bluuebunny/crossref_metadata_2025 huggingface dataset:
Hatay’da Bir Okul-Kilise: Kırıkhan Ruhban Okulu
Authors: ÖZKAN Servet
Published: April 2021

Osmanlı Devleti’nde 19. yüzyıl, misyonerlik faaliyetlerinin yoğun olarak yaşandığı bir dönemi kapsamıştır. Oluşan bu yoğunlukta, Tanzimat (1839) ve Islahat Fermanlarının (1856) ilan edilmesi sonrasında gelen reformların ve yabancı devletlere tanınan imtiyazların büyük etkisi olmuştur. Yüzyıl boyunca Osmanlı, her alanda eğitimli bireyler yetiştirmek için yeni okullar inşa ederken, yabancı devletler de Osmanlı topraklarında eğitim kurumu açma hakkına sahip olmuştur. Bu nedenle Amerika, Fransa, İngiltere, Almanya ve İtalya gibi devletler, elde ettikleri çeşitli ayrıcalıklarla Osmanlı coğrafyasında birçok okul açmış ve bu okullar aracılığı ile misyonerlik faaliyetleri yürütmüştür. Bu devletlerden Fransa, daha önce elde ettiği kapitülasyonlar sayesinde Osmanlıdaki misyonerlik çalışmalarına ve okullaşma faaliyetlerine erken başlama imkânı bulmuştur. Fransa’nın gönderdiği çeşitli misyoner gruplar, İstanbul ve Anadolu’nun pek çok yerinde okul açma çalışmalarını hızlandırmıştır. Bunlara örnek eğitim kurumlarından biri de Hatay’ın Kırıkhan ilçesinde bulunmaktadır. Cizvit ve Lazarist misyonerlerinin iş birliği ile açılan ve Kırıkhan Ruhban Okulu olarak anılan okul, Fransız eğitim kurumları içinde plan kuruluşu ve mimari özellikleri ile farklı bir örnek teşkil etmektedir. Okul ve kilisenin tek yapı bünyesinde birleşmesi, Kırıkhan Ruhban Okulu’nun diğer Fransız okullarından ayrılması ve ünik bir örnek olarak değerlendirilmesi açısından önem arz etmektedir. Bunun yanı sıra cephe biçimlenişi ve farklı pencere düzeniyle de okul kendine has özellikler taşımaktadır. Çoğunlukla tarih alanında yapılmış çalışmalara konu olduğu görülen yapının, sanat ve mimarlık tarihi disipliniyle kapsamlı olarak değerlendirilmediği anlaşılmaktadır. Bu çalışmada okul, mimari özellikleri ile tanıtılmış ve sanat tarihi disiplini çerçevesinde detaylı olarak incelenmiştir.
The Fate of the Russian inTelligentsia in the XX Century. Re-Reading Milestones
Authors:   Institute of Philosophy, Renmin University of China, Qinyan An
Published: April 2021

The article provides an analysis of historical events in Russia in the 20th century from the point of view of the influence of the Russian intelligentsia on them, its the­oretical and practical activities. The starting point for the author is the collection Milestones (1909) and the criticism of the intelligentsia, which is the main meaning of the articles in this collection. The author shows that, despite the great influence of the intellectuals on the fate of Russia, they was not able to fully realize its ideals, and the fate of many of them was tragic. Their ideals were in contradiction with the real life of Russia, and later of the Soviet Union, they did not take into account the peculiarities of the development of the Russian and then the Soviet state and society. Their attempts to go against social practice inevitably ended in failure, while the de­sire to act in accordance with social practice often led to results that were contrary to their ideals. According to the author, the fate of the Russian intelligentsia in the 20th century confirmed the correctness of the materialist understanding of history, according to which, in the absence of ideals, movement forward has neither a driv­ing force nor a direction, and without reliance on practice, all ideals turn into utopia. Therefore, the correct solution to the problem of connecting excellent ideals and ob­jective practice is a matter of high political art. In the process of modernizing a backward state, the intelligentsia has a special mission.
Ludwig Wittgenstein As a Fictional Character. Part I
Authors:   Russian Christian Humanitarian Academy, Koval Oxana A. , Kriukova Ekaterina B. ,   Sociological Institute of the Russian Academy of Sciences
Published: April 2021

