bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementasi Metode Jet Tempur Dalam Meningkatkan Bimbingan Baca Tulis Al Qur’an Di MTs Negeri 1 Kota Kediri
Authors: Murtado Mu'min Ali , Miftahudin
Published: February 2021

The implementation of Jet Tempur Method can improve Al Qur'an reading guidance at Lirboyo Islamic Boarding School. These preliminary data form the basis of this research in First Middle School Of Islamic State 1 Kediri City. This research uses a descriptive qualitative approach by exploring data in depth according to the focus of the study. Data collection by observation, interview and documentation. After the data is collected and analyzed qualitatively, the data is processed by data reduction, data presentation and drawing conclusions. The results showed that (1) ustadaz at First Middle School Of Islamic State 1 Kediri had implemented Al Qur'an reading and writing guidance, with the jet fighter method well starting the planning, implementation and follow-up stages of the implementation of the fighter jet method which had given a good impact on students, (2) the results of the learning of reading and reading guidance of the Qur'an can be known through daily demonstrations by asking students to face their teacher and then evaluating and formative exams, final semester exams.
Suomenkieliset kalannimitykset Åbo Tidningarissa 1771–1772
Authors: Uusitalo Harri
Published: February 2021

Turun Akatemian piirissä toimineen Aurora-seuran julkaisema Tidningar utgifne af ett sällskap i Åbo oli ensimmäinen Suomessa ilmestynyt sanomalehti. Siinä julkaistiin vuosina 1771−1772 Pehr Adrian Gaddin kirjoittama neliosainen artikkelisarja Försök til Ichtyologia Fennica, joka käsitteli Suomen kalastoa. Kielihistoriallisesta näkökulmasta artikkelit ovat kiinnostavia, koska niissä mainitaan lukuisia suomenkielisiä kalannimityksiä.

Tämä tutkimus keskittyy tarkastelemaan ennen kaikkea Gaddin artikkelien kalojen suomenkielisiä nimityksiä. Tavoitteena on saada selville, mitkä kalannimitykset esiintyvät jo vanhemmissa kirjallisissa lähteissä. Toisaalta on kiinnostavaa selvittää, minkä suomenkielisten nimitysten kirjalliset ensiesiintymät ovat Gaddin artikkeleissa ja millainen tausta näillä nimityksillä on. Tutkimuksessa käy ilmi, että ensiesiintymiä on useita.
Production of proteolytic enzymes in mast cells, fibroblasts, vascular smooth muscle and endothelial cells cultivated under normoxic or hypoxic conditions
Authors: Maxová H , Bačáková L , Lisá V , Novotná J , Tomášová H , Vízek M , Herget J
Published: February 2021

Matrix metalloproteinases (MMPs) is a family of proteolytic
enzymes involved in remodeling of extracellular matrix. Although
proteolytic enzymes are produced by many cell types, mast cells
seem to be more important than other types in remodeling of
pulmonary arteries during hypoxia. Therefore, we tested in vitro
production of MMPs and serine proteases in four cell types (mast
cells, fibroblasts, vascular smooth muscle cells and endothelial
cells) cultivated for 48 h under normoxic or hypoxic (3 % O2)
conditions. MMP-13 was visualized by immunohistochemistry,
MMP-2 and MMP-9 were detected by zymography in cell lysates.
Enzymatic activities (MMPs, tryptase and chymase) were
estimated in the cultivation media. Hypoxia had a minimal effect
on total MMP activity in the cultivation media of all types of cells,
but immunofluorescence revealed higher intensity of MMP-13 in
the cells exposed to hypoxia except of fibroblasts. Tryptase
activity was three times higher and chymase activity twice higher
in mast cells cultivated in hypoxia than in those cultured in
normoxia. Among all cell types studied here, mast cells are the
most abundant source of proteolytic enzymes under normoxic
and hypoxic conditions. Moreover, in these cells hypoxia
increases the production of both specific serine proteases
tryptase and chymase, which can act as MMPs activators.
Interaction of glutamate- and adenosine-induced decrease of acetylcholine quantal release at frog neuromuscular junction
Authors: Adámek S , Shakirzyanova AV , Malomouzh AI , Naumenko NV , Vyskočil F
Published: February 2021

In a frog neuromuscular preparation of m. sartorius, glutamate
had a reversible dose-dependent inhibitory effect on both
spontaneous miniature endplate potentials (MEPP) and nerve
stimulation-evoked endplate potentials (EPP). The effect of
glutamate on MEPP and EPP is caused by the activation of
metabotropic glutamate receptors, as it was eliminated by MCPG,
an inhibitor of group I metabotropic glutamate receptors. The
depression of evoked EPP, but not MEPP frequency was removed
by inhibiting the NO production in the muscle by L-NAME and by
ODQ that inhibits the soluble NO-sensitive guanylyl cyclase. The
glutamate-induced depression of the frequency of spontaneous
MEPP is apparently not caused by the stimulation of the NO
cascade. The particular glutamate-stimulated NO cascade
affecting the evoked EPP can be down-regulated also by
adenosine receptors, as the glutamate and adenosine actions are
not additive and application of adenosine partially prevents the
further decrease of quantal content by glutamate. On the other
hand, there is no obvious interaction between the glutamatemediated inhibition of EPP and inhibitory pathways triggered by
carbacholine and ATP. The effect of glutamate on the evoked
EPP release might be due to NO-mediated modulation
(phosphorylation) of the voltage-dependent Ca2+ channels at the
presynaptic release zone that are necessary for evoked quantal
release and open during EPP production.
The Dialectics of the Visual and the Book Culture in the Postmodern Era
Authors:   Pacific Higher Naval School, Tsareva Nadezhda A.
Published: February 2021

