bluuebunny/crossref_metadata_2025 huggingface dataset:
Abraham Gazed upon the Stars and Said ‘innī saqīm’: The Influence of a ṣaḥīḥ ḥadīth on the Interpretation of Q. 37:88–89, and a Thematic and Structural Reading of Abraham's Story in the Qur'an
Authors: Mustafa Alsulaimi Nadeen
Published: July 2021

Historically mufassirs have disagreed on the meaning of the words innī saqīm spoken by Abraham as he gazed upon the stars in Q. 37:88–89. This lack of consensus can be traced back to the existence of a ṣaḥīḥ ḥadīth concerning the three lies that Abraham is said to have spoken in his lifetime. Some exegetes have attempted to reconcile the Qur'anic verses with this ḥadīth by emphasising Abraham's integrity and truthfulness and his use of white lies ( al-maʿārīḍ), while others have ignored the ḥadīth and instead rely on a contextual reading. This article analyses the meaning of Q. 37:88–89, and also explores the other suras that reference this narrative (Q. 6, Q. 21, and Q. 26). To do this it will utilise ring theory ( naẓariyyat al-tanāẓur) and exegesis of the Qur'an by the Qur'an ( tafsīr al-Qurʾān bi'l-Qurʾān), as well as the concept of the interconnectedness of Q. 37 and Q. 38 (inasmuch as these two consecutive suras both elaborate on the attributes of Abraham), so as to explore how this approach influences our understanding of this narrative. It will posit that the reference to ‘gazing upon the stars’ in Q. 37 is not synonymous with the reference to ‘looking at the planets’ in Q. 6, and that Abraham's people were well aware of his belief in God, and consequently did not correlate his gazing at the stars with belief in them. The study concludes that a contextual reading of the sura indicates that first, the phrase innī saqīm in Q. 37:88 connotes ‘contemplation’; second, the ‘sickness’ mentioned in Q. 37:89 denotes sickness of the body and mind, and that Q. 21 and Q. 26 affirm that Abraham's people understood it as such; and finally, that Q. 38 confirms the strength of Abraham's argument.
Clinical cases of difficulty in interpreting the results of 24 hour blood pressure monitoring in men of military age
Authors: Cherniаkova A. Yu.
Published: July 2021

The article describes 2 clinical cases with signs of deliberate manipulation by patients of the results of ambulatory BP monitoring, leading to an increase of mean blood pressure. Such findings, as experience shows, are often revealed in men of military age. The value of additional recording channels, such as ECG, physical activity and body position, rheopneumogram, for an objective assessment of such findings is shown. The main factors that can lead to an increase in blood pressure during ABPM are listed. Conclusion examples for describing such changes are given.
Figurative comparisons and eponims in functional diagnostics. Part 4. Other methods of functional diagnostic
Authors: Zaikina M. P. , Zaikina N. V.
Published: July 2021

This article is the fourth of a series of materials that tell about figurative comparisons and eponyms in modern functional diagnostics. Daily ECG monitoring, ECG treadmill test, daily blood pressure monitoring, spirometry, cardiorespiratory monitoring were considered. The names of great scientists who have made a great contribution to the history of medicine are given: Holter, Bruce — ‘father of the cardiology of exercises’, Tiffeneau, Gensler. Figurative comparisons like ‘electric storm’, ‘white coat hypertension’, ‘shark’s tooth’, ‘fat guy ‘Joe’ are described. The terms that will be discussed in the article have not only scientific, but also applied meaning. The article will be useful and interesting to students of medical universities, residents and doctors, whom it will help to check and, possibly, update their knowledge.
PENDIDIKAN KARAKTER ANAK USIA DINI MODEL BEYOND CENTRE AND CIRCLE TIME
Authors: Alfianti Nurlia , Shofa Lubis Nada
Published: July 2021

This study aims to analyze early childhood character education through the Beyond Center and Circle Time model. This research is in the form of a literature review, carried out by collecting and analyzing data in the form of books; journal; website; articles and the Law of the Republic of Indonesia relating to the center learning model for early childhood character education. Meanwhile, the analysis of these data is carried out by using the content analysis method. The results showed that character education could be carried out appropriately through the center learning model (BCCT). This can be seen from the center learning process that emphasizes character values.
Orally Administrable Therapeutic Nanoparticles for the Treatment of Colorectal Cancer
Authors: Ying Kangkang , Bai Bingjun , Gao Xing , Xu Yuzi , Wang Hangxiang , Xie Binbin
Published: July 2021

Colorectal cancer (CRC) is one of the most common and lethal human malignancies worldwide; however, the therapeutic outcomes in the clinic still are unsatisfactory due to the lack of effective and safe therapeutic regimens. Orally administrable and CRC-targetable drug delivery is an attractive approach for CRC therapy as it improves the efficacy by local drug delivery and reduces systemic toxicity. Currently, chemotherapy remains the mainstay modality for CRC therapy; however, most of chemo drugs have low water solubility and are unstable in the gastrointestinal tract (GIT), poor intestinal permeability, and are susceptible to P-glycoprotein (P-gp) efflux, resulting in limited therapeutic outcomes. Orally administrable nanoformulations hold the great potential for improving the bioavailability of poorly permeable and poorly soluble therapeutics, but there are still limitations associated with these regimes. This review focuses on the barriers for oral drug delivery and various oral therapeutic nanoparticles for the management of CRC.
Alpha-Synuclein Pathology Coincides With Increased Number of Early Stage Neural Progenitors in the Adult Hippocampus
Authors: Bender Hannah , Fietz Simone A. , Richter Franziska , Stanojlovic Milos
Published: July 2021

