bluuebunny/crossref_metadata_2025 huggingface dataset:
GÜZEL SANATLAR LİSESİ VİYOLONSEL ÖĞRENCİLERİNİN BİREYSEL ÇALGI ÇALIŞMA ALIŞKANLIK DÜZEYLERİNİN KARŞILAŞTIRILMASI
Authors: ALBAYRAK Ceren , BULUT Damla
Published: March 2021

Bu araştırmada Güzel Sanatlar Lisesi viyolonsel öğrencilerinin bireysel çalgı çalışma
alışkanlık düzeyleri çeşitli değişkenlere göre incelenmiştir. Araştırmada betimsel nitelikte genel
tarama modeli kullanılmıştır. Çalışma grubu, amaçlı örneklem yöntemlerinden maksimum
çeşitlilik örnekleme tekniği kullanılarak belirlenmiştir. Araştırmanın örneklemini Türkiye’nin yedi
bölgesinde bulunan çeşitli illerdeki 14 Güzel Sanatlar Liselerinin müzik bölümü 1., 2., 3., ve 4.
sınıf düzeyinde eğitim alan 128 viyolonsel öğrencisi oluşturmaktadır. Veri toplama araçlarında
ilk olarak öğrencilerin demografik özellikleriyle ilgili bilgi sahibi olmak için “Kişisel Bilgi Formu”
kullanılmıştır. Öğrencilerin bireysel çalgı dersine ilişkin çalgı çalışma alışkanlarını tespit etmek
üzere Küçükosmanoğlu, Babacan, Babacan ve Yüksel (2016) tarafından geliştirilen “Bireysel
Çalgı Çalışma Alışkanlıkları Ölçeği” kullanılmıştır. Elde edilen veriler SPSS 24.0 for Windows
programına aktarılarak istatistiksel analizleri yapılmıştır. Verilerin normallik dağılımı ShapiroWilk Testi ile kontrol edilmiştir. Öğrencilerin, çalgı çalışma alışkanlık düzeylerinin cinsiyete bağlı
olarak anlamlı fark olup olmadığını araştırmak üzere (ilişkisiz) gruplar t testi uygulanmıştır.
Öğrencilerin, çalgı çalışma alışkanlık düzeylerinin sınıf, okulun bulunduğu bölge, bireysel
çalgılarını günde ve haftada çalıştıkları süreye bağlı olarak anlamlı fark olup olmadığını
araştırmak üzere Kruskal-Wallis H testi uygulanmıştır. Anlamlı fark bulunduğu durumda ise
hangi gruplar arasında anlamlı fark olduğunu araştırmak üzere post-hoc Mann-Whitney U testi
yapılmıştır. Araştırmanın sonucunda Güzel Sanatlar Lisesi viyolonsel öğrencilerinin bireysel
çalgı çalışma alışkanlık düzeylerinin yüksek olduğu ve öğrencilerin bireysel çalgı çalışma
alışkanlıklarında, öğrenim gördükleri sınıf düzeyi dışında, cinsiyet, çalışma süreleri, öğrenim
gördükleri bölgelere göre anlamlı farklılıklar olduğu tespit edilmiştir. Araştırmanın sonuçlarına
göre çeşitli öneriler sunulmuştur
A New Perspective on Pedagogical Content Knowledge: Intellectual and Emotional Characteristics of Science Teachers
Authors: DURAN Muharrem , USAK Muhammet , HSIEH Ming-Yuan , UYGUN Harun
Published: March 2021

The purpose of this study was to analyze the development of pedagogical content knowledge (PCK) of science teachers with different teaching experience on acids and bases and offer new domains of PCK which describe the relationship between PCK and emotional characteristics of teachers and their intellectual knowledge in science teaching. The research was carried out with the participation of six science teachers with different teaching experience. In the selection of participants, teaching the subject of acids and bases at least once, three and ten times, and being willing to participate in the study were the required criteria. Face to face interviews, videos and classroom observation forms, a pedagogical content knowledge form and academic follow-up forms are the assessment tools that were used in the study. It was found out that the teachers’ intellectual knowledge and positive emotional characteristics contributed to their pedagogical content knowledge. Teachers who were able to create effective learning environments with sufficient level of intellectual knowledge and positive emotional characteristics had more qualified pedagogical content knowledge. These properties had a significant role in students’ understanding.
An Empirical Study of Green Marketing on Perceived Value based on Brand Image in Smart Health Care Industry
Authors: LI Jianqing
Published: March 2021

Along with emerging international ideological trend of environmental protection, governments in the world also make green regulations. Nevertheless, the promotion of environmental protection should be started from the source prevention. Domestic government therefore positively counsel and encourage enterprises to become green enterprises. Along with the satisfaction with consumer needs, enterprises provide high-quality, environment-friendly, safe & healthy products. In addition, it becomes the indicators for the sustainable management of modern enterprises to promote products and environmental awareness through effective green marketing. Aiming at consumers of smart health care industry in Fujian Province, total 420 copies of questionnaire are distributed, and 325 valid copies are retrieved, with the retrieval rate 77%. The research results are summarized as below. Since smart health care industry would consume a lot of energy and wastes in consumers’ consumption or health care process, environmental protection should be taken into account in the operation management in smart health care industry. Promoting the environmental philosophy of smart health care industry with green marketing could match consumers’ environmental concept to enhance the brand image of smart health care industry. Green service in smart health care industry adds the green appeal in the original products and service, and the product and service quality would not be reduced for saving resources; the essence and differentiation of products and service therefore become the factors in consumers’ choices and perceived value. Smart health care industry, on the other hand could enhance the advantage of products and service for environmental and social appeal. According to the results, suggestions are proposed, expecting to help domestic smart health care industry practice green marketing, lead the public emphasis on environmental protection, enhance smart health care industry, and shape the brand image to maintain the competitiveness of domestic smart health care industry and achieve the goal of sustainable management.
Blended Learning - The Efficiency of Video Resources and YouTube in the Modern Dental Education
Authors: DASCALU Cristina Gena , ANTOHE Magda Ecaterina , ZEGAN Georgeta , BURLEA Stefan Lucian , CARAUSU Elena Mihaela , CIUBARA Anamaria , PURCAREA Victor Lorin
Published: March 2021