In these latter days, there is a clear tendency towards convergence in the com­plex relationship between the two language practices – fiction and philosophy. On the one hand, philosophy increasingly turns to the interpretation of important literary texts. On the other hand, literature responds to the challenges of modern thought. This paper focuses on the creative heritage and personality of Ludwig Wittgenstein, the main initiator of “linguistic turn”, from the point of view not of philosophical, but of literary reception. The art of the word in the 20th century was strongly charged due to the language problems. That is why it could not pass over in silence the philosopher, who showed that language activity is one of the fundamental factors in understanding the world. Different authors, such as Terry Eagleton, Bruce Duffy, Winfried G. Sebald, Umberto Eco, Edgar Lawrence Doctorow, Arkadii Dragomoshchenko, brought out in their works – directly or indirectly – a character undoubtedly similar to Wittgenstein. Eventually, the combination of different aspects creates an integral portrait of the Austrian thinker, representing an adequate alternative to philosophical approaches. The fic­titious space of literature allows us to show something that philosophy is unable to say – because of its disciplinary limits and its need to stay inside the facts and laws of logic. This confirms the well-known thesis of “Tractatus Logico-Philo­sophicus”: “What can be shown, cannot be said” (4.1212).
Encyclopedia of Russian Philosophy As Scientific Project
Authors:   Lomonosov Moscow State University, Maslin Michail A.
Published: April 2021

Press conference of the authors and editors devoted to the Third edition of Ency­clopedia Russian Philosophy had been held at January 21 in International press-center of MIA Rossiya-Segodnya [Maslin 2020]. Philosophers – authors of En­cyclopedia, members and guests of Zinoviev club, journalists took part in the event. Among the speakers were: full member of Russian Academy of Sciences A.A. Guseinov, Editor of Encyclopedia, professor Emeritus of Moscow State University M.A. Maslin, director of the publishing house “World of Philosophy” P.P. Aprishko, editor-in-chief A.P. Polyakov, vice-director of Institute of Philoso­phy Russian Academy of Sciences A.V. Chernyaev, executive director of Zi­noviev’s Center V.A. Lepekhine [Press Conference 2020]. The article is devoted to analyses of encyclopedia as philosophical genre reflected the statue of philo­sophical knowledge in Russian culture and it’s social and cultural resonance. The significance of this publication for the modern world philosophical commu­nity lies in the fact that the authors sought to bring together and present different opinions about Russia's intellectual culture and capture a holistic image of Rus­sian philosophy in the variety of its key directions.
Social Philosophy, Social Studies or Generality: the Problem of the Crisis of Sociology
Authors:   MGIMO-Russian Ministry of Foreign Affairs, Simonyan Renald H. ,   Institute of Economics, Russian Academy of Sciences
Published: April 2021

In recent decades, the crisis of sociology has been increasingly discussed in the social science discourse. Many well-known Russian and foreign socio­logists have already spoken out on this issue. Discussions about the theoreti­cal decline, the decline in the social status of sociological science, its transforma­tion from fundamental to applied knowledge are reproduced at congresses and conferences, in numerous publications. The bibliography devoted to the cri­sis of sociology has dozens of sources, and this stream does not decrease. In line with this popular topic, the author substantiates his approach to the analysis of the crisis problem in sociology, which is based on epistemologi­cal contradictions laid down in the creation of the specialized science of so­ciety in the middle of the 19th century – during the rise of positivism, which denies classical philosophy and focuses on an empirical approach, demon­strated high efficiency in the natural sciences, yielding positive results. The article substantiates that the rejection of abstract thinking, the narrowing of the boundaries of knowledge to the framework of empirical knowledge, the reduction of cognitive activity to practical experience, the primacy of methodology over theory are the birth traumas of sociology that brought it to its current position.
Humboldtian Man vs. Utopian Future: On the Mission of University in the Modern World
Authors:   Inter-regional Non-Governmental Organization “Russian Society for History and Philosophy of Science”, Tukhvatulina Liana A.
Published: April 2021

The article analyzes the significance of Wilhelm von Humboldt’s philosophical ideas about the model of the organization of university education in light of modern challenges. The fundamental ideas of the Humboldt’s project are dis­cussed. The “fictitiousness” of the university as a social institution was the most important advantage of Humboldt's educational strategy. The educational agenda here is not determined by institutional interests, which means that it turns out to be flexible and does not seek to maintain the status quo. At the same time, it is the destruction of “fictitiousness” and the university's establishment as a “real” social institution that becomes one of the most important symptoms of the crisis in the modern academic world. One of the vivid expressions of this crisis is the priority of quantitative indicators of the educational process's effectiveness. The key difference of a modern university is its aspiration for the future. In turn, an appeal to the future turns out to be a pseudo-strategy of the educational process, since the future itself is an unattainable goal. At the same time, Hum­boldt’s project suggested that only in the image of a person does the ultimate goal of education find unlimited development opportunities. The author believes that returning to the “Humboldtian man” can be an important task for university reform in the modern world.
Mythogenesis and Anthropogenesis
Authors:   Amur State University, Zabiyako Andrey P.
Published: April 2021