Alpha-synuclein pathology driven impairment in adult neurogenesis was proposed as a potential cause of, or at least contributor to, memory impairment observed in both patients and animal models of Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB). Mice overexpressing wild-type alpha-synuclein under the Thy-1 promoter (Thy1-aSyn, line 61) uniquely replicate early cognitive deficits together with multiple other characteristic motor and non-motor symptoms, alpha-synuclein pathology and dopamine loss. Here we report overt intracellular accumulation of phosphorylated alpha-synuclein in the hippocampus of these transgenic mice. To test whether this alters adult neurogenesis and total number of mature neurons, we employed immunohistochemistry and an unbiased stereology approach to quantify the distinct neural progenitor cells and neurons in the hippocampal granule cell layer and subgranular zone of 6 (prodromal stage) and 16-month (dopamine loss) old Thy1-aSyn mice. Surprisingly, we observed an increase in the number of early stage, i.e., Pax6 expressing, progenitors whereas the numbers of late stage, i.e., Tbr2 expressing, progenitors and neurons were not altered. Astroglia marker was increased in the hippocampus of transgenic mice, but this was not specific to the regions where adult neurogenesis takes place, arguing against a commitment of additional early stage progenitors to the astroglia lineage. Together, this uncovers a novel aspect of alpha-synuclein pathology in adult neurogenesis. Studying its mechanisms in Thy1-aSyn mice could lead to discovery of effective therapeutic interventions for cognitive dysfunction in PD and DLB.
α-Synuclein: An All-Inclusive Trip Around its Structure, Influencing Factors and Applied Techniques
Authors: Bisi Nicolò , Feni Lucia , Peqini Kaliroi , Pérez-Peña Helena , Ongeri Sandrine , Pieraccini Stefano , Pellegrino Sara
Published: July 2021

Alpha-synuclein (αSyn) is a highly expressed and conserved protein, typically found in the presynaptic terminals of neurons. The misfolding and aggregation of αSyn into amyloid fibrils is a pathogenic hallmark of several neurodegenerative diseases called synucleinopathies, such as Parkinson’s disease. Since αSyn is an Intrinsically Disordered Protein, the characterization of its structure remains very challenging. Moreover, the mechanisms by which the structural conversion of monomeric αSyn into oligomers and finally into fibrils takes place is still far to be completely understood. Over the years, various studies have provided insights into the possible pathways that αSyn could follow to misfold and acquire oligomeric and fibrillar forms. In addition, it has been observed that αSyn structure can be influenced by different parameters, such as mutations in its sequence, the biological environment (e.g., lipids, endogenous small molecules and proteins), the interaction with exogenous compounds (e.g., drugs, diet components, heavy metals). Herein, we review the structural features of αSyn (wild-type and disease-mutated) that have been elucidated up to present by both experimental and computational techniques in different environmental and biological conditions. We believe that this gathering of current knowledge will further facilitate studies on αSyn, helping the planning of future experiments on the interactions of this protein with targeting molecules especially taking into consideration the environmental conditions.
Functional Polymorphisms in the p53 Pathway Genes on the Genetic Susceptibility to Zika Virus Teratogenesis
Authors: Gomes Julia A. , Sgarioni Eduarda , Vieira Igor A. , Fraga Lucas R. , Ashton-Prolla Patrícia , Terças-Tretell Ana Cláudia P. , da Silva Juliana H. , Ribeiro Bethânia F.R. , Galera Marcial F. , de Oliveira Thalita M. , Carvalho de Andrade Maria Denise F. , Carvalho Isabella F. , Schuler-Faccini Lavínia , Vianna Fernanda S. L.
Published: July 2021

Congenital Zika Syndrome (CZS) occurs in up to 42% of individuals exposed to ZIKV prenatally. Deregulation in gene expression and protein levels of components of the p53 signaling pathway, such as p53 and MDM2, due to ZIKV infection has been reported. Here, we evaluate functional polymorphisms in genes of the p53 signaling pathway as risk factors to CZS. Forty children born with CZS and forty-eight children exposed to ZIKV, but born without congenital anomalies were included in this study. Gestational and sociodemographic information as well as the genotypic and allelic frequencies of functional polymorphisms in TP53, MDM2, MIR605 and LIF genes were compared between the two groups. We found children with CZS exposed predominantly in the first trimester and controls in the third trimester (p<0.001). Moreover, children with CZS were predominantly from families with a lower socioeconomic level (p=0.008). We did not find a statistically significant association between the investigated polymorphisms and development of CZS; however, by comparing individuals with CZS and lissencephaly or without lissencephaly, we found a significative difference in the allelic frequencies of the TP53 rs1042522, which is associated with a more potent p53-induced apoptosis (p=0.007). Our findings suggest that the TP53 rs1042522 polymorphism should be better investigate as a genetic risk factor for the development of lissencephaly in children with CZS.
Comparing SARS-CoV-2 Testing in Anterior Nasal Vestibular Swabs vs. Oropharyngeal Swabs
Authors: Li Meiyan , Wei Ruoyan , Yang Yaling , He Taiwen , Shen Yinzhong , Qi Tangkai , Han Tian , Song Zhigang , Zhu Zhaoqin , Ma Xiaopeng , Lin Yixiao , Yuan Yasheng , Zhao Keqing , Lu Hongzhou , Zhou Xingtao
Published: July 2021

Purpose

To investigate the sensitivity of SARS-CoV-2 testing in specimens collected from the anterior nasal vestibules of COVID-19 patients.