The media-enhanced teaching techniques became popular in the last years because they stimulate the students' engagement and motivation. The educational movies uploaded on YouTube became nowadays a highly used resource for learning in the academic environment. We conducted an opinion survey among the students at the Faculty of Dental Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Romania, about their agreement and interest in using educational movies as didactic tools, compared with the traditional teaching methods, and about the features they prefer in such materials. The study group included 170 students with average age 20.93 ± 2.751. Most students (91.2%) use didactic movies in their practical training; 77.6% think that the didactic movies from YouTube contain correct scientific information. 74.6% of the students like to learn using didactic movies, 39.7% of them appreciate the oral speech accompanied by PowerPoint Presentations and 46.6% like the oral speech accompanied by written explanations, with no significant differences between genders and age groups. The most popular features of the educational movies are: human narrator (94.7%), who speaks in Romanian (82.4%). The narrator’s speech must be accompanied by animated schemes with explanations (90.6%) and drawings (93.5%). The movie must have a clear structure, evolving from basic to complex (85.9%). The educational movies uploaded on YouTube are an adequate source of information for the dental students; the professionals in universities must survey better the scientific quality of such materials.
The Importance of Customized Biometric Correlations in the Prevention of Growth and Development Disorders – A Determining Factor in the Social Integration of Children and Adolescents with Mental Disabilities
Authors: ALBU Dinu-Florin , ONOFRIESCU Mircea , NADA Elena-Silvia , ION George , MILICESCU Stefan , ALBU Stefan-Dimitrie , ALBU Cristina-Crenguta
Published: March 2021

This research illustrates a complex, observational, longitudinal, comparative and noninterventional biometric study on the evaluation, in dynamics, of stature-weight development, in children with Down syndrome (DS), compared to children with varying degrees of mental retardation (MR), by repeatedly determining their height and weight, as well as by correlating these two parameters, in order to highlight the harmonious or disharmonious aspect of their stature-weight development. For this purpose, from patients’ medical files, we extracted the data regarding the periodic, annual, height and weight determinations of 50 preschoolers and schoolchildren, institutionalized in two Special Schools in Bucharest, which we compared with the standard tables used for Romanian population. The results showed that all children with DS show a disharmonious stature-weight development, with excess weight, as a consequence of both chromosomal trisomy and associated congenital malformations, especially heart malformations. In children with MR, the results showed a great phenotypic variability in terms of their stature-weight development. Thus, there were several cases in which the stature-weight development was harmonious, but, in the vast majority of cases, the results showed the presence of harmonious stature-weight development periods, which alternate with disharmonious stature-weight development periods, with weight surplus or weight deficit, alternation, which can be explained both by the involvement of genetic factors, and especially by the involvement of environmental, exogenous or endogenous factors.
The Relationship between the Creativity Levels of Music Pre-service Teachers and the Preferences of a Teacher Model Supporting Creativity
Authors: ARIKHAN Emine , COBAN Sibel
Published: March 2021

In this study, the relationship between the creativity levels of music pre-service teachers and their teacher model preferences that support creativity were investigated. The research was conducted with correlation model, which is one of the quantitative research methods. A total of 110 fourth grade students studying in the Department of Music in three different universities in the 2017-2018 academic year participated to the study. In the study, ‘Kaufman Creativity Areas Scale Turkish Form (KCAS-TF)’ and ‘Teacher Index Supporting Creativity (TISC)’ were used as data collection tools. It has been determined that there are positive correlations between the scores of the music pre-service teachers obtained from the KCAS-TF and the CFTIS scales, but the presence of this relationship in some subcomponents could not be confirmed. In the study, it was observed that the candidates who willingly chose the department of music teaching had higher scores from the evaluation sub-dimension of the (TISC). According to the results of the (KCAS-TF), it was concluded that the scores of the teacher candidates who do not want to teach after graduation from the artistic performance and creativity sub-dimension were lower than those who wanted to teach music.
The Correlations among Social Interaction, Knowledge Sharing and Innovation Capability- Case on Medical Technology Industry
Authors: CHEN Chih-Ming , LEE Chin-Lung , CHI Hung-Jen , YEH Tzu-Jiun , HUANG Kai-Ping
Published: March 2021

