko , Minamizawa Kiyoshi , Namiki Takao , Mimura Masaru , Watanabe Kenji , Makino Toshiaki
Published: May 2021

Liquorice is usually used as crude drug in traditional Japanese Kampo medicine and traditional Chinese medicine. Liquorice-containing glycyrrhizin (GL) can cause pseudohyperaldosteronism as a side effect. Previously, we identified 18β-glycyrrhetyl-3-O-sulfate (3) as a GL metabolite in Eisai hyperbilirubinuria rats (EHBRs) with the dysfunction of multidrug resistance-related protein (Mrp2). We speculated that 3 was associated with the onset of liquorice-induced pseudohyperaldosteronism, because it was mainly detected in serum of patients with suspected to have this condition. However, it is predicted that other metabolites might exist in the urine of EHBRs orally treated with glycyrrhetinic acid (GA). We explored other metabolites in the urine of EHBRs, and investigated the pharmacokinetic profiles of the new metabolite in EHBRs and normal Sprague-Dawley rats. We further analyzed the serum concentrations of the new metabolite in the patients of pseudohyperaldosteronism. Finally, we developed the analyzing method of these metabolites as a preventive biomarker for the onset of pseudohyperaldosteronism using an enzyme-linked immunosorbent assay (ELISA). We isolated a new GL metabolite, 18β-glycyrrhetyl-3-O-sulfate-30-O-glucuronide (4). Compound 4 significantly inhibited rat type-2 11β-hydroxysteroid dehydrogenase (11β-HSD2) and was a substrate of both organic anion transporter (OAT) 1 and OAT3. Compound 4 was also detected in the serum of patients with suspected pseudohyperaldosteronism at an approximately 10-fold lower concentrations than 3, and these concentrations were positively correlated. Compound 4 showed a lower serum concentration and weaker inhibitory titer on 11β-HSD2 than 3. We developed an enzyme-linked immunosorbent assay system using an anti-18β-glycyrrhetyl-3-O-glucuronide (3MGA) monoclonal antibody to measure the serum concentration of 3 to facilitate the measurement of biomarkers to predict the onset of pseudohyperaldosteronism. Although we found 4 as the secondary candidate causative agent, 3 could be the main potent preventive biomarker of liquorice-induced pseudohyperaldosteronism. Compound 3 was detected in serum at a higher concentration than GA and 4, implying that 3 may be a pharmacologically active ingredient mediating not only the development of pseudohyperaldosteronism but anti-inflammatory effects in humans administered GL or other liquorice-containing preparations.
The Role of Tumor Inflammatory Microenvironment in Lung Cancer
Authors: Tan Zhaofeng , Xue Haibin , Sun Yuli , Zhang Chuanlong , Song Yonglei , Qi Yuanfu
Published: May 2021

Lung cancer is the most common and fatal malignant tumor in the world. The tumor microenvironment (TME) is closely related to the occurrence and development of lung cancer, in which the inflammatory microenvironment plays an important role. Inflammatory cells and inflammatory factors in the tumor inflammatory microenvironment promote the activation of the NF-κB and STAT3 inflammatory pathways and the occurrence, development, and metastasis of lung cancer by promoting immune escape, tumor angiogenesis, epithelial–mesenchymal transition, apoptosis, and other mechanisms. Clinical and epidemiological studies have also shown a strong relationship among chronic infection, inflammation, inflammatory microenvironment, and lung cancer. The relationship between inflammation and lung cancer can be better understood through the gradual understanding of the tumor inflammatory microenvironment, which is advantageous to find more therapeutic targets for lung cancer.
Hypoxic Hypoxia and Brain Function in Military Aviation: Basic Physiology and Applied Perspectives
Authors: Shaw David M. , Cabre Gus , Gant Nicholas
Published: May 2021