The object of research in the present work is the issue of the coexistence of the book and the visual cultures. Contemporary culture, having become informational, has transformed into a society of visual culture. The phenomenon of visual culture of post-industrial society is examined as a specific type of information and as a process. The processes of virtualization of life are becoming the distinctive feature of contemporary informational technologies. Information in the present era is exerting its influence on the user of technologies to a much greater degree as it was the case earlier. But the author does not agree with the negative evaluation of visualization as a replication of the set model of communication which impoverishes human thought. The reasons for this intellectual impoverishment and the lowering of the overall cultural level of the consumer have not been incited by art works of visual culture. These processes are conditioned by the specificity of contemporary mass culture which forms the “midrange” personality. Descriptions and comparisons are given of the model of the sociocultural mechanism of informational impact of art works pertaining to visual and book culture. The attempt is made to answer the question of whether visual culture possesses a systematic predominating status, or whether it must be examined as one of the directions of culture of the informational society. The conclusion is reached about the prospects of coexistence and interpenetration of the visual and the book culture with each other.
The General Intonation in the Performance of “Boris Godunov” of Vsevolod Meyerhold — Sergei Prokofiev
Authors:   Moscow State P.I. Tchaikovsky Conservatory, Porshnev Ivan D.
Published: February 2021

The article dwells upon the process of the artistic cooperation between Vsevolod Meyerhold and Sergei Prokofiev by the example of their collaborative work on Alexander Pushkin’s play “Boris Godunov.” The preparation for the actualization of the conception had started long before the main rehearsing period — in 1934, after the issuance of the edict of the Politburo of the Central Committee of the VKP(b) (Communist Party) “Concerning the Foundation of the All-Union Pushkin Committee in connection with the centennial anniversary of the death of Alexander Sergeyevich Pushkin.” The performance was supposed to have become the appropriate response to the festivities of the Pushkin jubilee, but it never got round to being performed at that time. The peculiarities of the interpretation of the drama in the dialogue of the two Masters are examined on the basis of the materials connected with the history of the creation of the performance and the music to it. Analysis is made of the semantic content of the musical numbers (“The Song of the Lonely Wanderer” and the “Songs of Loneliness”), which carry out the function of the through leit-motifs and indirectly characterize Boris Godunov and the Pretender, and also play an important role in the formation of the “general intonation” of the performance. The conclusion is arrived at that the “politically saturated” production of Vsevolod Meyerhold and Sergei Prokofiev touched upon the prohibited “territory of meanings”: the denoted implication unwittingly projected itself on the personal fate of the ruler of the Soviet state.
“Jephthah’s Daughter” by Amy Beach: the Biblical World in the Words of a Woman
Authors:   Petrozavodsk State Glazunov Conservatoire, Sysolyatina Sofiya V.
Published: February 2021

The article examines from the positions of musical content by means of analysis of the musical and poetical the composition “Jephthah’s Daughter” by Amy Beach, an American composer of the late 19th and early 20th century, a member of the “Boston six” — a group of American composers of the turn of the century, also known as the New England School, among which Amy Beach was the only woman. “Jephthahʼs Daughter” is a concert aria for voice and orchestra, which is interesting in the context of the composer’s musical legacy, as well as an exemplary composition of its era. The aria is devoted to the Biblical subject matter or, more precisely, the well-known Old Testament plot of the sacrifi ce of the daughter of the Israelite judge Jephthah. Besides the analysis of the musical fabric, the article examines the author’s approach to the subject of the principle of the choice of the material and the work with the textual sources — the Biblical story and the French poem, which comprised the basis of the aria’s text. As a result, the conclusion is arrived at about the composer’s artistic intentions and about the conceptual component of the work. The article contains information about Amy Beach’s biography, her artistic approach, her attitude to religious subject matter and social problems of the society contemporary to her, in particular, the issues of equal rights for women.
The Metamorphoses of Impressionism at the Turn of the Centuries
Authors:   Center for Comprehensive Art Studies, Saratov State L. V. Sobinov Conservatory, Demchenko Alexander I.
Published: February 2021

The concept of the “Silver Age” is usually correlated with certain phenomena of the Russian artistic culture of the turn of the 19th and 20th centuries. However, it is absolutely clear that this was not a purely national phenomenon and it is appropriate to spread its “geography” onto analogous artefacts of the entire European space of that time. Upon close examination it turns out that many aesthetic components of the late 19th and early 20th century developed under the auspices of the “Silver Age”: late Romanticism, Symbolism, the so-called Decadence, the Moderne Style, etc., — everything which were characterized with brightly expressed personalized accents, individual-subjective predilections and various degrees of aesthetization of artistic creativity. The author of the article considers that similar assertions are also applicable in regard to many sides of Impressionism — one of the most influential artistic directions of these years, especially in its late stage. But first of all the article specifies certain questions of evolution of this direction and its substance, since we must frequently confront with an excessively expansive understanding of this conception.
Ancient Musical Discoveries in Slovakia
Authors:   Academy of Arts, Strenacikova Maria
Published: February 2021