In the period of the 19th – beginning of the 21th century in the study of mythol­ogy three paradigms of the study of mythogenesis have consistently dominated – historical, non-historical and historical-cognitive. The historical-cognitive para­digm is based on the latest scientific results in the field of archeology, anthro­pology and cognitive science. The modern model of anthropogenesis assumes the existence of general regularities of development of three types of Homo – Homo sapiens, Neanderthals and Denisovans. There are reasons that are not only Homo sapiens, but also the Neanderthals and Denisovans had high cognitive ca­pabilities and signs of modern human behavior. The most important foundations of mythogenesis are the functioning of language and the activity of the imagina­tion. All three populations of ancient mankind reached a cognitive minimum, which opened the way to mythogenesis. Signs of mythogenesis are clearly recorded no later than the time of the transition from the Middle to Upper Pale­olithic, during the Early Aurignacian, but the beginning of this process goes back to an earlier period.
Non velut Reges, sed ministros et praecones veritatis: Pastor in the Early Modern Philosophical Discourse
Authors:   Saint Tikhon’s Orthodox University of the Humanities, Vorontsov Sergey A.
Published: April 2021

Early Modern philosophy pays some attention to the image of minister of reli­gion. While its anticlericalism is well known, the positive program of pastor seems to be neglected. This article considers the structure and grounds of this positive image, concentrating on the texts of Hobbes, Spinoza and Pufendorf. It argues that the universal and yet subjective natural light turns out to be the key element for the image of pastor. The method of mathematical demonstration al­lows early Modern philosophers to establish the clear and distinct grounds of morality. They demand the same basis for the pastoral care that should consist of teaching and preaching. The same universal and subjective grounds underlie the division of power and authority between sovereign and individual. Conse­quently, pastor is deprived of any form of power except for the power of demon­stration. The doctrine preached by the pastor should be coherent to the natural light. The use of eloquence or any (other) form of coercion is not allowed for him. Otherwise this doctrine is designated as superstition, i.e. political, moral and epistemic evil. This kind of reasoning brings the pastor under control of in­stances of the reason (represented e.g. by the philosophers) and the sovereign. Finally, the assumption is made that the structure of this ideal Early Modern pas­tor sets the limits of rational-legal order of authority of the religious leader.
Theology as an Icon: Phenomenological Interpretation of the Greak Fathers by Jean-Luc Marion
Authors:   National Research University Higher School of Economics, Yampolskaya Anna V.
Published: April 2021

The paper analysesinterpretations of the Church Fathers by Jean-Luc Marion, a leading figure of the French Phenomenology. For Marion, the theological dis­course should function as an icon: the task of theology is to make God manifest as invisible and inaccessible. According to Marion, Areopagite’s theology is not, properly speaking, “apophatic” or “negative”, because the aim of the theological discourse is not to produce either positive or negative statements concerning God; indeed, such a discourse would remain a captive of onto-theology and would function as an idol. Areopagite does not only name God, he praises divine names in prayer. This allows Marion to interpret Areopagite's theology as a per­formative speech act where praise acts by transforming the speaker. This per­formativity, which is proper to the theological discourse, is inseparable from a particular kind of phenomenalisation of God, although the mode of this phe­nomenalisation differs from that of the apophantic discourse. Divine names do not describe God, but praise Him as the Requisite, making the speaker the one who requires. In later works, Marion interprets divine names as “saturated phe­nomena”. The theologian cannot be described as an agent of phenomenalisation of the Revelation, even though he remains a receiver and a medium of this phe­nomenalisation, thus acquiring the status of its witness, the status of a “gifted one” (l’adonné): receiving his very self from what is made manifest in this phe­nomenalisation. The divine name appeals to the speaker, who makes this calling manifest in his naming reply. The Revelation is revealed to the theologian, and hereby the Revelation reveals the theologian himself.
Two-volume Dynamic CT Pulmonary Perfusion: Contrast Timing Optimization 
Authors: Zhao Yixiao , Hubbard Logan , Malkasian Shant , Abbona Pablo , Molloi Sabee
Published: April 2021