In face of the advance of technology, increase in competitors, and shortening product life cycle, enterprises could face market change and competition with other enterprises through constant innovation, e.g. creation of new knowledge, to maintain corporate competitive advantage. With better relationship between team members and other members, members present more social interaction to acquire more knowledge. In order to maintain more relational capital, individuals would invest in more resources, including interaction with others or providing message, resources, or knowledge required for others. In this case, individuals with more social interaction would be willing to share knowledge with others. Employees in medical technology industry in Fujian, as the research samples, are distributed 450 copies of questionnaire in this study. After deducting invalid and incomplete ones, 316 valid copies are retrieved, with the retrieval rate 70%. According to the results, suggestions are proposed, expecting to help employees in medical technology industry possess high-level professional knowledge and skills to deal with complicated work and develop the effectiveness of organizational resource application, regardless of medical technology industry product knowledge or customer needs, to achieve organizational performance.
Onecut Regulates Core Components of the Molecular Machinery for Neurotransmission in Photoreceptor Differentiation
Authors: Vassalli Quirino Attilio , Colantuono Chiara , Nittoli Valeria , Ferraioli Anna , Fasano Giulia , Berruto Federica , Chiusano Maria Luisa , Kelsh Robert Neil , Sordino Paolo , Locascio Annamaria
Published: March 2021

Photoreceptor cells (PRC) are neurons highly specialized for sensing light stimuli and have considerably diversified during evolution. The genetic mechanisms that underlie photoreceptor differentiation and accompanied the progressive increase in complexity and diversification of this sensory cell type are a matter of great interest in the field. A role of the homeodomain transcription factor Onecut (Oc) in photoreceptor cell formation is proposed throughout multicellular organisms. However, knowledge of the identity of the Oc downstream-acting factors that mediate specific tasks in the differentiation of the PRC remains limited. Here, we used transgenic perturbation of theCiona robustaOc protein to show its requirement for ciliary PRC differentiation. Then, transcriptome profiling between the trans-activation and trans-repression Oc phenotypes identified differentially expressed genes that are enriched in exocytosis, calcium homeostasis, and neurotransmission. Finally, comparison of RNA-Seq datasets inCionaand mouse identifies a set of Oc downstream genes conserved between tunicates and vertebrates. The transcription factor Oc emerges as a key regulator of neurotransmission in retinal cell types.
Growth Hormone/Insulin Growth Factor Axis in Sex Steroid Associated Disorders and Related Cancers
Authors: Bleach Rachel , Sherlock Mark , O’Reilly Michael W. , McIlroy Marie
Published: March 2021

To date, almost all solid malignancies have implicated insulin-like growth factor (IGF) signalling as a driver of tumour growth. However, the remarkable level of crosstalk between sex hormones, the IGF-1 receptor (IGF-1R) and its ligands IGF-1 and 2 in endocrine driven cancers is incompletely understood. Similar to the sex steroids, IGF signalling is essential in normal development as well as growth and tissue homoeostasis, and undergoes a steady decline with advancing age and increasing visceral adiposity. Interestingly, IGF-1 has been found to play a compensatory role for both estrogen receptor (ER) and androgen receptor (AR) by augmenting hormonal responses in the absence of, or where low levels of ligand are present. Furthermore, experimental, and epidemiological evidence supports a role for dysregulated IGF signalling in breast and prostate cancers. Insulin-like growth factor binding protein (IGFBP) molecules can regulate the bioavailability of IGF-1 and are frequently expressed in these hormonally regulated tissues. The link between age-related disease and the role of IGF-1 in the process of ageing and longevity has gained much attention over the last few decades, spurring the development of numerous IGF targeted therapies that have, to date, failed to deliver on their therapeutic potential. This review will provide an overview of the sexually dimorphic nature of IGF signalling in humans and how this is impacted by the reduction in sex steroids in mid-life. It will also explore the latest links with metabolic syndromes, hormonal imbalances associated with ageing and targeting of IGF signalling in endocrine-related tumour growth with an emphasis on post-menopausal breast cancer and the impact of the steroidal milieu.
Illuminating ALS Motor Neurons With Optogenetics in Zebrafish
Authors: Asakawa Kazuhide , Handa Hiroshi , Kawakami Koichi
Published: March 2021

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive degeneration of motor neurons in the brain and spinal cord. Spinal motor neurons align along the spinal cord length within the vertebral column, and extend long axons to connect with skeletal muscles covering the body surface. Due to this anatomy, spinal motor neurons are among the most difficult cells to observein vivo. Larval zebrafish have transparent bodies that allow non-invasive visualization of whole cells of single spinal motor neurons, from somas to the neuromuscular synapses. This unique feature, combined with its amenability to genome editing, pharmacology, and optogenetics, enables functional analyses of ALS-associated proteins in the spinal motor neuronsin vivowith subcellular resolution. Here, we review the zebrafish skeletal neuromuscular system and the optical methods used to study it. We then introduce a recently developed optogenetic zebrafish ALS model that uses light illumination to control oligomerization, phase transition and aggregation of the ALS-associated DNA/RNA-binding protein called TDP-43. Finally, we will discuss how this disease-in-a-fish ALS model can help solve key questions about ALS pathogenesis and lead to new ALS therapeutics.
miR-26a Reverses Multidrug Resistance in Osteosarcoma by Targeting MCL1
Authors: Li Ming , Ma Wei
Published: March 2021