The article is devoted to the musical artefacts discovered on the territory of Slovakia. During the remotest ancient periods of time music served chiefly as a means for ceremonies, cults and magic rituals, and accompanied the process of work. Present-day perceptions about music in prehistorical times are formed from various types of evidence: archeological artifacts, pictures, carved figures and musical instruments. The most ancient of the latter are various rattles and pipes. An inherent part of musical activities was formed by dances and singing. Although there is an absence of direct evidence of the sound of the instruments, it may be presumed that during the first stages of the development of music one of its most important aspects was rhythm. Melodies were simple and consisted of few pitches with small intervals in between them, which comprised a basic motive, subsequently repeated numerous times.
The Attributive Features of the Hero as a Category of Musical Poetics in Pieces from the Children’s Musical Repertoire
Authors:   Ufa State Institute of Arts named after Zagir Ismagilov, Baikieva Rimma M.
Published: February 2021

The article offers means of defining the features of the hero as a structure of the musical text of pieces from the children’s repertoire. Since any kind of artistic text is created in accordance with unified semantics-bearing laws, the category of the musical hero is examined along with such categories of poetics as the author, the protagonist, the image, the dialogue, the scene, the subject matter, the idea, which, nonetheless, up to now have continued to be relegated to the sphere of metaphors. Nonetheless, the description of the features of the hero on the basis of intonational lexis of various types of etymology is seen as presenting its result. Demonstration of the indicated features incorporates a particular mechanism of semantic analysis, which makes it possible to elucidate the lexical structures manifesting the hero. Semantic analysis has shown that the category of the hero is presented in the musical text structurally; it may be described both as a biologically definite being and a socially concrete personality. Moreover, pieces from the children’s repertoire are endowed with the capacity of manifesting the personified hero who represents living nature. The attributing of the hero also sees the participation of the heading, which, nonetheless, does not always indicate the hero directly. However, the heading always (whether directly or indirectly) depicts the hero’s place of action and the world surrounding him.The hero receives his attribution most often in musical speech and in plastic models. Besides the “audible” and “visible” attributes, the hero in an artistic text is also actualized through the features of evaluative character: with their help the author, who is situated “off-screen,” endows the hero with the biological and characterological features of a human being. Study of musical content from the point of view of the categories of musical poetics may make the interaction of the analytical aspect with performance practice more effectual and productive. At the same time, the various approaches to the art of performance shall inevitably acquire new features which bring the performer’s activities in the questions of articulation and intonation closer with dramatic art.
The Acoustic Images of Quasi-Ensemble Music-Making in the Slow Section of Mozart’s Clavier Sonata in B-flat Major, К. 570
Authors:   Ufa State Institute of Arts named after Zagir Ismagilov, Danilova Yana Yu.
Published: February 2021

Music for clavier from the 18th century graphically recreates the acoustic images of the musical instruments and models of quasi-ensemble music making of that period. This tradition of “reflected musical texts” was typical for the Baroque period, when piano music presented a quasi-ensemble score condensed into two-staff notation. The acoustic features of the European practice of music-making in ensembles have also been universally reflected in the musical graphics of the piano sonatas of the Viennese Classicists – Haydn, Mozart and Beethoven. On the basis of the observations of this migration within the musical text of the slow movement of Mozart’s Sonata in B-flat minor K. 570, the article demonstrates the modifications of the structural dialogic models of Baroque practice and the process of their transformation into unfolded narrative-contextual signs, the peculiar features of the musical scores, and the acoustic images of the 18th century music-making practice.
The Great Saratov Triad of the Early 20th Century
Authors:   Saratov State L.V. Sobinov Conservatory, Demchenko Alexander I.
Published: February 2021

Saratov is justifiably called one of the most significant centers of the artistic culture of the Russian Near-Volga Region. When analyzing the condition of that domain of the plastic arts represented by painting and graphics, it is necessary to state that during the course of the entire 19th century (not to mention the previous century) the figures of the artists were merely episodic: Jean Baptiste Savin, a Frenchman in his origin (famous for his portraits and watercolors), watercolor painter Maria Zhukova, Andrei Godin (who was the first teacher of Mikhail Vrubel) and Feodor Vassiliev (the first instructor of Victor Borisov-Musatov), portraitists and church painters Lev Igorev and Nikolai Rossov. For the most part, the artists who worked beyond the confines of Saratov were its natives, who were veritably well-known artists – Vassily Zhuravlev and Alexei Kharlamov. The high flourishing of painting in Saratov at the end of the 19th and the beginning of the 20th century was prepared by the activities of Hector Baracchi, originally from Italy, and graduate from the St. Petersburg Academy of the Arts Vassily Konovalov. They exerted a decisive influence on the local artistic school, the main representatives of which were Victor Borisov-Musatov, Pavel Kuznetsov, Piotr Utkin, Alexander Savinov, Kuzma Petrov-Vodkin (a native of Khvalynsk), as well as sculptor Alexander Matveyev. However, there were three names which have become the most “celebrated” for Saratov, which led the brilliant assemblage of remarkable artists pertaining to the visual arts and were in the vanguard of the so-called era of “cultural boom,” as the high artistic accomplishments of the late 19th and early 20th century are sometimes referred to. They are Victor Borisov-Musatov, Pavel Kuznetsov and Kuzma Petrov-Vodkin. The present essay is devoted to them.
The Contemporary Visual Didactic Directive in the Project “The Life of Remarkable Melodies”
Authors:   Bashkir State Pedagogical University named after M. Akmulla, Shteynberg Valery E.
Published: February 2021