Methods

A cross-sectional analysis was performed on 30 patients with a confirmed diagnosis of COVID-19 at the Shanghai Public Health Clinical Center from March 14, 2020 to March 21, 2020. Paired specimens were collected from both the anterior nasal vestibule and the oropharynx from all patients. All specimens were tested for SARS-CoV-2 using reverse transcription-polymerase chain reaction (RT-PCR) assays.

Results

Of the 30 patients with confirmed COVID-19, 17 patients (56.7%) tested positive for SARS-CoV-2 when oropharyngeal specimens were used, while 20 patients (66.7%) tested positive when nasal swab specimens were used. There was no statistically significant difference in sensitivity between the two methods.

Conclusions

Respiratory swabs collected from the nasal vestibule offer a less invasive alternative to oropharyngeal swabs for specimen collection in the detection of SARS-CoV-2 infection, and have adequate sensitivity.
From Readership to Usership: Communicating Heritage Digitally Through Presence, Embodiment and Aesthetic Experience
Authors: Bertrand Stéphanie , Vassiliadi Martha , Zikas Paul , Geronikolakis Efstratios , Papagiannakis George
Published: July 2021

The primary mission of cultural institutions, including heritage sites and museums, is to perform and perpetuate Cultural Heritage (CH) by ideally transforming audiences into stewards of that heritage. In recent years, these institutions have increasingly turned to Mixed Reality (MR) technologies to expand and democratize public access to Cultural Heritage—a trend that is called upon to accelerate with COVID-19—because these technologies provide opportunities for more remote outreach, and moreover, can make partial remains or ruins more relatable to the public. But as emerging evaluations indicate, existing MR intangible and tangible Digital Cultural Heritage (DCH) applications are largely proving inadequate to engaging audiences beyond an initial fascination with the immersive 3D visualization of heritage sites and artefacts owing in part to misguided storytelling or non-compelling narratives. They fail to effectively communicate the significance of Cultural Heritage to audiences and impress upon them its value in a lasting way due to their overreliance on an education-entertainment-touristic consumption paradigm. Building on the recent case made for Literature-based MR Presence, this article examines how the literary tradition of travel narratives can be recruited to enhance presence and embodiment, and further elicit aesthetic experiences in Digital Cultural Heritage applications by drawing on recent findings from the fields of Extended Reality (XR), cognitive literary science and new museology. The projected effects of this innovative approach are not limited to an increase in audience engagement on account of a greater sense of presence and embodiment. This approach is also expected to prompt a different kind of public involvement characterized by a personal valuation of the heritage owing to aesthetic experience. As the paper ultimately discusses, this response is more compatible both with MR applications’ default mode of usership, and with newly emerging conceptions of a user-centered museum (e.g., the Museum 3.0), thereby providing a narrative roadmap for future Virtual Museum (VM) applications better suited to the primary mission of transmitting and perpetuating Cultural Heritage.
Risk Factors of Pulmonary Arterial Hypertension and Its Relationship With Atrial Fibrillation in Patients With Obstructive Hypertrophic Cardiomyopathy
Authors: Nie Changrong , Zhu Changsheng , Xiao Minghu , Lu Zhengyang , Yang Qiulan , Meng Yanhai , Wu Rong , Wang Shuiyun
Published: July 2021

Background: Pulmonary arterial hypertension (PH) is a common complication in patients with obstructive hypertrophic cardiomyopathy (OHCM). The risk factor of PH in patients with OHCM has not been fully elucidated, and even atrial fibrillation (AF) was considered a risk factor of PH. Thus, our study aimed to investigate risk factors of PH and the relationship between PH and AF in patients with OHCM.

Methods: We retrospectively enrolled 483 consecutive patients diagnosed with OHCM at Fuwai Hospital (Beijing, China) from January 2015 to December 2017. Clinical and echocardiographic parameters were compared between patients with and without PH.

Results: Eighty-two (17.0%) patients were diagnosed with PH in this study. Compared to patients without PH, those with PH were significantly older, had a lower body mass index (BMI), were more likely to be female and more symptomatic [New York Heart Association Class 3 or 4 symptoms], and had a higher AF prevalence. A multivariate analysis indicated that AF was an independent risk factor of PH (odds ratio [OR] 2.31, 95% confidence interval [CI] 1.03–5.20, p = 0.042). Moreover, PH was independently associated with a higher AF incidence after adjusting for age and left atrial diameter (OR 2.24, 95% CI 1.07–4.72, p = 0.034).

Conclusion: AF was independently associated with PH in patients with OHCM. Further, PH was significantly associated with an increased risk of AF, which suggested that AF could aggravate PH and that PH may promote AF processes, forming a vicious circle.
Haplotypic Associations and Differentiation of MHC Class II Polymorphic Alu Insertions at Five Loci With HLA-DRB1 Alleles in 12 Minority Ethnic Populations in China
Authors: Cun Yina , Shi Lei , Kulski Jerzy K. , Liu Shuyuan , Yang Jia , Tao Yufen , Zhang Xinwen , Shi Li , Yao Yufeng
Published: July 2021