The multidrug resistance (MDR) acquired in human osteosarcoma is a huge obstacle for effective chemotherapy. Recently, microRNA-26a (miR-26a) has been associated with the pathogenesis and progression of osteosarcoma. However, whether it regulates MDR in osteosarcoma is unknown. We show here that miR-26a expression declines in chemoresistant osteosarcoma after neoadjuvant chemotherapy, and its expression correlates with clinical outcome. In addition, compared with sensitive parental cells, miR-26a expression also declines in osteosarcoma MDR cells, together suggesting a negative correlation between miR-26a expression and MDR development in osteosarcoma. We also show that the enforced expression of miR-26a reverses MDR in osteosarcoma cells, and conversely, miR-26a knockdown confers MDR in chemosensitive osteosarcoma cells treated with doxorubicin, methotrexate, or cisplatin. Mechanistically, miR-26a directly targets the pro-survival protein myeloid cell leukemia 1 (MCL1), and in turn, the enforced expression of MCL1 markedly antagonizes miR-26a-decreased MDR in osteosarcoma MDR cells, therefore demonstrating that miR-26a reverses MDR in osteosarcoma by targeting MCL1. Lastly, miR-26a reverses resistance to doxorubicin in osteosarcoma MDR cells xenografted in nude mice. Collectively, these results reveal a negative role and the underlying mechanism of miR-26a in the regulation of MDR in human osteosarcoma, implying a potential tactic of manipulating miR-26a for overcoming MDR in osteosarcoma chemotherapy.
Napabucasin Induces Mouse Bone Loss by Impairing Bone Formation via STAT3
Authors: Huang Xiangru , Jin Anting , Wang Xijun , Gao Xin , Xu Hongyuan , Chung Miri , Dai Qinggang , Yang Yiling , Jiang Lingyong
Published: March 2021

The novel small molecule Napabucasin (also known as BBI608) was shown to inhibit gene transcription driven by Signal Transducer and Activator of Transcription 3 (STAT3), which is considered a promising anticancer target. Many preclinical studies have been conducted in cancer patients examining the selective targeting of cancer stem cells by Napabucasin, but few studies have examined side effects of Napabucasin in the skeleton system. In the present study, we found treating bone marrow mesenchymal stem cells (BMSCs) with Napabucasin in vitro impaired their osteogenic differentiation. In terms of mechanisms, Napabucasin disrupted differentiation of BMSCs by inhibiting the transcription of osteogenic gene osteocalcin (Ocn) through STAT3. Moreover, through micro-CT analysis we found 4 weeks of Napabucasin injections induced mouse bone loss. Histological analysis revealed that Napabucasin-induced bone loss in mice was the result of impaired osteogenesis. In conclusion, this study provided evidence for the effect of Napabucasin on mouse bone homeostasis and revealed its underlying mechanisms in vivo and in vitro.
Quantum Solvers for Plane-Wave Hamiltonians: Abridging Virtual Spaces Through the Optimization of Pairwise Correlations
Authors: Bylaska Eric J. , Song Duo , Bauman Nicholas P. , Kowalski Karol , Claudino Daniel , Humble Travis S.
Published: March 2021

For many-body methods such as MCSCF and CASSCF, in which the number of one-electron orbitals is optimized and independent of the basis set used, there are no problems with using plane-wave basis sets. However, for methods currently used in quantum computing such as select configuration interaction (CI) and coupled cluster (CC) methods, it is necessary to have a virtual space that is able to capture a significant amount of electron-electron correlation in the system. The virtual orbitals in a pseudopotential plane-wave Hartree–Fock calculation, because of Coulomb repulsion, are often scattering states that interact very weakly with the filled orbitals. As a result, very little correlation energy is captured from them. The use of virtual spaces derived from the one-electron operators has also been tried, and while some correlations are captured, the amount is quite low. To overcome these limitations, we have been developing new classes of algorithms to define virtual spaces by optimizing orbitals from small pairwise CI Hamiltonians, which we term as correlation optimized virtual orbitals with the abbreviation COVOs. With these procedures, we have been able to derive virtual spaces, containing only a few orbitals, which are able to capture a significant amount of correlation. The focus in this manuscript is on using these derived basis sets to target full CI (FCI) quality results for H2 on near-term quantum computers. However, the initial results for this approach were promising. We were able to obtain good agreement with FCI/cc-pVTZ results for this system with just 4 virtual orbitals, using both FCI and quantum simulations. The quality of the results using COVOs suggests that it may be possible to use them in other many-body approaches, including coupled cluster and Møller–Plesset perturbation theories, and open up the door to many-body calculations for pseudopotential plane-wave basis set methods.
Lipopolysaccharide Preparation Derived From Porphyromonas gingivalis Induces a Weaker Immuno-Inflammatory Response in BV-2 Microglial Cells Than Escherichia coli by Differentially Activating TLR2/4-Mediated NF-κB/STAT3 Signaling Pathways
Authors: Qiu Che , Yuan Zhen , He Zhiyan , Chen Huiwen , Liao Yue , Li Shiliang , Zhou Wei , Song Zhongchen
Published: March 2021