The article presents a searching-experimental Project “The Life of Remarkable Melodies” (“LRM”), the conception of which is based on the application of the didactic principle of multidimensionality to the phenomenon of the “musical image” in the form of specially selected and ranged creative arrangements and performances of remarkable melodies in assembly works — mono-anthologies, as well as on the technology of comparative music listening. According to the latter, the listener — the User of the “LRM” Project — intuitively emphasizes the distinctive features of the arrangement and specifies his or her preferences. The peculiarity of the “LRM” Project is in the convenient multipage interface and the exclusive title included in the text of Testimonial RU 2018612220: Instructional Program Complex “The Life of Remarkable Melodies.” For the aggrandizement of demonstrativeness, the article makes use of didactic means of figurative visualization of knowledge, which would initiate a synesthetic perception of depicted informative and operative components, facilitating the process of operating it in the teaching process. In particular, a visual didactic directive is introduced of the logical-semantic type, the “Self-Effectivity of the User of the LRM Project,” obtained by modeling information presented in a natural language. It realizes the conception of construction of semantic networks, moreover, the figurative form of the directive is provided by the graphics of a “solar” — radial type.
Evaluasi Keberhasilan Kelompok Pendukung ASI Eksklusif (KP-ASI) terhadap Cakupan ASI Eksklusif
Authors: Kaparang Mercy Joice , Nurbaeti Sri , Damayanti Vivi Putri
Published: February 2021

Kesiapan seorang ibu untuk memberikan ASI secara eksklusif kepada bayinya dapat dipengaruhi dari berbagai arah baik dari keluarga, tenaga kesehatan, ataupun peer support (dukungan sebaya) dalam komunitas ibu menyusui yang menyelesaikan permasalahan ibu selama pemberian ASI. Tujuan kegitan mengevaluasi keberhasilan Kelompok Pendukung ASI Eksklusif (KP-ASI) terhadap cakupan ASI eksklusif. Metode yang digunakan merupakan ceramah dan tanya jawab, diskusi pendampingan, evaluasi melalui pemberian kuesioner. Sasaran yaitu KP-ASI terhadap ibu dengan kehamilan usia 28-40 minggu pada trimester III hingga menyusui bayi sebanyak 56 responden. Hasil kegiatan ini menunjukkan dari 56 responden, terdiri dari 28 orang ibu yang bergabung dengan KP-ASI, bayi yang diberikan ASI eksklusif sebesar 82,1%. Adapun, sebanyak 28 orang ibu yang tidak bergabung dengan KP-ASI, bayi yang diberikan ASI eksklusif sebesar 14,3%. Kesimpulan dalam kegiatan ini yaitu KP-ASI terhadap cakupan ASI eksklusif tercapai. Berdasarkan hasil kegiatan, disarankan bagi puskesmas KP-ASI tidak hanya ditujukan bagi kader posyandu dan sebagian ibu akan tetapi bagi seluruh ibu yang akan mempunyai bayi sehingga pemberian ASI dilakukan secara eksklusif dan cakupan ASI dapat meningkat secara signifikan.
Next-Generation Cancer Biomarkers: Extracellular Vesicle DNA as a Circulating Surrogate of Tumor DNA
Authors: Amintas Samuel , Vendrely Véronique , Dupin Charles , Buscail Louis , Laurent Christophe , Bournet Barbara , Merlio Jean-Philippe , Bedel Aurélie , Moreau-Gaudry François , Boutin Julian , Dabernat Sandrine , Buscail Etienne
Published: February 2021

Extracellular vesicles (EVs) are produced by healthy tissues and tumor cells and are released in various bodily fluids, including blood. They are limited by bilayer phospholipidic membranes, and they carry a rich content in biomolecules. Their release cleanses the cells of their waste or serves as functional local and distant cell–cell communication and molecular exchange particles. This rich and heterogeneous content has been given intense attention in cancer physiopathology because EVs support cancer control and progression. Because of their specific active cargo, they are being evaluated as carriers of liquid biopsy biomarkers. Compared to soluble circulating biomarkers, their complexity might provide rich information on tumor and metastases status. Thanks to the acquired genomic changes commonly observed in oncogenic processes, double-stranded DNA (dsDNA) in EVs might be the latest most promising biomarker of tumor presence and complexity. This review will focus on the recent knowledge on the DNA inclusion in vesicles, the technical aspects of EV-DNA detection and quantification, and the use of EV-DNA as a clinical biomarker.
Prediction of the Variability of Changes in the Intensity and Frequency of Climate Change Reinforced Multi-Day Extreme Precipitation in the North-Central Vietnam Using General Circulation Models and Generalized Extreme Value Distribution Method
Authors: Giang Pham Quy
Published: February 2021