Purpose: To develop and validate an optimal timing protocol for a low-radiation-dose CT pulmonary perfusion technique using only two volume scans.Methods: A total of 24 swine (48.5±14.3 kg) underwent contrast-enhanced dynamic CT. Multiple contrast injections were made under different pulmonary perfusion conditions, resulting in a total of 147 complete pulmonary arterial input functions(AIFs). Using all the AIF curves, an optimal contrast timing protocol was developed for a first-pass, two-volume dynamic CT perfusion technique (one at the base and the other at the peak of AIF curve). A subset of 14 swine with 70 CT acquisitions were used to validate the prospective timing protocol. The prospective two-volume perfusion measurements were quantitatively compared to the previously validated retrospective perfusion measurements with t-test, linear regression and Bland-Altman analysis. Results: The pulmonary artery time-to-peak ( Tpa) was related to one-half of the contrast injection duration( Tinj/2) by Tpa = 1.06 Tinj/2 + 0.90 (r=0.97). The prospective two-volume perfusion measurements (P­­PRO) were related to the retrospective measurements (PRETRO) by PPRO=0.87PRETRO+0.56 (r=0.88). The CT dose index and size-specific dose estimate of the two-volume CT technique were estimated to be 28.4 and 47.0mGy, respectively. Conclusion: The optimal timing protocol can enable an accurate, low-radiation-dose two-volume dynamic CT perfusion technique.
Splay Tree Hybridized Multicriteria ant Colony and Bregman Divergencive Firefly Optimized Vlsi Floorplanning
Authors: Balakrishnan Srinivasan , Venkatesan R.
Published: April 2021

Floorplanning is a basic designing step in VLSI circuit to estimate chip area before the optimized placement of digital blocks and their connections. The process of Floorplanning involves identifying the locations, shape, and size of components in a chip. The floorplanning is a hard problem since the consumption of energy and heat generation was high for the placement of modules. In order to improve the optimized floor planning, a novel Splay tree Hybridized Multicriteria Ant Colony and Bregman Divergencive Firefly Optimized Floor Planning (STHMAC-BDFOFP) technique is proposed. Main objective of STHMAC-BDFOFP technique is to efficient floor planning with minimum time. Initially, a number of modules are given with their connections obtained from benchmark dataset. In STHMAC-BDFOFP, a Splay tree-based non-slicing floor planning model constructing trees via modeling geometric relationship among modules. A splay tree is build after performing different operations namely splaying, join, split, insertion, and deletion on modules for floor planning. The constructed floorplan design is optimized by Hybridized Multicriteria Ant Colony and Bregman Divergencive Firefly algorithm. At first, the ant colony optimization is applied for finding the local optimum solution from the population of modules in the Splay tree with Multicriteria functions namely energy consumption, heat generation, space occupied, and wire length. Depends on fitness measure, the local optimum solution is determined. Then the global solution is attained by applying the Bregman Divergencive Firefly ranked algorithm. In this way, optimum modules in the splay tree are identified and obtain efficient floorplanning in VLSI design. Discussed results indicate that STHMAC-BDFOFP technique improves the performance of energy and heat aware floor planning as compared to conventional works.
A Comparison of Tobacco Product Prevalence by Different Frequency of Use Thresholds Across Three US Surveys 
Authors: Sánchez-Romero Luz María , Cadham Christopher J. , Hirschtick Jana L. , Mattingly Delvon T. , Cho Beomyoung , Fleischer Nancy L. , Brouwer Andrew , Mistry Ritesh , Land Stephanie R. , Meza Rafael , Levy David
Published: April 2021

Background: With the increasing changes in tobacco use patterns, “current use” definition and the survey used may have important implications for monitoring population use trends. Methods: Using three US surveys (2014/15 TUS-CPS, NHIS and PATH), we compared the adult (age 18+) prevalence of four product groups (cigarettes, other combustibles, smokeless tobacco, and e-cigarettes) based on three past 30-day frequency of use thresholds: 1+, 10+, and 25+ days. We also examined mutually exclusive single, dual, and polytobacco users as a percentage of total users for each product group. Results: Regardless of threshold or product, the prevalence was higher in PATH followed by NHIS and TUS-CPS, in some cases by large percentages. The differences in cigarette and smokeless tobacco use prevalence in going from the 1+ to 10+ days and to the 25+ days threshold were minimal. Applying different frequency thresholds had the largest impact on other combustibles prevalence, with a 60% reduction with the 10+ days threshold and a 80% reduction with the 25+ days threshold, compared to the 1+ days threshold, followed by e-cigarettes with 40% and 60% reductions, respectively. The proportion of dual and polytobacco users decreased considerably when using the 10+ vs. the 1+ days threshold and polytobacco use was almost non-existent with the 25+ days threshold. Conclusion: The estimated prevalence of each tobacco product use depends largely on the survey and frequency of use threshold adopted. The choice of survey and frequency threshold merits serious consideration when monitoring patterns of tobacco use.
Naturally Nasal-esophageal Fiberscope in COVID-19 Pandemic - Prevent Sneezing Without Anesthesia
Authors: Tsunoda Koichi , Hentona Ko , Yoshiharu Yamanobe
Published: April 2021