The analysis of polymorphic variations in the human major histocompatibility complex (MHC) class II genomic region on the short-arm of chromosome 6 is a scientific enquiry to better understand the diversity in population structure and the effects of evolutionary processes such as recombination, mutation, genetic drift, demographic history, and natural selection. In order to investigate associations between the polymorphisms of HLA-DRB1 gene and recent Alu insertions (POALINs) in the HLA class II region, we genotyped HLA-DRB1 and five Alu loci (AluDPB2, AluDQA2, AluDQA1, AluDRB1, AluORF10), and determined their allele frequencies and haplotypic associations in 12 minority ethnic populations in China. There were 42 different HLA-DRB1 alleles for ethnic Chinese ranging from 12 alleles in the Jinuo to 28 in the Yugur with only DRB1∗08:03, DRB1∗09:01, DRB1∗12:02, DRB1∗14:01, DRB1∗15:01, and DRB1∗15:02 present in all ethnic groups. The POALINs varied in frequency between 0.279 and 0.514 for AluDPB2, 0 and 0.127 for AluDQA2, 0.777 and 0.995 for AluDQA1, 0.1 and 0.455 for AluDRB1 and 0.084 and 0.368 for AluORF10. By comparing the data of the five-loci POALIN in 13 Chinese ethnic populations (including Han-Yunnan published data) against Japanese and Caucasian published data, marked differences were observed between the populations at the allelic or haplotypic levels. Five POALIN loci were in significant linkage disequilibrium with HLA-DRB1 in different populations and AluDQA1 had the highest percentage association with most of the HLA-DRB1 alleles, whereas the nearby AluDRB1 indel was strongly haplotypic for only DRB1∗01, DRB1∗10, DRB1∗15 and DRB1∗16. There were 30 five-locus POALIN haplotypes inferred in all populations with H5 (no Alu insertions except for AluDQA1) and H21 (only AluDPB2 and AluDQA1 insertions) as the two predominant haplotypes. Neighbor joining trees and principal component analyses of the Alu and HLA-DRB1 polymorphisms showed that genetic diversity of these genomic markers is associated strongly with the population characteristics of language family, migration and sociality. This comparative study of HLA-DRB1 alleles and multilocus, lineage POALIN frequencies of Chinese ethnic populations confirmed that POALINs whether investigated alone or together with the HLA class II alleles are informative genetic and evolutionary markers for the identification of allele and haplotype lineages and genetic variations within the same and/or different populations.
Genetic Polymorphism of rs13306146 Affects α2AAR Expression and Associated With Postpartum Depressive Symptoms in Chinese Women Who Received Cesarean Section
Authors: Duan Kai Ming , Fang Chao , Yang Si Qi , Yang Shu Ting , Xiao Ji Dong , Chang Huang , Lin Guo Xin , Zhang Liang Bin , Peng Ming Chao , Liu Zhao Qian , Wang Sai Ying
Published: July 2021

Postpartum depressive symptom (PDS) is a common psychological and mental disorder after giving birth. Our previous studies showing the application of dexmedetomidine, an α2-AR agonist, can significantly improve maternal sleep, as well as relieve and reduce the incidence of PDS. This study investigated the association between α2AAR gene polymorphisms and PDS. A total of 568 cesarean section patients were enrolled; the incidence of PDS is 18.13% (103 with PDS, 465 with non-PDS). The Edinburgh Postpartum Depression Scale score ≥10 was used to diagnose PDS at 42 days after delivery. The single-nucleotide polymorphisms of α2AR were sequenced by pyrosequencing. The effect of rs13306146 A > G polymorphism on α2AR transcription and the regulation of miR-646 on α2AR expression were assessed by dual luciferase reporter assays or gene transfection. Increased stress during pregnancy, poor relationship between mother-in-law and daughter-in-law, spousal relationship, domestic violence, antenatal depression, self-harm ideation, and stressful life events were all associated with increased PDS incidence (p < 0.05). The logistic regression analysis found that the α2AAR rs13306146 polymorphism was associated with PDS after adjusting confounding variables. The transcriptional function of the α2AAR rs13306146 A allele was decreased compared with the G allele, and the α2AAR expression level was correspondingly decreased (p < 0.05), as the strongest binding ability of miR-646 to the α2AAR rs13306146 AA genotype. The effect of α2AAR rs13306146 A > G polymorphism may change the binding ability of miR-646 at the 3′UTR of the α2AAR gene, affecting the expression of α2AAR. This study supports the involvement of the norepinephrine system in the pathogenesis of PDS. Genotypes of α2AAR may be novel and useful biomarkers for PDS.
Genomic and Chemical Diversity of Commercially Available High-CBD Industrial Hemp Accessions
Authors: Johnson Matthew S. , Wallace Jason G.
Published: July 2021

High consumer demand for cannabidiol (CBD) has made high-CBD hemp (Cannabis sativa) an extremely high-value crop. However, high demand has resulted in the industry developing faster than the research, resulting in the sale of many hemp accessions with inconsistent performance and chemical profiles. These inconsistencies cause significant economic and legal problems for growers interested in producing high-CBD hemp. To determine the genetic and phenotypic consistency in available high-CBD hemp varieties, we obtained seed or clones from 22 different named accessions meant for commercial production. Genotypes (∼48,000 SNPs) and chemical profiles (% CBD and THC by dry weight) were determined for up to 8 plants per accession. Many accessions–including several with the same name–showed little consistency either genetically or chemically. Most seed-grown accessions also deviated significantly from their purported levels of CBD and THC based on the supplied certificates of analysis. Several also showed evidence of an active tetrahydrocannabinolic acid (THCa) synthase gene, leading to unacceptably high levels of THC in female flowers. We conclude that the current market for high-CBD hemp varieties is highly unreliable, making many purchases risky for growers. We suggest options for addressing these issues, such using unique names and developing seed and plant certification programs to ensure the availability of high-quality, verified planting materials.
Identification of the SARS-CoV-2 Entry Receptor ACE2 as a Direct Target for Transcriptional Repression by Miz1
Authors: Yang Jing , Perez Edith A. , Hou Changchun , Zhang Pin , Van Scoyk Michelle , Winn Robert A. , Rong Lijun , Liu Jing
Published: July 2021