Alzheimer’s disease (AD) is a degenerative disease of the central nervous system with unclear etiology and pathogenesis. In recent years, as the infectious theory and endotoxin hypothesis of AD has gained substantial attention, several studies have proposed that Porphyromonas gingivalis (P. gingivalis), one of the main pathogenic bacteria of chronic periodontitis, and the lipopolysaccharide (LPS) of P. gingivalis may lead to AD-like pathological changes and cognition impairment. However, research on the relationship between P. gingivalis-LPS and neuroinflammation is still lacking. Our study aimed to investigate the effects of P. gingivalis-LPS preparation on immuno-inflammation in microglial cells and further compared the differential inflammatory response induced by P. gingivalis-LPS and Escherichia coli (E. coli) LPS preparations. The results showed that P. gingivalis-LPS could upregulate the gene expression and release of pro-inflammatory factors in BV-2 microglial cells, including IL-1β, IL-6, TNF-α, IL-17, and IL-23. We also observed an increase in the level of Toll-like receptor 2/4 (TLR2/4) and NF-κB/STAT3 signaling. Moreover, the changes mentioned above were more significant in the E. coli-LPS group and the effects of both kinds of LPS could be differentially reversed by the administration of the TLR2 inhibitor C29 and TLR4 inhibitor TAK-242. The molecular simulation showed that the binding affinity of P. gingivalis-lipid A to TLR4-MD-2 was weaker than E. coli-lipid A, which was probably due to the presence of fewer acyl chains and phosphate groups of P. gingivalis-lipid A than E. coli-lipid A. We conclude that P. gingivalis-LPS could activate TLR2/4-mediated NF-κB/STAT3 signaling pathways, which ultimately resulted in an immune-inflammatory response in BV-2 microglia. In contrast to E. coli-LPS, P. gingivalis-LPS is a weaker TLR2/4 agonist and NF-κB/STAT3 signaling activator. Furthermore, the different fatty acid chains and phosphate groups between P. gingivalis-lipid A and E. coli-lipid A may be the reason for the weaker activating properties of P. gingivalis-LPS.
Sudden Death and Coronary Artery Anomalies
Authors: Rizzo Stefania , De Gaspari Monica , Frescura Carla , Padalino Massimo , Thiene Gaetano , Basso Cristina
Published: March 2021

Congenital coronary artery anomalies (CAA) include a wide spectrum of malformations present at birth with various clinical manifestations and degrees of severity. Patients may be asymptomatic, and CAA may be an incidental finding during cardiac imaging or at autopsy. However, in other cases, ischemia-related signs and symptoms, leading to an increased risk of sudden cardiac death (SCD), often as first presentation may occur. In this chapter, we discuss the normal anatomy of the coronary arteries (CA) and the pathology of CAA at risk of SCD, including our experience with victims of SCD among the young population (age <40 years) and among athletes.
Tooth-Bone-Borne Vs. Bone-Borne Palatal Expanders: A Systematic Review
Authors: Yacout Yomna M. , Hassan Mohamed G. , El-Harouni Nadia M. , Ismail Hanan A. , Zaher Abbas R.
Published: March 2021

The aim of this review was to evaluate the current evidence regarding post-treatment effects of tooth-bone-borne vs. bone-borne expanders. A search was conducted in MEDLINE via PubMed, Web of Science, Scopus, Cochrane Library, Google Scholar, and Open Gray; in addition to a hand search in reference lists of selected articles and creating a search alert in electronic databases. Selection criteria included randomized and prospective clinical trials comparing post-expansion skeletal and/or dento-alveolar effects of tooth-bone-borne expanders to those of bone-borne expanders. Following study retrieval and selection, relevant data was extracted, and risk of bias was assessed using the revised RoB 2 tool for randomized clinical trials. After examining 10 full text articles, one randomized clinical trial was finally included. The study compared the dento-alveolar effects of tooth-bone-borne and bone-borne expanders, following expansion and after 6 months, using digital dental casts. Using the RoB 2 tool, the study was judged overall to show some concerns. A definitive conclusion could not be drawn from this systematic review due to the scarcity of clinical trials tackling the research question. A need for future well-conducted research was highlighted in this review.
Cholesterol Accumulation as a Driver of Hepatic Inflammation Under Translational Dietary Conditions Can Be Attenuated by a Multicomponent Medicine
Authors: Mueller Andrea M. , Kleemann Robert , Gart Eveline , van Duyvenvoorde Wim , Verschuren Lars , Caspers Martien , Menke Aswin , Krömmelbein Natascha , Salic Kanita , Burmeister Yvonne , Seilheimer Bernd , Morrison Martine C.
Published: March 2021

Background

Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is characterised by dysfunctional lipid metabolism and cholesterol homeostasis, and a related chronic inflammatory response. NAFLD has become the most common cause of chronic liver disease in many countries, and its prevalence continues to rise in parallel with increasing rates of obesity. Here, we evaluated the putative NAFLD-attenuating effects of a multicomponent medicine consisting of 24 natural ingredients: Hepar compositum (HC-24).

Methods

Ldlr-/-.Leiden mice were fed a high-fat diet (HFD) with a macronutrient composition and cholesterol content comparable to human diets for 24 weeks to induce obesity-associated metabolic dysfunction, including hepatic steatosis and inflammation. HC-24 or vehicle control was administered intraperitoneally 3 times/week (1.5 ml/kg) for the last 18 weeks of the study. Histological analyses of liver and adipose tissue were combined with extensive hepatic transcriptomics analysis. Transcriptomics results were further substantiated with ELISA, immunohistochemical and liver lipid analyses.