Background: We are laryngologists, to observe natural phonatory and swallowing functions, in every clinical examination with trans-nasal laryngeal fiberscope (TNLF), before the observation, we use epinephrine to enlarge and smoothen inside common nasal meatus (bottom of nostril), then insert wet swab inside the nose, like a swab culture in nasopharynx. In particular current COVID-19 pandemic situation, this careful technique prevents any complications even nasal bleeding, painfulness, and inducing sneezing. Here we introduce our routine to observe esophageal movement in swallowing in natural setting (sitting position) without anesthesia.Case presentation: A case was 70-year-old female who complained something stuck esophagus or strange sensation below the larynx and pharynx. After enlarge and smoothen inside common nasal meatus we insert the TNLF (slim type ⌀29mm fiberscope, VNL8-J10, PENTAX Medical, Tokyo, Japan.) in a same way. Then observe the phonatory and swallowing movement of vocal folds. To get natural movements we had never used any anesthesia. There was no pathological condition in the pyriform sinus, we asked a patient to swallow the fiberscope. At that timing we push the TNLF and insert the tip a bit deeper simultaneously with swallowing, which make the fiberscope easily enter the esophagus like the insertion of nasogastric tube. Then asked the patient to swallow sip of water or saliva, the lumen of esophagus cleared and enlarged. This makes to observe esophagus easily without any air supply. The esophagus is completely normal except glycogenic acanthosis with tone enhancement scan. Conclusions: The advance point of this examination is easily able to perform in sitting position without anesthesia, also takes only a minute and minimum invasive to observe the physiologically natural swallowing. It is also possible without anesthesia until esophagogastric junction using with a thin type flexible bronchoscopy. In the future, diameter of gastric fiberscope even with narrow band imaging (NBI) function might be gradually getting thinner. Before that time every physician should know this technique. Just insert along the bottom of nose.
Southern Ocean convection shutdown controls potential for long-term climate warming by greenhouse gases
Authors: Gjermundsen Ada , Nummelin Aleksi , Olivié D. , Bentsen Mats , Seland Øyvind , Schulz Michael
Published: April 2021

The effective climate sensitivity (EffCS) estimates the equilibrium near-surface temperature increase due to an doubling of the atmospheric carbon dioxide concentration, and is a widely used metric to characterise potential global warming. Cloud feedback, with considerable contribution from marine boundary layer clouds over the Southern Ocean (SO), has been identified as the main source to the spread and the increase in EffCS in the Earth System Models participating in phase 6 of the Coupled Model Intercomparison Project (CMIP6).

We trace the difference in EffCS between the Community Earth System Model (CESM2, EffCS of 5.3K) and the Norwegian Earth System model (NorESM2; EffCS of 2.5K), to SO circulation response. NorESM2 stores more heat at depth than CESM2, which delays the SO surface warming, SO cloud response, and ultimately the global surface warming by centuries in comparison to CESM2. The link between SO and EffCS is seen across 41 CMIP6 models; those with a low EffCS exhibit substantial deep SO warming. The observed slow surface but fast subsurface SO warming supports the notion of SO control over EffCS.
Integrating transcriptome and proteome analysis to determine the lignin synthesis pathway involved in Panax notoginseng in fungal stress
Authors: Yang Qian , Li Jianbin , Xiao Lin , Peng Jiani , Sun Jialing , cui xiuming
Published: April 2021