Acute hypobaric hypoxia (HH) is a major physiological threat during high-altitude flight and operations. In military aviation, although hypoxia-related fatalities are rare, incidences are common and are likely underreported. Hypoxia is a reduction in oxygen availability, which can impair brain function and performance of operational and safety-critical tasks. HH occurs at high altitude, due to the reduction in atmospheric oxygen pressure. This physiological state is also partially simulated in normobaric environments for training and research, by reducing the fraction of inspired oxygen to achieve comparable tissue oxygen saturation [normobaric hypoxia (NH)]. Hypoxia can occur in susceptible individuals below 10,000 ft (3,048 m) in unpressurised aircrafts and at higher altitudes in pressurised environments when life support systems malfunction or due to improper equipment use. Between 10,000 ft and 15,000 ft (4,572 m), brain function is mildly impaired and hypoxic symptoms are common, although both are often difficult to accurately quantify, which may partly be due to the effects of hypocapnia. Above 15,000 ft, brain function exponentially deteriorates with increasing altitude until loss of consciousness. The period of effective and safe performance of operational tasks following exposure to hypoxia is termed the time-of-useful-consciousness (TUC). Recovery of brain function following hypoxia may also lag beyond arterial reoxygenation and could be exacerbated by repeated hypoxic exposures or hyperoxic recovery. This review provides an overview of the basic physiology and implications of hypoxia for military aviation and discusses the utility of hypoxia recognition training.
Prolonged Elevation of Arterial Stiffness Following Peak Aerobic Exercise in Individuals With Chronic Stroke
Authors: Noguchi Kenneth S. , Moncion Kevin , Wiley Elise , MacDonald Maureen J. , Richardson Julie , Roig Marc , Tang Ada
Published: May 2021

Background

Stroke is a highly disabling condition and is the second leading cause of death globally. Engaging in aerobic exercise is important for the prevention of a recurrent stroke through improving markers of cardiovascular health such as blood pressure and arterial stiffness. While higher intensities of aerobic exercise generally elicit greater cardioprotective effects, little is known about the acute cardiovascular effects of a single session of high intensity aerobic exercise in people with stroke. The objective of this study was to model the recovery of arterial stiffness (carotid-femoral pulse wave velocity, cfPWV), heart rate and blood pressure following peak intensity aerobic exercise in individuals with chronic stroke.

Methods

Ten participants with chronic stroke (mean ± SD age = 56.9 ± 11.8 years, median [IQR] years post-stroke = 2.9 [1.9]) performed a symptom-limited cardiopulmonary exercise test (CPET) on a recumbent stepper. Before the CPET, resting cfPWV, heart rate and blood pressure were measured. Immediately following the CPET, all outcomes were measured again continuously for 20 min to use all available observations (n = 245 observations) and capture any potential non-linear changes. Mixed model analyses were then applied to model post-exercise changes of cfPWV, heart rate and blood pressure.

Results

Carotid-femoral pulse wave velocity was increased from rest following the CPET (9.0 ± 0.53 to 9.9 ± 0.52 m/s, p < 0.001) and remained elevated for 20 min into post-exercise recovery, independent of heart rate (p = 0.001). Heart rate also increased from baseline (71.2 ± 3.2 to 77.4 ± 3.1 bpm, p < 0.001) and remained elevated for 10 min post-exercise (p < 0.001). Finger systolic blood pressure was reduced from rest (117.3 ± 4.7 to 111.8 ± 4.6 mmHg, p < 0.001) and remained reduced for 15 min after exercise (p < 0.001). There were no significant differences in finger diastolic or mean arterial pressures from rest.

Conclusion

This was the first study to capture continuous changes in cfPWV following peak aerobic exercise in any clinical population. The present study revealed that cfPWV is elevated for 20 min after peak aerobic exercise in individuals with stroke, which was independent of heart rate. These findings suggest there may be autonomic imbalances in large arteries following peak intensity aerobic exercise in individuals with stroke.
Histone Deacetylase 5 Is an Early Epigenetic Regulator of Intermittent Hypoxia Induced Sympathetic Nerve Activation and Blood Pressure
Authors: Wang Ning , Peng Ying-Jie , Su Xiaoyu , Prabhakar Nanduri R. , Nanduri Jayasri
Published: May 2021

Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA). Long term IH (LT-IH) triggers epigenetic reprogramming of the redox state involving DNA hypermethylation in the carotid body chemo reflex pathway resulting in persistent sympathetic activation and hypertension. Present study examined whether IH also activates epigenetic mechanism(s) other than DNA methylation. Histone modification by lysine acetylation is another major epigenetic mechanism associated with gene regulation. Equilibrium between the activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs) determine the level of lysine acetylation. Here we report that exposure of rat pheochromocytoma (PC)-12 cells to IH in vitro exhibited reduced HDAC enzyme activity due to proteasomal degradation of HDAC3 and HDAC5 proteins. Mechanistic investigations showed that IH-evoked decrease in HDAC activity increases lysine acetylation of α subunit of hypoxia inducible factor (HIF)-1α as well as Histone (H3) protein resulting in increased HIF-1 transcriptional activity. Trichostatin A (TSA), an inhibitor of HDACs, mimicked the effects of IH. Studies on rats treated with 10 days of IH or TSA showed reduced HDAC activity, HDAC5 protein, and increased HIF-1 dependent NADPH oxidase (NOX)-4 transcription in adrenal medullae (AM) resulting in elevated plasma catecholamines and blood pressure. Likewise, heme oxygenase (HO)-2 null mice, which exhibit IH because of high incidence of spontaneous apneas (apnea index 72 ± 1.2 apnea/h), also showed decreased HDAC activity and HDAC5 protein in the AM along with elevated circulating norepinephrine levels. These findings demonstrate that lysine acetylation of histone and non-histone proteins is an early epigenetic mechanism associated with sympathetic nerve activation and hypertension in rodent models of IH.
Genome-Wide Analysis of the DUF4228 Family in Soybean and Functional Identification of GmDUF4228–70 in Response to Drought and Salt Stresses
Authors: Leng Zhi-Xin , Liu Ying , Chen Zhan-Yu , Guo Jun , Chen Jun , Zhou Yong-Bin , Chen Ming , Ma You-Zhi , Xu Zhao-Shi , Cui Xi-Yan
Published: May 2021

Domain of unknown function 4228 (DUF4228) proteins are a class of proteins widely found in plants, playing an important role in response to abiotic stresses. However, studies on the DUF4228 family in soybean (Glycine max L.) are sparse. In this study, we identified a total of 81 DUF4228 genes in soybean genome, named systematically based on their chromosome distributions. Results showed that these genes were unevenly distributed on the 20 chromosomes of soybean. The predicted soybean DUF4228 proteins were identified in three groups (Groups I–III) based on a maximum likelihood phylogenetic tree. Genetic structure analysis showed that most of the GmDUF4228 genes contained no introns. Expression profiling showed that GmDUF4228 genes were widely expressed in different organs and tissues in soybean. RNA-seq data were used to characterize the expression profiles of GmDUF4228 genes under the treatments of drought and salt stresses, with nine genes showing significant up-regulation under both drought and salt stress further functionally verified by promoter (cis-acting elements) analysis and quantitative real-time PCR (qRT-PCR). Due to its upregulation under drought and salt stresses based on both RNA-seq and qRT-PCR analyses, GmDUF4228-70 was selected for further functional analysis in transgenic plants. Under drought stress, the degree of leaf curling and wilting of the GmDUF4228-70-overexpressing (GmDUF4228-70-OE) line was lower than that of the empty vector (EV) line. GmDUF4228-70-OE lines also showed increased proline content, relative water content (RWC), and chlorophyll content, and decreased contents of malondialdehyde (MDA), H2O2, and O2–. Under salt stress, the changes in phenotypic and physiological indicators of transgenic plants were the same as those under drought stress. In addition, overexpression of the GmDUF4228-70 gene promoted the expression of marker genes under both drought and salt stresses. Taken together, the results indicated that GmDUF4228 genes play important roles in response to abiotic stresses in soybean.
ThCOL2 Improves the Salt Stress Tolerance of Tamarix hispida
Authors: Lei Xiaojin , Tan Bing , Liu Zhongyuan , Wu Jing , Lv Jiaxin , Gao Caiqiu
Published: May 2021

The CONSTANS-LIKE (COL) transcription factor has been reported to play important roles in regulating plant flowering and the response to abiotic stress. To clone and screen COL genes with excellent salt tolerance from the woody halophyte Tamarix hispida, 8 ThCOL genes were identified in this study. The expression patterns of these genes under different abiotic stresses (high salt, osmotic, and heavy metal) and abscisic acid (ABA) treatment were detected using quantitative real-time PCR (qRT-PCR). The expression levels of 8 ThCOL genes changed significantly after exposure to one or more stresses, indicating that these genes were all stress-responsive genes and may be involved in the stress resistance response of T. hispida. In particular, the expression level of ThCOL2 changed significantly at most time points in the roots and leaves of T. hispida under salt stress and after ABA treatments, which may play an important role in the response process of salt stress through a mechanism dependent on the ABA pathway. The recombinant vectors pROKII–ThCOL2 and pFGC5941–ThCOL2 were constructed for the transient transformation of T. hispida, and the transient infection of T. hispida with the pROKII empty vector was used as the control to further verify whether the ThCOL2 gene was involved in the regulation of the salt tolerance response of T. hispida. Overexpression of the ThCOL2 gene in plants under 150 mM NaCl stress increased the ability of transgenic T. hispida cells to remove reactive oxygen species (ROS) by regulating the activity of protective enzymes and promoting a decrease in the accumulation of O2– and H2O2, thereby reducing cell damage or cell death and enhancing salt tolerance. The ThCOL2 gene may be a candidate gene associated with excellent salt tolerance. Furthermore, the expression levels of some genes related to the ABA pathway were analyzed using qRT-PCR. The results showed that the expressions of ThNCED1 and ThNCED4 were significantly higher, and the expressions of ThNCED3, ThZEP, and ThAAO3 were not significantly altered in OE compared with CON under normal conditions. But after 24 h of salt stress, the expressions of all five studied genes all were lower than the normal condition. In the future, the downstream genes directly regulated by the ThCOL2 transcription factor will be searched and identified to analyze the salt tolerance regulatory network of ThCOL2.
COVID-19 in Italy: Performing Power and Emotions
Authors: De Blasio Emiliana , Selva Donatella
Published: May 2021