Flooding of downstream agricultural fields and cities is normally caused by consecutive days of extreme precipitation in upstream areas. As climate change is widely projected to accelerate the hydrological cycle, concerns about the increase in frequency and intensity of extreme precipitation arise. The present study used Pattern Scaling coupled with Generalized Extreme Value (GEV) distribution to calculate changes in multi-day extreme precipitation in the North Central Vietnam in 2050, 2070, and 2090 under three AR5’s Representative Concentration Pathways RCP2.6, RCP6.0 and RCP8.5. Twenty long-term historical observation stations in the study area with daily data mostly date back to more than 50 years were employed and 5-day maximum total precipitation was analyzed. The results reveal an agreement among the employed GCMs on an increase in the intensity and a shortening of the return periods of extreme precipitation, with the most reinforced trend occurring under RCP8.5, followed by RCP6.0 and then RCP2.6. This indicates that the risk of associated floods is likely to increase, especially under higher RCPs. Therefore, planning and decision making of durable infrastructure along with flood mitigation strategies to cope with such events are recommended.
Living at the Edge: Increasing Stress for Plants 2–13 Years After the Retreat of a Tropical Glacier
Authors: Anthelme Fabien , Cauvy-Fraunié Sophie , Francou Bernard , Cáceres Bolívar , Dangles Olivier
Published: February 2021

Rapid warming is a major threat for the alpine biodiversity but, at the same time, accelerated glacial retreat constitutes an opportunity for taxa and communities to escape range contraction or extinction. We explored the first steps of plant primary succession after accelerated glacial retreat under the assumption that the first few years are critical for the success of plant establishment. To this end, we examined plant succession along a very short post-glacial chronosequence in the tropical Andes of Ecuador (2–13 years after glacial retreat). We recorded the location of all plant individuals within an area of 4,200 m2divided into plots of 1 m2. This sampling made it possible to measure the responses of the microenvironment, plant diversity and plants traits to time since the glacial retreat. It also made it possible to produce species-area curves and to estimate positive interactions between species. Decreases in soil temperature, soil moisture, and soil macronutrients revealed increasing abiotic stress for plants between two and 13 years after glacial retreat. This increasing stress seemingly explained the lack of positive correlation between plant diversity and time since the glacial retreat. It might explain the decreasing performance of plants at both the population (lower plant height) and the community levels (lower species richness and lower accumulation of species per area). Meanwhile, infrequent spatial associations among plants indicated a facilitation deficit and animal-dispersed plants were almost absent. Although the presence of 21 species on such a small sampled area seven years after glacial retreat could look like a colonization success in the first place, the increasing abiotic stress may partly erase this success, reducing species richness to 13 species after 13 years and increasing the frequency of patches without vegetation. This fine-grain distribution study sheds new light on nature's responses to the effects of climate change in cold biomes, suggesting that faster glacial retreat would not necessarily result in accelerated plant colonization. Results are exploratory and require site replications for generalization.
Gene Banks as Reservoirs to Detect Recent Selection: The Example of the Asturiana de los Valles Bovine Breed
Authors: Boitard Simon , Paris Cyriel , Sevane Natalia , Servin Bertrand , Bazi-Kabbaj Kenza , Dunner Susana
Published: February 2021

Gene banks, framed within the efforts for conserving animal genetic resources to ensure the adaptability of livestock production systems to population growth, income, and climate change challenges, have emerged as invaluable resources for biodiversity and scientific research. Allele frequency trajectories over the few last generations contain rich information about the selection history of populations, which cannot be obtained from classical selection scan approaches based on present time data only. Here we apply a new statistical approach taking advantage of genomic time series and a state of the art statistic (nSL) based on present time data to disentangle both old and recent signatures of selection in the Asturiana de los Valles cattle breed. This local Spanish originally multipurpose breed native to Asturias has been selected for beef production over the last few generations. With the use of SNP chip and whole-genome sequencing (WGS) data, we detect candidate regions under selection reflecting the effort of breeders to produce economically valuable beef individuals, e.g., by improving carcass and meat traits with genes such as MSTN, FLRT2, CRABP2, ZNF215, RBPMS2, OAZ2, or ZNF609, while maintaining the ability to thrive under a semi-intensive production system, with the selection of immune (GIMAP7, GIMAP4, GIMAP8, and TICAM1) or olfactory receptor (OR2D2, OR2D3, OR10A4, and 0R6A2) genes. This kind of information will allow us to take advantage of the invaluable resources provided by gene bank collections from local less competitive breeds, enabling the livestock industry to exploit the different mechanisms fine-tuned by natural and human-driven selection on different populations to improve productivity.
Genetically Modified Rabbits for Cardiovascular Research
Authors: Fan Jianglin , Wang Yanli , Chen Y. Eugene
Published: February 2021