Multiple lines of evidence have demonstrated that cigarette smoke or Chronic Obstructive Pulmonary Disease upregulates angiotensin-converting enzyme 2, the cellular receptor for the entry of the severe acute respiratory syndrome coronavirus 2, which predisposes individuals to develop severe Coronavirus disease 2019. The reason for this observation is unknown. We recently reported that the loss of function of Miz1 in the lung epithelium in mice leads to a spontaneous COPD-like phenotype, associated with upregulation of angiotensin-converting enzyme 2. We also reported that cigarette smoke exposure downregulates Miz1 in lung epithelial cells and in mice, and Miz1 is also downregulated in the lungs of COPD patients. Here, we provide further evidence that Miz1 directly binds to and represses the promoter of angiotensin-converting enzyme 2 in mouse and human lung epithelial cells. Our data provide a potential molecular mechanism for the upregulation of angiotensin-converting enzyme 2 observed in smokers and COPD patients, with implication in severe Coronavirus disease 2019.
The CD8 T Cell-Epstein-Barr Virus-B Cell Trialogue: A Central Issue in Multiple Sclerosis Pathogenesis
Authors: Veroni Caterina , Aloisi Francesca
Published: July 2021

The cause and the pathogenic mechanisms leading to multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), are still under scrutiny. During the last decade, awareness has increased that multiple genetic and environmental factors act in concert to modulate MS risk. Likewise, the landscape of cells of the adaptive immune system that are believed to play a role in MS immunopathogenesis has expanded by including not only CD4 T helper cells but also cytotoxic CD8 T cells and B cells. Once the key cellular players are identified, the main challenge is to define precisely how they act and interact to induce neuroinflammation and the neurodegenerative cascade in MS. CD8 T cells have been implicated in MS pathogenesis since the 80’s when it was shown that CD8 T cells predominate in MS brain lesions. Interest in the role of CD8 T cells in MS was revived in 2000 and the years thereafter by studies showing that CNS-recruited CD8 T cells are clonally expanded and have a memory effector phenotype indicatingin situantigen-driven reactivation. The association of certain MHC class I alleles with MS genetic risk implicates CD8 T cells in disease pathogenesis. Moreover, experimental studies have highlighted the detrimental effects of CD8 T cell activation on neural cells. While the antigens responsible for T cell recruitment and activation in the CNS remain elusive, the high efficacy of B-cell depleting drugs in MS and a growing number of studies implicate B cells and Epstein-Barr virus (EBV), a B-lymphotropic herpesvirus that is strongly associated with MS, in the activation of pathogenic T cells. This article reviews the results of human studies that have contributed to elucidate the role of CD8 T cells in MS immunopathogenesis, and discusses them in light of current understanding of autoreactivity, B-cell and EBV involvement in MS, and mechanism of action of different MS treatments. Based on the available evidences, an immunopathological model of MS is proposed that entails a persistent EBV infection of CNS-infiltrating B cells as the target of a dysregulated cytotoxic CD8 T cell response causing CNS tissue damage.
Inflammasome-Induced Osmotic Pressure and the Mechanical Mechanisms Underlying Astrocytic Swelling and Membrane Blebbing in Pyroptosis
Authors: Zheng Zihui , Wang Tingting , Chen Jiahui , Qiu Huimin , Zhang Chencheng , Liu Weizhen , Qin Simiao , Tian Jilai , Guo Jun
Published: July 2021

Cell swelling and membrane blebbing are characteristic of pyroptosis. In the present study, we explored the role of intracellular tension activity in the deformation of pyroptotic astrocytes. Protein nanoparticle-induced osmotic pressure (PN-OP) was found to be involved in cell swelling and membrane blebbing in pyroptotic astrocytes, and was associated closely with inflammasome production and cytoskeleton depolymerization. However, accumulation of protein nanoparticles seemed not to be absolutely required for pyroptotic permeabilization in response to cytoskeleton depolymerization. Gasdermin D activation was observed to be involved in modification of typical pyroptotic features through inflammasome-induced OP upregulation and calcium increment. Blockage of nonselective ion pores can inhibit permeabilization, but not inflammasome production and ion influx in pyroptotic astrocytes. The results suggested that the inflammasomes, as protein nanoparticles, are involved in PN-OP upregulation and control the typical features of pyroptotic astrocytes.
Butorphanol Promotes Macrophage Phenotypic Transition to Inhibit Inflammatory Lung Injury via κ Receptors
Authors: Luan Guangxin , Pan Fan , Bu Lina , Wu Kaixuan , Wang Aizhong , Xu Xiaotao
Published: July 2021