Background Plants are constantly threatened by various pathogens in a challenging environment. Altemaria panax Whetzel is a destructive pathogen that affects many plants, including Panax notoginseng, and significantly reduces the yield and product quality of Panax notoginseng. It is not clear how Panax notoginseng responds to pathogen infection.Methods Using the advanced advantages of transcriptome and proteomics technology, we studied the response of Panax notoginseng to Altemaria panax stress.Results Compared with the control, fungal infection caused significant changes in the Panax notoginseng transcriptome and proteome. Specifically, a total of 136,100 transcripts and 4,468 proteins were identified. The integration of transcriptome and proteome profiles revealed many candidate transcripts/proteins, which may be involved in lignin synthesis during the activation of defense responses by Panax notoginseng. Many genes and proteins are induced or inhibited by fungi. Among them, the expression levels of genes PAL, 4CL, COMT, CAD and POX in the lignin synthesis pathway are significantly increased, which indicates that the fungus activates the defense response of Panax notoginseng.Conclusions As far as we know, this is the first time that transcriptome and proteome analysis have been combined to study the response of Panax notoginseng to disease. This study provides a wide range of new information about the transcriptome, proteome and their correlation of Panax notoginseng in response to fungal stress. The analysis of this resource allows us to examine the mechanisms of transcription and protein diversification, which expands the knowledge of the complexities of the transcriptome and proteome in traditional Chinese medicines.
Over-representation of MEF-2 isoforms (A/C) is associated with HTLV-1-induced acute ATLL and their recruitment to 3’LTR facilitates HBZ expression from the antisense promoter via interactions with Menin and Jun D
Authors: Madugula Kiran , Joseph Julie , Teixeira Vanessa , Ginwala Rashida , Demarino Catherine , Kashanchi Fatah , Rushing Amanda , Lemasson Isabelle , Wilson Sydney , Sales Dominc , Harhaj Edward , Janakiram Murali , Ye B. Hilda , Khan Zafar K , Jain Pooja
Published: April 2021

Background. HTLV-1 is a complex human retrovirus and an etiologic agent causing a malignant and intractable T-cell neoplasia termed Adult T-cell leukemia and lymphoma (ATLL). Patients suffering from ATLL present with poor prognoses and a dearth of treatment options warranting a continuous need to develop novel therapeutic targets. In contrast to the HTLV-1 transactivator protein Tax, HTLV-1 bZIP protein (HBZ) maintains its expression in ATLL cells. The HBZ gene is encoded from the antisense strand of the provirus and is not under the transcriptional control of the 5’ long terminal repeat (LTR) unlike other viral genes such as Tax. Few modifications have been reported in the 3’LTR, which regulates HBZ expression. Herein, we delineate the activities of a transcription factor MEF (Myocyte enhancer factor)-2 at both 5’ and 3’LTRs in the context of ATLL progression and maintenance. Results. In this study, we report that two MEF isoforms (2A and 2C) are highly overexpressed in acute ATLL patients from North America. These isoforms are recruited to the viral promoters at both the 5’ and 3’LTRs. Their knockdown by shRNAs resulted in the downregulation of Tax and HBZ expression as well as a significant decrease in proliferation and cell cycle arrest in ATLL cells. Similarly, chemical inhibition of MEF proteins by MC1568 (a selective Class IIa HDAC inhibitor) resulted in the cytotoxicity of ATLL cells in vitro as well as reduction of proviral load and viral gene expression in vivo. At the molecular level, high enrichment of MEF-2C occurred at the 3’LTR along with cofactors Menin, Jun D, and Sp1/Sp3 thus providing a novel mechanism of regulation at the antisense promoter of HTLV-1. Conclusions. This study establishes MEF-2 as critical players in ATLL, which interacts with Tax and HBZ at their respective promoters highlighting a novel mechanism of regulation at the 3’LTR involving Jun D and Menin. MEF signaling represent a potential target for therapeutic intervention.
Estimating the impact of Tiny Targets in reducing the incidence of gambiense sleeping sickness in the North West Uganda focus
Authors: Bessell Paul , Esterhuizen Johan , Lehane Mike , Longbottom Joshua , Mugenyi Albert , Selby Richard , Tirados Inaki , Torr Steve J , Waiswa Charles , Wamboga Charles , Hope Andrew
Published: April 2021