Rabbits are one of the most used experimental animals for investigating the mechanisms of human cardiovascular disease and lipid metabolism because they are phylogenetically closer to human than rodents (mice and rats). Cholesterol-fed wild-type rabbits were first used to study human atherosclerosis more than 100 years ago and are still playing an important role in cardiovascular research. Furthermore, transgenic rabbits generated by pronuclear microinjection provided another means to investigate many gene functions associated with human disease. Because of the lack of both rabbit embryonic stem cells and the genome information, for a long time, it has been a dream for scientists to obtain knockout rabbits generated by homologous recombination-based genomic manipulation as in mice. This obstacle has greatly hampered using genetically modified rabbits to disclose the molecular mechanisms of many human diseases. The advent of genome editing technologies has dramatically extended the applications of experimental animals including rabbits. In this review, we will update genetically modified rabbits, including transgenic, knock-out, and knock-in rabbits during the past decades regarding their use in cardiovascular research and point out the perspectives in future.
Case Report: Simultaneous Hyperprogression and Fulminant Myocarditis in a Patient With Advanced Melanoma Following Treatment With Immune Checkpoint Inhibitor Therapy
Authors: Barham Whitney , Guo Ruifeng , Park Sean S. , Herrmann Joerg , Dong Haidong , Yan Yiyi
Published: February 2021

We report here a patient with stage IV mucosal melanoma treated with dual immune checkpoint inhibitor (ICI) therapy (Nivolumab/Ipilimumab) who experienced rapid disease progression and metastatic spread within three weeks of first infusion. Surprisingly, this patient also developed fulminant myocarditis within the same time frame. Immunohistochemical staining of the primary tumor and a metastatic omental lesion revealed robust CD8+ PD-1+ T cell infiltration after ICI treatment, as would be expected following immune activation. However, the CD8+ T cell infiltrate was largely negative for both Granzyme B and TIA-1, suggesting these T cells were not capable of effective tumor lysis. We discuss the possibility that heightened pro-inflammatory T cell activity (rather than tumor-directed cytolytic activity) was induced by anti-PD-1 and anti-CTLA-4, which could have provoked both rapid tumor resistance mechanisms and myocarditis. This case highlights the fact that the mere presence of tumor infiltrating lymphocytes (TILs) does not necessarily correlate to ICI response and that additional functional markers are necessary to differentiate between inflammatory and cytolytic CD8+ TILs.
Single-Cell RNA Sequencing Reveals the Expansion of Cytotoxic CD4+ T Lymphocytes and a Landscape of Immune Cells in Primary Sjögren’s Syndrome
Authors: Hong Xiaoping , Meng Shuhui , Tang Donge , Wang Tingting , Ding Liping , Yu Haiyan , Li Heng , Liu Dongzhou , Dai Yong , Yang Min
Published: February 2021

Objective

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease, and its pathogenetic mechanism is far from being understood. In this study, we aimed to explore the cellular and molecular mechanisms that lead to pathogenesis of this disease.

Methods

We applied single-cell RNA sequencing (scRNA-seq) to 57,288 peripheral blood mononuclear cells (PBMCs) from five patients with pSS and five healthy controls. The immune cell subsets and susceptibility genes involved in the pathogenesis of pSS were analyzed. Flow cytometry was preformed to verify the result of scRNA-seq.

Results

We identified two subpopulations significantly expand in pSS patients. The one highly expressing cytotoxicity genes is named as CD4+ CTLs cytotoxic T lymphocyte, and another highly expressing T cell receptor (TCR) variable gene is named as CD4+ TRAV13-2+ T cell. Flow cytometry results showed the percentages of CD4+ CTLs, which were profiled with CD4+ and GZMB+ staining; the total T cells of 10 patients with pSS were significantly higher than those of 10 healthy controls (P= 0.008). The expression level of IL-1β in macrophages, TCL1A in B cells, as well as interferon (IFN) response genes in most cell subsets was upregulated in the patients with pSS. Susceptibility genes including HLA-DRB5, CTLA4, and AQP3 were highly expressed in patients with pSS.

Conclusions

Our data revealed disease-specific immune cell subsets and provided some potential new targets of pSS. Specific expansion of CD4+ CTLs may be involved in the pathogenesis of pSS, which might give valuable insights for therapeutic interventions of pSS.
Enterovirus Infections Are Associated With the Development of Celiac Disease in a Birth Cohort Study
Authors: Oikarinen Maarit , Puustinen Leena , Lehtonen Jussi , Hakola Leena , Simell Satu , Toppari Jorma , Ilonen Jorma , Veijola Riitta , Virtanen Suvi M. , Knip Mikael , Hyöty Heikki
Published: February 2021

Enterovirus and adenovirus infections have been linked to the development of celiac disease. We evaluated this association in children who developed biopsy-proven celiac disease (N = 41) during prospective observation starting from birth, and in control children (N = 53) matched for the calendar time of birth, sex, and HLA-DQ genotype. Enterovirus and adenovirus infections were diagnosed by seroconversions in virus antibodies in longitudinally collected sera using EIA. Enterovirus infections were more frequent in case children before the appearance of celiac disease-associated tissue transglutaminase autoantibodies compared to the corresponding period in control children (OR 6.3, 95% CI 1.8–22.3; p = 0.005). No difference was observed in the frequency of adenovirus infections. The findings suggest that enterovirus infections may contribute to the process leading to celiac disease.
Magnitude and Kinetics of T Cell and Antibody Responses During H1N1pdm09 Infection in Inbred Babraham Pigs and Outbred Pigs
Authors: Edmans Matthew , McNee Adam , Porter Emily , Vatzia Eleni , Paudyal Basu , Martini Veronica , Gubbins Simon , Francis Ore , Harley Ross , Thomas Amy , Burt Rachel , Morgan Sophie , Fuller Anna , Sewell Andrew , Charleston Bryan , Bailey Mick , Tchilian Elma
Published: February 2021