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is characterized by diffuse inflammation of the lung parenchyma and refractory hypoxemia. Butorphanol is commonly used clinically for perioperative pain relief, but whether butorphanol can regulate LPS-induced alveolar macrophage polarization is unclear. In this study, we observed that butorphanol markedly attenuated sepsis-induced lung tissue injury and mortality in mice. Moreover, butorphanol also decreased the expression of M1 phenotype markers (TNF-α, IL-6, IL-1β and iNOS) and enhanced the expression of M2 marker (CD206) in alveolar macrophages in the bronchoalveolar lavage fluid (BALF) of LPS-stimulated mice. Butorphanol administration reduced LPS-induced numbers of proinflammatory (M1) macrophages and increased numbers of anti-inflammatory (M2) macrophages in the lungs of mice. Furthermore, we found that butorphanol-mediated suppression of the LPS-induced increases in M1 phenotype marker expression (TNF-α, IL-6, IL-1β and iNOS) in bone marrow-derived macrophages (BMDMs), and this effect was reversed by κ-opioid receptor (KOR) antagonists. Moreover, butorphanol inhibited the interaction of TLR4 with MyD88 and further suppressed NF-κB and MAPKs activation. In addition, butorphanol prevented the Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF)-mediated IFN signaling pathway. These effects were ameliorated by KOR antagonists. Thus, butorphanol may promote macrophage polarization from a proinflammatory to an anti-inflammatory phenotype secondary to the inhibition of NF-κB, MAPKs, and the TRIF-mediated IFN signaling pathway through κ receptors.
Deregulation of the Kallikrein Protease Family in the Salivary Glands of the Sjögren’s Syndrome ERdj5 Knockout Mouse Model
Authors: Moustardas Petros , Yamada-Fowler Naomi , Apostolou Eirini , Tzioufas Athanasios G. , Turkina Maria V. , Spyrou Giannis
Published: July 2021

Introduction

The purpose of this study was to identify differentially expressed proteins in salivary glands of the ERdj5 knockout mouse model for Sjögren’s syndrome and to elucidate possible mechanisms for the morbid phenotype development. At the same time, we describe for the first time the sexual dimorphism of the murine submandibular salivary gland at the proteome level.

Methods

We performed Liquid Chromatography/Mass Spectrometry in salivary gland tissues from both sexes of ERdj5 knockout and 129SV wildtype mice. The resulting list of proteins was evaluated with bioinformatic analysis and selected proteins were validated by western blot and immunohistochemistry and further analyzed at the transcription level by qRT-PCR.

Results

We identified 88 deregulated proteins in females, and 55 in males in wildtype vs knockout comparisons. In both sexes, Kallikrein 1b22 was highly upregulated (fold change>25, ANOVA p<0.0001), while all other proteases of this family were either downregulated or not significantly affected by the genotype. Bioinformatic analysis revealed a possible connection with the downregulated NGF that was further validated by independent methods. Concurrently, we identified 416 proteins that were significantly different in the salivary gland proteome of wildtype female vs male mice and highlighted pathways that could be driving the strong female bias of the pathology.

Conclusion

Our research provides a list of novel targets and supports the involvement of an NGF-mediating proteolytic deregulation pathway as a focus point towards the better understanding of the underlying mechanism of Sjögren’s syndrome.
Patient-Ventilator Synchronization During Non-invasive Ventilation: A Pilot Study of an Automated Analysis System
Authors: Letellier Christophe , Lujan Manel , Arnal Jean-Michel , Carlucci Annalisa , Chatwin Michelle , Ergan Begum , Kampelmacher Mike , Storre Jan Hendrik , Hart Nicholas , Gonzalez-Bermejo Jesus , Nava Stefano
Published: July 2021

Background: Patient-ventilator synchronization during non-invasive ventilation (NIV) can be assessed by visual inspection of flow and pressure waveforms but it remains time consuming and there is a large inter-rater variability, even among expert physicians. SyncSmart™ software developed by Breas Medical (Mölnycke, Sweden) provides an automatic detection and scoring of patient-ventilator asynchrony to help physicians in their daily clinical practice. This study was designed to assess performance of the automatic scoring by the SyncSmart software using expert clinicians as a reference in patient with chronic respiratory failure receiving NIV.

Methods: From nine patients, 20 min data sets were analyzed automatically by SyncSmart software and reviewed by nine expert physicians who were asked to score auto-triggering (AT), double-triggering (DT), and ineffective efforts (IE). The study procedure was similar to the one commonly used for validating the automatic sleep scoring technique. For each patient, the asynchrony index was computed by automatic scoring and each expert, respectively. Considering successively each expert scoring as a reference, sensitivity, specificity, positive predictive value (PPV), κ-coefficients, and agreement were calculated.

Results: The asynchrony index assessed by SynSmart was not significantly different from the one assessed by the experts (18.9 ± 17.7 vs. 12.8 ± 9.4, p = 0.19). When compared to an expert, the sensitivity and specificity provided by SyncSmart for DT, AT, and IE were significantly greater than those provided by an expert when compared to another expert.

Conclusions:SyncSmart software is able to score asynchrony events within the inter-rater variability. When the breathing frequency is not too high (<24), it therefore provides a reliable assessment of patient-ventilator asynchrony; AT is over detected otherwise.
Spider Mites Singly Infected With Either Wolbachia or Spiroplasma Have Reduced Thermal Tolerance
Authors: Zhu Yu-Xi , Song Zhang-Rong , Zhang Yi-Yin , Hoffmann Ary A. , Hong Xiao-Yue
Published: July 2021