Background Riverine species of tsetse (Glossina) transmit Trypanosoma brucei gambiense which causes Gambian human African trypanosomiasis (gHAT), a neglected tropical disease. Uganda aims to eliminate gHAT as a public health problem through detection and treatment of human cases and vector control. The latter is being achieved through the deployment of ‘Tiny Targets’, insecticide-impregnated panels of material which attract and kill tsetse. We analysed the spatial and temporal distribution of cases of gHAT in Uganda during the period 2010-2019 to assess whether Tiny Targets have had an impact on disease incidence.Methods To quantify the deployment of Tiny Targets, we mapped the rivers and their associated watersheds in the intervention area. We then categorised each of these on a 0-3 scale according to whether Tiny Targets were absent (0), present only in neighbouring watersheds (1), present in the watersheds but not all neighbours (2) or present in the watershed and all neighbours (3). We overlaid all cases that were diagnosed between 2000 and 2020 and assessed whether the probability of finding cases in a watershed changed following the deployment of targets. We also estimated the number of cases averted by tsetse control.Results We found that following the deployment of Tiny Targets in a watershed there are fewer cases of HAT (p=0.007). We estimate that during the intervention period 2012-2019 we should have expected 48 cases (95% confidence intervals = 40-57) compared to the 36 cases observed. The results are robust to a range of sensitivity analyses.Conclusions Tiny Targets have reduced the incidence of gHAT by 25% in North Western Uganda.
In Vivo Antiplasmodial Activities and Acute Toxicity Assessment of Two Plant Cocktail Extracts Commonly Used Among Southwestern Nigerians.
Authors: Omagha Rachel , Idowu E.T. , Alimba C.G. , Otubanjo A.O , Agbaje E.O.
Published: April 2021

Discovering and developing the desired antimalarials continue to be a necessity especially due to treatment failures, drug resistance, limited availability and affordability of pharmaceutical antimalarials, costs and logistical problems especially in poor malarious countries. This study investigated the efficacies of two plant cocktails; CtA and CtB, selected based on their traditional usage. Activities of the cocktail extracts, chloroquine and pyrimethamine against Plasmodium berghei berghei were evaluated using the suppressive, curative and prophylactic test models, after oral and intraperitoneal acute toxicity determination of the plant cocktails in accordance with Lorke method. Data was analyzed using SPSS software version 23.0 with level of significance set at P<0.05. The median lethal dose was determined to be higher than 5000 mg/kg body weight orally for both CtA and CtB; and 316.23 mg/kg body weight intraperitoneally for CtA. Each cocktail exhibited high dose dependent Plasmodium berghei berghei inhibition which was 96.95%, 99.13% in the CtA800 mg/kg, CtB800 mg/kg doses in the curative groups respectively, 96.46%, 78.62% for CtA800mg/kg, CtB800mg/kg doses in the suppressive groups respectively, and 65.05%, 88.80% for CtA800mg/kg, CtB800mg/kg doses in the prophylactic groups respectively. Throughout the observation periods, the standard drugs, chloroquine phosphate and pyrimethamine maintained higher inhibitions up to 100%. These findings demonstrate that CtA and CtB possess good antimalarial abilities and calls for their development and standardization as effective and readily available antimalarial options. The acute toxicity results obtained underscore the importance of obtaining information on toxicities of medicinal plant remedies before their administration in both humans and animals.
Anti-Markovnikov Hydro(amino)alkylation of Vinylarenes via Photoredox Catalysis
Authors: Wu Zhao , Gockel Samuel , Hull Kami
Published: April 2021

Photoredox catalysis is a powerful means to generate odd-electron species under mild reaction conditions from a wide array of radical precursors. Herein, we present the application of this powerful catalytic manifold to address the hydroaminoalkylation and hydroalkylation of electronically diverse vinylarenes. Utilizing easily accessible α-silyl amine reagents, secondary and tertiary amine moieties can be installed onto monoaryl and diaryl alkenes to access valuable products, including g,g-diarylamines pharmacophores. This reaction was further extended to allow for generalized alkene hydroalkylation leveraging common alkyl radical precursors, such as organotrifluoroborate salts and carboxylic acids. Thus, under a unified system, both hydroaminoalkylation and hydroalkylation of alkenes are achieved. The substrate scope is evaluated through 54 examples, the synthetic utility of the method is demonstrated, and preliminary mechanistic insights are presented.
IL6ST–induced muscarinic receptor opens goblet cell associated antigen passages to suppress alcoholic liver disease
Authors: Karin Michael , Llorente Cristina , Bruellman Ryan , Cabré Noemí , Brea Rocío , Pell Nuria , Maccioni Luca , Alghafri Ameera , Zhou Rongrong , Gao Bei , Duan Yi , Liu Junlai , Taniguchi Koji , Newberry Rodney , Fouts Derrick , Brenner David , Starkel Peter , Schnabl Bernd
Published: April 2021