We have used the pig, a large natural host animal for influenza with many physiological similarities to humans, to characterize αβ, γδ T cell and antibody (Ab) immune responses to the 2009 pandemic H1N1 virus infection. We evaluated the kinetic of virus infection and associated response in inbred Babraham pigs with identical MHC (Swine Leucocyte Antigen) and compared them to commercial outbred animals. High level of nasal virus shedding continued up to days 4 to 5 post infection followed by a steep decline and clearance of virus by day 9. Adaptive T cell and Ab responses were detectable from days 5 to 6 post infection reaching a peak at 9 to 14 days. γδ T cells produced cytokinesex vivoat day 2 post infection, while virus reactive IFNγ producing γδ T cells were detected from day 7 post infection. Analysis of NP tetramer specific and virus specific CD8 and CD4 T cells in blood, lung, lung draining lymph nodes, and broncho-alveolar lavage (BAL) showed clear differences in cytokine production between these tissues. BAL contained the most highly activated CD8, CD4, and γδ T cells producing large amounts of cytokines, which likely contribute to elimination of virus. The weak response in blood did not reflect the powerful local lung immune responses. The immune response in the Babraham pig following H1N1pdm09 influenza infection was comparable to that of outbred animals. The ability to utilize these two swine models together will provide unparalleled power to analyze immune responses to influenza.
Advances in Human Immune System Mouse Models for Studying Human Hematopoiesis and Cancer Immunotherapy
Authors: Mian Syed A. , Anjos-Afonso Fernando , Bonnet Dominique
Published: February 2021

Immunotherapy has established itself as a promising tool for cancer treatment. There are many challenges that remain including lack of targets and some patients across various cancers who have not shown robust clinical response. One of the major problems that have hindered the progress in the field is the dearth of appropriate mouse models that can reliably recapitulate the complexity of human immune-microenvironment as well as the malignancy itself. Immunodeficient mice reconstituted with human immune cells offer a unique opportunity to comprehensively evaluate immunotherapeutic strategies. These immunosuppressed and genetically modified mice, with some overexpressing human growth factors, have improved human hematopoietic engraftment as well as created more functional immune cell development in primary and secondary lymphoid tissues in these mice. In addition, several new approaches to modify or to add human niche elements to further humanize these immunodeficient mice have allowed a more precise characterization of human hematopoiesis. These important refinements have opened the possibility to evaluate not only human immune responses to different tumor cells but also to investigate how malignant cells interact with their niche and most importantly to test immunotherapies in a more preclinically relevant setting, which can ultimately lead to better success of these drugs in clinical trials.
Circulating Myeloid Regulatory Cells: Promising Biomarkers in B-Cell Lymphomas
Authors: Ferrant Juliette , Lhomme Faustine , Le Gallou Simon , Irish Jonathan M. , Roussel Mikael
Published: February 2021

The monocyte/macrophage lineage has been shown to be involved in the promotion of a protumoral tumor microenvironment and resistance to treatment in B cell lymphomas. However, it is still poorly described at the single cell level, and tissue samples are not easily accessible. Thus, a detailed analysis of the circulating myeloid cell compartment in the different B lymphomas is needed to better understand the mechanisms of resistance to treatment and identify at risk patients. In this Perspective, we review current knowledge on the phenotypic and functional description of the circulating monocytic lineage in B cell lymphomas and provide first insights into the heterogeneity of these cell populations in health and lymphoma, using mass cytometry. Indeed, the monocytic compartment is a continuum more than distinct subpopulations, as demonstrated by our high-resolution approach, explaining the sometimes confusing and contradictory conclusions on the prognostic impact of the different populations, including monocytes and monocytic myeloid derived suppressor cells (M-MDSC). By identifying S100A9high monocytic cells as a potential biomarker in diffuse large B cell lymphoma (DLBCL) in this proof-of-concept preliminary study including a limited number of samples, we underline the potential of circulating myeloid regulatory cells as diagnostic and prognostic biomarkers in B-cell lymphomas.
CBP Bromodomain Inhibition Rescues Mice From Lethal Sepsis Through Blocking HMGB1-Mediated Inflammatory Responses
Authors: Bi Xiaowen , Jiang Baolin , Zhou Jinyi , Fan Xirui , Yan Xintong , Liang Juanjuan , Luo Lan , Yin Zhimin
Published: February 2021

CREB binding protein (CBP), a transcriptional coactivator and acetyltransferase, is involved in the pathogenesis of inflammation-related diseases. High mobility group box-1 protein (HMGB1) is a critical mediator of lethal sepsis, which has prompted investigation for the development of new treatment for inflammation. Here, we report that the potent and selective inhibition of CBP bromodomain by SGC-CBP30 blocks HMGB1-mediated inflammatory responses in vitro and in vivo. Our data suggest that CBP bromodomain inhibition suppresses LPS-induced expression and release of HMGB1, when the inhibitor was given 8 h post LPS stimulation; moreover, CBP bromodomain inhibition attenuated pro-inflammatory activity of HMGB1. Furthermore, our findings provide evidence that SGC-CBP30 down-regulated rhHMGB1-induced activation of MAPKs and NF-κB signaling by triggering the reactivation of protein phosphatase 2A (PP2A) and the stabilization of MAPK phosphatase 1 (MKP-1). Collectively, these results suggest that CBP bromodomain could serve as a candidate therapeutic target for the treatment of lethal sepsis via inhibiting LPS-induced expression and release of HMGB1 and suppressing the pro-inflammatory activity of HMGB1.
Enhanced Production of Astaxanthin by Co-culture of Paracoccus haeundaensis and Lactic Acid Bacteria
Authors: Choi Seong Seok , Seo Yong Bae , Nam Soo-Wan , Kim Gun-Do
Published: February 2021