Heritable symbionts play an essential role in many aspects of host ecology in a temperature-dependent manner. However, how temperature impacts the host and their interaction with endosymbionts remains largely unknown. Here, we investigated the impact of moderate (20°C) and high (30 and 35°C) temperatures on symbioses between the spider mite Tetranychus truncatus and two maternally inherited endosymbionts (Wolbachia and Spiroplasma). We found that the thermal tolerance of mites (as measured by survival after heat exposure) was lower for mites that were singly infected with either Wolbachia or Spiroplasma than it was for co-infected or uninfected mites. Although a relatively high temperature (30°C) is thought to promote bacterial replication, rearing at high temperature (35°C) resulted in losses of Wolbachia and particularly Spiroplasma. Exposing the mites to 20°C reduced the density and transmission of Spiroplasma but not Wolbachia. The four spider mite strains tested differed in the numbers of heat shock genes (Hsps) induced under moderate or high temperature exposure. In thermal preference (Tp) assays, the two Wolbachia-infected spider mite strains preferred a lower temperature than strains without Wolbachia. Our results show that endosymbiont-mediated spider mite responses to temperature stress are complex, involving a combination of changing endosymbiont infection patterns, altered thermoregulatory behavior, and transcription responses.
The Differential Growth Inhibition of Phytophthora spp. Caused by the Rare Sugar Tagatose Is Associated With Species-Specific Metabolic and Transcriptional Changes
Authors: Chahed Abdessalem , Lazazzara Valentina , Moretto Marco , Nesler Andrea , Corneo Paola Elisa , Barka Essaid Ait , Pertot Ilaria , Puopolo Gerardo , Perazzolli Michele
Published: July 2021

Tagatose is a rare sugar with no negative impacts on human health and selective inhibitory effects on plant-associated microorganisms. Tagatose inhibited mycelial growth and negatively affected mitochondrial processes in Phytophthora infestans, but not in Phytophthora cinnamomi. The aim of this study was to elucidate metabolic changes and transcriptional reprogramming activated by P. infestans and P. cinnamomi in response to tagatose, in order to clarify the differential inhibitory mechanisms of tagatose and the species-specific reactions to this rare sugar. Phytophthora infestans and P. cinnamomi activated distinct metabolic and transcriptional changes in response to the rare sugar. Tagatose negatively affected mycelial growth, sugar content and amino acid content in P. infestans with a severe transcriptional reprogramming that included the downregulation of genes involved in transport, sugar metabolism, signal transduction, and growth-related process. Conversely, tagatose incubation upregulated genes related to transport, energy metabolism, sugar metabolism and oxidative stress in P. cinnamomi with no negative effects on mycelial growth, sugar content and amino acid content. Differential inhibitory effects of tagatose on Phytophthora spp. were associated with an attempted reaction of P. infestans, which was not sufficient to attenuate the negative impacts of the rare sugar and with an efficient response of P. cinnamomi with the reprogramming of multiple metabolic processes, such as genes related to glucose transport, pentose metabolism, tricarboxylic acid cycle, reactive oxygen species detoxification, mitochondrial and alternative respiration processes. Knowledge on the differential response of Phytophthora spp. to tagatose represent a step forward in the understanding functional roles of rare sugars.
Hsa_circRNA_100146 Promotes Prostate Cancer Progression by Upregulating TRIP13 via Sponging miR-615-5p
Authors: Zeng Liang , Liu Yi-min , Yang Ning , Zhang Tao , Xie Huang
Published: July 2021

Objective: This study was conducted for investigating the functions of circular RNA circRNA_100146 (circRNA_100146) in the development of prostate cancer (PCa) and identifying the underlying mechanisms of the circRNA_100146/miR-615-5p/TRIP13 axis.

Materials and Methods: Under the support of RT-PCR, the expression of circRNA_100146 in PCa cells was examined. Cell Counting Kit-8 (CCK-8) assays and clone formation assays were applied to the assessment of cell proliferation. We then determined cell invasion and migration through transwell assays and wound healing assays. RNA pull-down assays and luciferase reporter assays were performed for the exploration of the regulatory effects of potential molecules on the expressions of the targeting genes. In addition, a nude mouse xenograft model was applied to demonstrate the oncogenic roles of circRNA_100146 in PCa.

Results: CircRNA_100146 expression was distinctly upregulated in PCa cells. Silencing of circRNA_100146 suppressed PCa cells’ invasion, migration, and proliferation. CircRNA_100146 sponged miR-615-5p to suppress its expressions, while miR-615-5p targeted the 3’-UTR of TRIP13 to repress the expression of TRIP13. In addition, we observed that knockdown of miR-615-5p reversed the suppression of circRNA_100146 silence on the proliferation and invasion of PCa cells. In addition, the tumor growth was also suppressed by silencing circRNA_100146 in vivo.

Conclusion: CircRNA_100146 is a tumor promoter in PCa, which promoted progression by mediating the miR-615-5p/TRIP13. CircRNA_100146 can be a potential candidate for targeted therapy of PCa.
How Does the Social Grouping of Animals in Nature Protect Against Sickness? A Perspective
Authors: Hart Lynette A. , Hart Benjamin L.
Published: July 2021