Results

HFD feeding induced obesity and metabolic dysfunction including adipose tissue inflammation and increased gut permeability. In the liver, HFD-feeding resulted in a disturbance of cholesterol homeostasis and an associated inflammatory response. HC-24 did not affect body weight, metabolic risk factors, adipose tissue inflammation or gut permeability. While HC-24 did not alter total liver steatosis, there was a pronounced reduction in lobular inflammation in HC-24-treated animals, which was associated with modulation of genes and proteins involved in inflammation (e.g., neutrophil chemokine Cxcl1) and cholesterol homeostasis (i.e., predicted effect on ‘cholesterol’ as an upstream regulator, based on gene expression changes associated with cholesterol handling). These effects were confirmed by CXCL1 ELISA, immunohistochemical staining of neutrophils and biochemical analysis of hepatic free cholesterol content. Intrahepatic free cholesterol levels were found to correlate significantly with the number of inflammatory aggregates in the liver, thereby providing a potential rationale for the observed anti-inflammatory effects of HC-24.

Conclusions

Free cholesterol accumulates in the liver of Ldlr-/-.Leiden mice under physiologically translational dietary conditions, and this is associated with the development of hepatic inflammation. The multicomponent medicine HC-24 reduces accumulation of free cholesterol and has molecular and cellular anti-inflammatory effects in the liver.
Ovarian Reserve Markers in Premature Ovarian Insufficiency: Within Different Clinical Stages and Different Etiologies
Authors: Jiao Xue , Meng Tingting , Zhai Yiwei , Zhao Lijuan , Luo Wei , Liu Peihao , Qin Yingying
Published: March 2021

Objective

To characterize the ovarian reserve indicators for premature ovarian insufficiency (POI) at different disease stages and with various etiologies.

Methods

According to different FSH levels and menstrual conditions, patients with normal ovarian reserve (NOR with 5 IU/L<FSH<10 IU/L, n=987), precursor stage of POI (pre-POI with 10 IU/L<FSH ≤ 25 IU/L, n=410), early POI (25 IU/L40 IU/L, n=454) were retrospectively screened and their records were abstracted from Reproductive Hospital Affiliated to Shandong University between 2014 and 2019. Based on the known etiologies, POI patients were subdivided into genetic, iatrogenic, autoimmune and idiopathic subsets according to the known etiologies. The phenotypic features were compared within different subgroups, and the predictive value of ovarian reserve markers was analyzed.

Results

The ovarian reserve indicators consecutively deteriorated with the progress of ovarian insufficiency, indicated as an increase of FSH and LH but decrease of AMH, inhibin B, AFC, E2 and T (P<0.01). Most of them changed significantly from NOR to pre-POI while remained relatively stable at a low level or even undetectable at early POI and POF stage. AMH showed the highest predictive value for pre-POI (AUC 0.932, 95% CI 0.918-0.945) and POI (AUC 0.944, 95% CI 0.933-0.954), and the combination of AMH and AFC was highly promising for early prediction. Additionally, significant differences existed in AMH, inhibin B and AFC among women with different etiologies of POI (P<0.05), and the genetic POI presented the worst hormone status.

Conclusions

Our study indicated a high heterogeneity of POI in both endocrine hormones and etiological phenotypes. The quantitative changes and cutoff values of AMH and AFC could provide new insights in the prediction and early diagnosis of POI.
Effects of Simulated Microgravity on the Proteome and Secretome of the Polyextremotolerant Black Fungus Knufia chersonesos
Authors: Tesei Donatella , Chiang Abby J. , Kalkum Markus , Stajich Jason E. , Mohan Ganesh Babu Malli , Sterflinger Katja , Venkateswaran Kasthuri
Published: March 2021

Black fungi are a group of melanotic microfungi characterized by remarkable polyextremotolerance. Due to a broad ecological plasticity and adaptations at the cellular level, it is predicted that they may survive in a variety of extreme environments, including harsh niches on Earth and Mars, and in outer space. However, the molecular mechanisms aiding survival, especially in space, are yet to be fully elucidated. Based on these premises, the rock-inhabiting black fungus Knufia chersonesos (Wt) and its non-melanized mutant (Mut) were exposed to simulated microgravity—one of the prevalent features characterizing space conditions—by growing the cultures in high-aspect-ratio vessels (HARVs). Qualitative and quantitative proteomic analyses were performed on the mycelia and supernatant of culture medium (secretome) to assess alterations in cell physiology in response to low-shear simulated microgravity (LSSMG) and to ultimately evaluate the role of cell-wall melanization in stress survival. Differential expression was observed for proteins involved in carbohydrate and lipid metabolic processes, transport, and ribosome biogenesis and translation via ribosomal translational machinery. However, no evidence of significant activation of stress components or starvation response was detected, except for the scytalone dehydratase, enzyme involved in the synthesis of dihydroxynaphthalene (DNH) melanin, which was found to be upregulated in the secretome of the wild type and downregulated in the mutant. Differences in protein modulation were observed between K. chersonesos Wt and Mut, with several proteins being downregulated under LSSMG in the Mut when compared to the Wt. Lastly, no major morphological alterations were observed following exposure to LSSMG. Similarly, the strains’ survivability was not negatively affected. This study is the first to characterize the response to simulated microgravity in black fungi, which might have implications on future astrobiological missions.
Causal Linkage Between Inflammatory Bowel Disease and Primary Sclerosing Cholangitis: A Two-Sample Mendelian Randomization Analysis
Authors: Xie Ying , Chen Xuejie , Deng Minzi , Sun Yuhao , Wang Xiaoyan , Chen Jie , Yuan Changzheng , Hesketh Therese
Published: March 2021

Background

Observational studies suggest an association between inflammatory bowel disease (IBD) [including ulcerative colitis (UC) and Crohn’s disease (CD)] and Primary sclerosing cholangitis (PSC), but the causal association between the two diseases remains unclear.