The article charts the notion of statehood emerging from the COVID-19 pandemic, considering the emotional repertoire and the themes addressed in the government’s crisis communication. The conception and performance of statehood and power in Italy during the COVID-19 emergency rely on four interrelated nodal points: (1) the state’s relationship to citizens, (2) the state’s relationship to regions and local governments, (3) the state’s relationship to politics and the Italian parliament, and (4) the state within international sphere. For each of those nodal points, we have analyzed relevant themes and rhetorical devices following a discourse-historical approach (DHA). Specific efforts have been made to identify the emotional repertoire mobilized by the Italian government in its communication. In the interplay between the dramatic context of crisis and an enduring trend toward the personalization of the government’s leadership, the source of legitimacy has shifted from traditional democratic procedures to the use of emotional capital. The analysis of the Italian government’s communication reveals the features of the emotional capital used during the pandemic, like the ability to display empathy toward citizens’ sufferings, the will to engage in dialog with social stakeholders, confidence in expertise, and the pride and determination to negotiate within the EU. The article concludes that the performance of the prime minister in expressing his emotional states has nurtured the conception of post-COVID statehood, consolidating his individual leadership and flawing the spaces of political conflict.
Reducing Implicit Cognitive Biases Through the Performing Arts
Authors: García-Arch Josué , Ventura-Gabarró Cèlia , Adamuz Pedro Lorente , Calvo Pep Gatell , Fuentemilla Lluís
Published: May 2021

The aim of the present research was to test whether involvement in a 14-days training program in the performing arts could reduce implicit biases. We asked healthy participants to complete an Implicit Association Test (IAT) to assess biased attitudes to physical illness in two separate sessions, before and after the training program. Two separate control groups matched by age, gender and educational level completed the two IAT sessions, separated by same number of days, without being involved in the training program. Results showed that participants who were involved in the training program reduced their implicit bias toward illness measured through IAT in the second session. This reduction in IAT measures was not observed in the control samples, despite the two IAT measures being matched in temporal delay with the experimental group. These findings suggest that an interventional program based on the performing arts could be effective in reducing levels of implicit biases among the general population.
Mirror Self-Recognition in Pigeons: Beyond the Pass-or-Fail Criterion
Authors: Wittek Neslihan , Matsui Hiroshi , Kessel Nicole , Oeksuez Fatma , Güntürkün Onur , Anselme Patrick
Published: May 2021

Spontaneous mirror self-recognition is achieved by only a limited number of species, suggesting a sharp “cognitive Rubicon” that only few can pass. But is the demarcation line that sharp? In studies on monkeys, who do not recognize themselves in a mirror, animals can make a difference between their mirror image and an unknown conspecific. This evidence speaks for a gradualist view of mirror self-recognition. We hypothesize that such a gradual process possibly consists of at least two independent aptitudes, the ability to detect synchronicity between self- and foreign movement and the cognitive understanding that the mirror reflection is oneself. Pigeons are known to achieve the first but fail at the second aptitude. We therefore expected them to treat their mirror image differently from an unknown pigeon, without being able to understand that the mirror reflects their own image. We tested pigeons in a task where they either approached a mirror or a Plexiglas barrier to feed. Behind the Plexiglas an unknown pigeon walked at the same time toward the food bowl. Thus, we pitched a condition with a mirror-self and a foreign bird against each other, with both of them walking close toward the food bowl. By a detailed analysis of a whole suit of behavioral details, our results make it likely that the foreign pigeon was treated as a competitor while the mirror image caused hesitation as if being an uncanny conspecific. Our results are akin to those with monkeys and show that pigeons do not equal their mirror reflection with a conspecific, although being unable to recognize themselves in the mirror.