Sickness behavior is broadly represented in vertebrates, usually in association with the fever response in response to acute infections. The reactions to sickness behavior in a group member or potential group member in humans is quite variable, depending upon circumstances. In animals, the reactions to sickness behavior in a group member or potential group member evoke a specific response that reflects the species-specific lifestyle. Groups of animals can employ varied strategies to reduce or address exposure to sickness. Most of these have scarcely been studied in nature from a disease perspective: (1) adjusting exposure to sick conspecifics or contaminated areas; (2) caring for a sick group member; (3) peripheralization and agonistic behaviors to strange non-group conspecifics; and (4) using special strategies at parturition when newborn are healthy but vulnerable. Unexplored in this regard is infanticide, where newborn that are born with very little immunity until they receive antibody-rich colostrum, could be a target of maternal infanticide if they manifest signs of sickness and could be infectious to littermates. The strategies used by different species are highly specific and dependent upon the particular circumstances. What is needed is a more general awareness and consideration of the possibilities that avoiding or adapting to sickness behavior may be driving some social behaviors of animals in nature.
Calretinin Immunoreactivity in the VIIIth Nerve and Inner Ear Endorgans of Ranid Frogs
Authors: Reichenberger Ingrid , Caussidier-Dechesne Claude J. , Straka Hans
Published: July 2021

Calcium-binding proteins are essential for buffering intracellular calcium concentrations, which are critical for regulating cellular processes involved in neuronal computations. One such calcium-binding protein, calretinin, is present in many neurons of the central nervous system as well as those which innervate cranial sensory organs, although often with differential distributions in adjacent cellular elements. Here, we determined the presence and distribution of calretinin-immunoreactivity in the peripheral vestibular and auditory system of ranid frogs. Calretinin-immunoreactivity was observed in ganglion cells innervating the basilar and amphibian papilla, and in a subpopulation of ganglion cells innervating the saccular epithelium. In contrast, none of the ganglion cells innervating the lagena, the utricle, or the three semicircular canals were calretinin-immunopositive, suggesting that this calcium-binding protein is a marker for auditory but not vestibular afferent fibers in the frog. The absence of calretinin in vestibular ganglion cells corresponds with the lack of type I hair cells in anamniote vertebrates, many of which in amniotes are contacted by the neurites of large, calyx-forming calretinin-immunopositive ganglion cells. In the sensory epithelia of all endorgans, the majority of hair cells were strongly calretinin-immunopositive. Weakly calretinin-immunopositive hair cells were distributed in the intermediate region of the semicircular canal cristae, the central part of the saccular macula, the utricular, and lagenar striola and the medial part of the amphibian papilla. The differential presence of calretinin in the frog vestibular and auditory sensory periphery might reflect a biochemical feature related to firing patterns and frequency bandwidths of self-motion versus acoustic stimulus encoding, respectively.
Effect of the Hypoxia Inducible Factor on Sorafenib Resistance of Hepatocellular Carcinoma
Authors: Zeng Zhi , Lu Qiliang , Liu Yang , Zhao Junjun , Zhang Qian , Hu Linjun , Shi Zhan , Tu Yifeng , Xiao Zunqiang , Xu Qiuran , Huang Dongsheng
Published: July 2021

Sorafenib a multi-target tyrosine kinase inhibitor, is the first-line drug for treating advanced hepatocellular carcinoma (HCC). Mechanistically, it suppresses tumor angiogenesis, cell proliferation and promotes apoptosis. Although sorafenib effectively prolongs median survival rates of patients with advanced HCC, its efficacy is limited by drug resistance in some patients. In HCC, this resistance is attributed to multiple complex mechanisms. Previous clinical data has shown that HIFs expression is a predictor of poor prognosis, with further evidence demonstrating that a combination of sorafenib and HIFs-targeted therapy or HIFs inhibitors can overcome HCC sorafenib resistance. Here, we describe the molecular mechanism underlying sorafenib resistance in HCC patients, and highlight the impact of hypoxia microenvironment on sorafenib resistance.
Predictive Radiomic Models for the Chemotherapy Response in Non-Small-Cell Lung Cancer based on Computerized-Tomography Images
Authors: Chang Runsheng , Qi Shouliang , Yue Yong , Zhang Xiaoye , Song Jiangdian , Qian Wei
Published: July 2021

The heterogeneity and complexity of non-small cell lung cancer (NSCLC) tumors mean that NSCLC patients at the same stage can have different chemotherapy prognoses. Accurate predictive models could recognize NSCLC patients likely to respond to chemotherapy so that they can be given personalized and effective treatment. We propose to identify predictive imaging biomarkers from pre-treatment CT images and construct a radiomic model that can predict the chemotherapy response in NSCLC. This single-center cohort study included 280 NSCLC patients who received first-line chemotherapy treatment. Non-contrast CT images were taken before and after the chemotherapy, and clinical information were collected. Based on the Response Evaluation Criteria in Solid Tumors and clinical criteria, the responses were classified into two categories: response (n = 145) and progression (n = 135), then all data were divided into two cohorts: training cohort (224 patients) and independent test cohort (56 patients). In total, 1629 features characterizing the tumor phenotype were extracted from a cube containing the tumor lesion cropped from the pre-chemotherapy CT images. After dimensionality reduction, predictive models of the chemotherapy response of NSCLC with different feature selection methods and different machine-learning classifiers (support vector machine, random forest, and logistic regression) were constructed. For the independent test cohort, the predictive model based on a random-forest classifier with 20 radiomic features achieved the best performance, with an accuracy of 85.7% and an area under the receiver operating characteristic curve of 0.941 (95% confidence interval, 0.898–0.982). Of the 20 selected features, four were first-order statistics of image intensity and the others were texture features. For nine features, there were significant differences between the response and progression groups (p < 0.001). In the response group, three features, indicating heterogeneity, were overrepresented and one feature indicating homogeneity was underrepresented. The proposed radiomic model with pre-chemotherapy CT features can predict the chemotherapy response of patients with non-small cell lung cancer. This radiomic model can help to stratify patients with NSCLC, thereby offering the prospect of better treatment.