Methods

We used two-sample Mendelian randomization (MR) to estimate the causal association between IBD and PSC. We chose single nucleotide polymorphisms (SNPs) data for analysis, obtained from previous genome-wide association studies (GWASs). Pleiotropy, heterogeneity, and sensitivity analyses were performed for quality control.

Results

We found that the causal associations between IBD (both UC and CD) and PSC were significant (e.g., IBD and PSC, Robust adjusted profile score (RAPS) OR = 1.29, 95% CI 1.16∼1.44,p< 0.01; UC and PSC, RAPS OR = 1.40, 95% CI 1.23∼1.58,p< 0.01; CD and PSC, RAPS OR = 1.13, 95% CI 1.02∼1.26,p= 0.02). MR Egger, IVW, and ML tests found statistical heterogeneity between determined IV estimates. The leave-one-out analysis also indicated the sensitivity of the SNPs (e.g., IBD and PSC, MR-Egger Q = 644.30,p< 0.01; UC and PSC, MR-Egger Q = 378.30,p< 0.01; UC and PSC, MR-Egger Q = 538.50,p< 0.01).

Conclusion

MR analyses support the positive causal effect of IBD (including UC and CD) on PSC in a European population. We provide suggestions for preventing and treating the two diseases.
Mumps Orchitis: Clinical Aspects and Mechanisms
Authors: Wu Han , Wang Fei , Tang Dongdong , Han Daishu
Published: March 2021

The causative agent of mumps is a single-stranded, non-segmented, negative sense RNA virus belonging to theParamyxoviridaefamily. Besides the classic symptom of painfully swollen parotid salivary glands (parotitis) in mumps virus (MuV)-infected men, orchitis is the most common form of extra-salivary gland inflammation. Mumps orchitis frequently occurs in young adult men, and leads to pain and swelling of the testis. The administration of MuV vaccines in children has been proven highly effective in reducing the incidence of mumps. However, a recent global outbreak of mumps and the high rate of orchitis have recently been considered as threats to male fertility. The pathogenesis of mumps orchitis remains largely unclear due to lack of systematic clinical data analysis and animal models studies. The alarming increase in the incidence of mumps orchitis and the high risk of the male fertility have thus become a major health concern. Recent studies have revealed the mechanisms by which MuV-host cells interact and MuV infection induces inflammatory responses in testicular cells. In this mini-review, we highlight advances in our knowledge of the clinical aspects and possible mechanisms of mumps orchitis.
Connection of BANK1, Tolerance, Regulatory B cells, and Apoptosis: Perspectives of a Reductionist Investigation
Authors: Le Berre Ludmilla , Chesneau Mélanie , Danger Richard , Dubois Florian , Chaussabel Damien , Garand Mathieu , Brouard Sophie
Published: March 2021

BANK1 transcript is upregulated in whole blood after kidney transplantation in tolerant patients. In comparison to patients with rejection, tolerant patients display higher level of regulatory B cells (Bregs) expressing granzyme B (GZMB+) that have the capability to prevent effector T cells proliferation. However, BANK1 was found to be decreased in these GZMB+ Bregs. In this article, we investigated seven different transcriptomic studies and mined the literature in order to make link between BANK1, tolerance and Bregs. As for GZMB+ Bregs, we found that BANK1 was decreased in other subtypes of Bregs, including IL10+ and CD24hiCD38hi transitional regulatory B cells, along with BANK1 was down-regulated in activated/differentiated B cells, as in CD40-activated B cells, in leukemia and plasma cells. Following a reductionist approach, biological concepts were extracted from BANK1 literature and allowed us to infer association between BANK1 and immune signaling pathways, as STAT1, FcγRIIB, TNFAIP3, TRAF6, and TLR7. Based on B cell signaling literature and expression data, we proposed a role of BANK1 in B cells of tolerant patients that involved BCR, IP3R, and PLCG2, and a link with the apoptosis pathways. We confronted these data with our experiments on apoptosis in total B cells and Bregs, and this suggests different involvement for BANK1 in these two cells. Finally, we put in perspective our own data with other published data to hypothesize two different roles for BANK1 in B cells and in Bregs.
Association Between Air Pollution and the Risk of Uveitis: A Nationwide, Population-Based Cohort Study
Authors: Bai Yi-Chiao , Wang Cheng-You , Lin Cheng-Li , Lai Jung-Nien , Wei James Cheng-Chung
Published: March 2021