This study aimed to determine the increase in astaxanthin production from Paracoccus haeundaensis by optimizing the medium conditions and co-culturing with lactic acid bacteria. In order to select a suitable strain to co-culture with P. haeundaensis, several strains were co-cultured with P. haeundaensis. Lactobacillus fermentum was selected as the optimal strain. Further to optimize the astaxanthin production in the co-culture, various medium conditions were tested and the PMF medium developed in this study was selected as the optimum medium. For the co-culture under optimal conditions, the dried cell mass and astaxanthin concentration were 1.84 ± 0.09 g/L and 821.09 ± 30.98 μg/g-dried cell weight, respectively, which was 2.5 times higher than that of the P. haeundaensis strain in the Luria-Bertani broth medium. In order to confirm the transcription level of the carotenoid biosynthesis genes such as crtE, crtB, crtI, crtY, crtZ, and crtW of P. haeundaensis in the co-culture, real-time qPCR was performed. Among the six carotenoid biosynthesis genes, crtI, crtY, and crtZ showed a significant difference in relative RNA levels. The mass culture was performed using a 5 L jar fermenter and the astaxanthin concentration was the same as that at the laboratory scale. These results may be used as reference for co-culture and astaxanthin production in carotenoid biosynthesis microorganisms.
Life History and Ecology of Bluenose Warehou (Hyperoglyphe antarctica, Centrolophidae) in the Southern Atlantic
Authors: Bell James B. , Laptikhovsky Vladimir , Barnes David K. A. , Benedet Ramon , Bridges Amelia E. , Glass James , Glass Warren , Green Rodney , Morley Simon A. , Robertson Simon , Robson Georgia R. , Stanton Harry , Azzopardi Freja , Trueman Clive N. , Yates Oliver , Collins Martin A.
Published: February 2021

Bluenose warehou (Hyperoglyphe antarctica) is a popular commercial fish in Australia and New Zealand, but its biology and ecology are very poorly known in other regions where it is found. We present here the first life history data for this species from the south Atlantic, focusing upon the exclusive economic zone (EEZ) of the United Kingdom Overseas Territory (UKOT) of Tristan da Cunha (TdC). Here, bluenose is known from several seamounts and island margins, typically occurring in waters between 200 and 1,000 m depth and is the target species of trawl and longline fishery operating since 1997. We use a suite of methods to describe important life history parameters, including length-weight and age-length relationships and size at recruitment, as well as examining commercial longline survey data to uncover habitat preferences of bluenose. This work has formed an important part of the United Kingdom government’s Blue Belt Program in TdC. It has underpinned the development of the first stock assessment for this species in the Atlantic, as well as a range of improved conservation measures for some of the more vulnerable species that occur in these areas, including seabirds and cold-water corals.
Effects of Symbiodiniaceae Phylotypes in Clades A–E on Progeny Performance of Two Giant Clams (Tridacna squamosa and T. crocea) During Early History Life Stages in the South China Sea
Authors: Long Chao , Zhang Yuehuan , Li Yunqing , Li Jun , Zhou Zihua , Qin Yanping , Li Xingyou , Ma Haitao , Wei Jinkuan , Zhou Yinyin , Noor Zohaib , Long Lijuan , Yu Ziniu
Published: February 2021

Unlike most bivalves, giant clams (tridacnids) harbor symbiotic microalgae (zooxanthellae) in their other fleshy bodies. The effects of mixed populations of zooxanthellae on larval metamorphosis has been reported in several papers, but there have been very few studies on the effects of single zooxanthella species on the establishment of symbiosis in giant clams. In this study, we obtained five pure zooxanthella species (clades A3, B1, C1, D1, E1) from antler coral by molecular identification, and analyzed their effects on the larval metamorphosis and progeny performance of two giant clams, Tridacna squamosa and T. crocea, in the South China Sea. Clam larvae with all five zooxanthella species underwent larval settlement and metamorphosis, and formed the zooxanthellal tubular system. There was some variation in metamorphic rate and time to metamorphosis between clams with different zooxanthella species, but no significant differences in size at metamorphosis. After metamorphosis, larvae with all zooxanthella types continued to develop normally. Mantle color was consistent within clam species and zooxanthella species had no effect on mantle color. However, clam progeny with clade E1 zooxanthellae were smaller than progeny with the other four zooxanthella clades (A3, B1, C1, and D1). Survival rate was over 90% for all progeny and there were no significant differences in survival between progeny with Symbiodinium clades A–E during the entire culture process. Two-way ANOVA analysis revealed that giant clam species was the main factor influencing progeny growth, with some variation in growth attributable to zooxanthella type. Our results provide new information on both the symbiotic relationship between giant clams and zooxanthellae and the mantle coloration of giant clams, and will be useful in giant clam seed production and aquaculture.