Previous studies have revealed an association between ocular surface disorders and air pollution, few studies have focused on the risk of uveitis. We aimed to investigate whether air pollution increases the risk of uveitis. We used the Taiwan Longitudinal Health Insurance Database (LHID) and the Taiwan Air Quality Monitoring Database (TAQMD) to conduct a retrospective cohort study. Air pollutant concentrations, including those of carbon dioxide (CO2), were grouped into four levels according to quartiles. The outcome was the incidence of uveitis, as defined in the International Classification of Diseases, Ninth Revision. We used univariable and multivariable Cox proportional hazard regression models to calculate the adjusted hazard ratios (aHRs) and determine the potential risk factors of uveitis. Overall, 175,489 subjects were linked to their nearby air quality monitoring stations. We found that for carbon monoxide, the aHRs of uveitis risk for the Q3 and Q4 levels were 1.41 (95% confidence interval (CI) = 1.23–1.61) and 2.19 (95% CI = 1.93–2.47), respectively, in comparison with those for the Q1 level. For nitric oxide, the aHRs for the Q3 and Q4 levels were 1.46 (95% CI = 1.27–1.67) and 2.05 (95% CI = 1.81–2.32), respectively. For nitrogen oxide (NOx), the aHRs for the Q2, Q3, and Q4 levels were 1.27 (95% CI = 1.11–1.44), 1.34 (95% CI = 1.16–1.53), and 1.85 (95% CI = 1.63–2.09), respectively. For total hydrocarbon (THC), the aHRs for the Q2, Q3, and Q4 levels were 1.42 (95% CI = 1.15–1.75), 3.80 (95% CI = 3.16–4.57), and 5.02 (95% CI = 4.19–6.02), respectively. For methane (CH4), the aHRs for the Q3 and Q4 levels were 1.94 (95% CI = 1.60–2.34) and 7.14 (95% CI = 6.01–8.48), respectively. In conclusion, air pollution was significantly associated with incidental uveitis, especially at high THC and CH4 levels. Furthermore, the uveitis risk appeared to increase with increasing NOx and THC levels.
The Hygiene Hypothesis and New Perspectives—Current Challenges Meeting an Old Postulate
Authors: Garn Holger , Potaczek Daniel Piotr , Pfefferle Petra Ina
Published: March 2021

During its 30 years history, the Hygiene Hypothesis has shown itself to be adaptable whenever it has been challenged by new scientific developments and this is a still a continuously ongoing process. In this regard, the mini review aims to discuss some selected new developments in relation to their impact on further fine-tuning and expansion of the Hygiene Hypothesis. This will include the role of recently discovered classes of innate and adaptive immune cells that challenges the old Th1/Th2 paradigm, the applicability of the Hygiene Hypothesis to newly identified allergy/asthma phenotypes with diverse underlying pathomechanistic endotypes, and the increasing knowledge derived from epigenetic studies that leads to better understanding of mechanisms involved in the translation of environmental impacts on biological systems. Further, we discuss in brief the expansion of the Hygiene Hypothesis to other disease areas like psychiatric disorders and cancer and conclude that the continuously developing Hygiene Hypothesis may provide a more generalized explanation for health burden in highly industrialized countries also relation to global changes.
Fundamentals of T Cell Metabolism and Strategies to Enhance Cancer Immunotherapy
Authors: Rangel Rivera Guillermo O. , Knochelmann Hannah M. , Dwyer Connor J. , Smith Aubrey S. , Wyatt Megan M. , Rivera-Reyes Amalia M. , Thaxton Jessica E. , Paulos Chrystal M.
Published: March 2021

Emerging reports show that metabolic pathways can be targeted to enhance T cell-mediated immunity to tumors. Yet, tumors consume key metabolites in the host to survive, thus robbing T cells of these nutrients to function and thrive. T cells are often deprived of basic building blocks for energy in the tumor, including glucose and amino acids needed to proliferate or produce cytotoxic molecules against tumors. Immunosuppressive molecules in the host further compromise the lytic capacity of T cells. Moreover, checkpoint receptors inhibit T cell responses by impairing their bioenergetic potential within tumors. In this review, we discuss the fundamental metabolic pathways involved in T cell activation, differentiation and response against tumors. We then address ways to target metabolic pathways to improve the next generation of immunotherapies for cancer patients.
Humanized Mice Exhibit Exacerbated Abscess Formation and Osteolysis During the Establishment of Implant-Associated Staphylococcus aureus Osteomyelitis
Authors: Muthukrishnan Gowrishankar , Wallimann Alexandra , Rangel-Moreno Javier , Bentley Karen L. de Mesy , Hildebrand Maria , Mys Karen , Kenney H. Mark , Sumrall Eric T. , Daiss John L. , Zeiter Stephan , Richards R. Geoff , Schwarz Edward M. , Moriarty T. Fintan
Published: March 2021

Staphylococcus aureus is the predominant pathogen causing osteomyelitis. Unfortunately, no immunotherapy exists to treat these very challenging and costly infections despite decades of research, and numerous vaccine failures in clinical trials. This lack of success can partially be attributed to an overreliance on murine models where the immune correlates of protection often diverge from that of humans. Moreover, S. aureus secretes numerous immunotoxins with unique tropism to human leukocytes, which compromises the targeting of immune cells in murine models. To study the response of human immune cells during chronic S. aureus bone infections, we engrafted non-obese diabetic (NOD)–scid IL2Rγnull (NSG) mice with human hematopoietic stem cells (huNSG) and analyzed protection in an established model of implant-associated osteomyelitis. The results showed that huNSG mice have increases in weight loss, osteolysis, bacterial dissemination to internal organs, and numbers of Staphylococcal abscess communities (SACs), during the establishment of implant-associated MRSA osteomyelitis compared to NSG controls (p < 0.05). Flow cytometry and immunohistochemistry demonstrated greater human T cell numbers in infected versus uninfected huNSG mice (p < 0.05), and that T-bet+ human T cells clustered around the SACs, suggesting S. aureus-mediated activation and proliferation of human T cells in the infected bone. Collectively, these proof-of-concept studies underscore the utility of huNSG mice for studying an aggressive form of S. aureus osteomyelitis, which is more akin to that seen in humans. We have also established an experimental system to investigate the contribution of specific human T cells in controlling S. aureus infection and dissemination.