Alcohol consumption is the seventh leading risk factor for death worldwide 1 48 and alcoholic liver disease (ALD) is the major cause of liver transplantation in the West 2 49 . Alcohol metabolites can 50 directly damage the liver, but the gut-liver axis also plays an important role in ALD pathogenesis, 51 acting through complex and obscure mechanisms. Although alcohol intake is associated with increased intestinal permeability 3 52 , it is not clear how the intestinal immune system affects liver 53 disease. Paradoxically, we found that chronic alcohol use increases intestinal goblet cell (GC) 54 number and mucin production in patients and mice. This, however, comes with the expense of 55 GC associated antigen passages (GAPs) closure and defective delivery of luminal antigens and 56 bacteria to lamina propria (LP) antigen presenting cells (APCs). IL-6 is one of several cytokines elevated in ALD that affects the liver and the intestine 4 57 . Although IL-6 expression correlates with disease severity 5 , IL-6 also exerts barrier protective effects 6 58 . We now show that GAPs are 59 controlled by intestinal IL-6 signal transducer (IL6ST/gp130). Although mice that express constitutively active gp130 in intestinal epithelial cells (IEC; gp130 60 Act/IEC mice) have fewer GCs 7 61 , they are ALD resistant due to increased GAP formation, which enhances the generation of 62 tolerogenic LP-APCs and production of IL-22 by type-3 innate lymphoid cells (ILC3s). GAP 63 opening induces an intestinal C-type regenerating islet derived-3 (Reg3) lectin-mediated 64 antibacterial defense, reducing bacterial translocation to the liver and preventing alcoholic 65 steatohepatitis. gp130 signaling exerted its protective effects via muscarinic acetylcholine (ACh) 66 receptor 4 (mAChR4), whose GC expression was induced by IL-6. Based on these findings, we 67 developed a new therapeutic approach, administering a mAChR4 positive allosteric modulator 68 (PAM) to stimulate intestinal GAP formation, thereby increasing tolerogenic LP-APCs and Reg3 69 expression, to prevent microbial translocation and protect mice from alcoholic steatohepatitis. 70 Our results show that IL6ST signaling modulates intestinal immunity through mAChR4. GAP 71 induction by mAChR4 PAMs is a promising strategy for enhancing intestinal immune tolerance 72 and interception in ALD and other diseases linked to uncontrolled microbial translocation.
Molecular Breeding of a Novel PTGMS Line of Wdr for Broad-spectrum Resistance to Blast Using Pi9, Pikh, and Pi5 Genes
Authors: Liu Yi , Zhang Fenyun , Luo Xingxing , Kong Deyan , Zhang Anning , Wang Feiming , Pan Zhongquan , Wang Jiahong , Bi Junguo , Luo Lijun , Liu Guolan , Yu Xinqiao
Published: April 2021

Background: The two-line method based on the photoperiod and thermo-sensitive genic male sterile (PTGMS) lines is more cost-effective, simple, and efficient than the three-line system based on cytoplasmic male-sterility (CMS). Blast and drought are the most prevalent biotic and abiotic stress factors that hamper rice production, respectively. Molecular techniques demonstrate higher efficacy in the pyramiding of disease resistance genes, providing green performance under the background of water-saving and drought-resistance rice.Results: This work employed molecular marker-assisted selection (MAS), conventional hybridization and high-intensity stress screening to integrate the broad-spectrum blast resistance genes Pi9, Pikh, and Pi5 into Huhan 1S. Subsequently a novel water-saving and drought-resistance rice (WDR) PTGMS line Huhan 74S was developed. The drought resistance of the new PTGMS line Huhan 74S was comparable to that of Huhan 1S. The artificial inoculation of 14 blast strains revealed that the resistance frequency of Huhan 74S was 85.7%. Based on the conditions of natural field induction, Huhan 74S and its hybrid combination revealed satisfactory resistance to leaf and neck blast. The identification outcomes of photo-thermal characteristics showed that the critical point of Huhan 74S fertility conversion had an average daily temperature of 23℃, and the stable sterile period in Shanghai lasted 51 days. The rice quality of Huhan 74S was grade 3 based on standards issued by the ministry. Also, both the agronomic and rice quality performances adhered to the conditions of two-line hybrid rice production.Conclusion: The newly bred PTGMS line Huhan 74S demonstrated a stable and lasting resistance to blast. Moreover, the hybrid combination showed a high yield potential and can be used in the breeding of high-yield, high-quality, disease-resistance two-line hybrid water-saving and drought-resistance rice (WDR), hence promoting sustainable rice production in China.
CRISPR/Cas-mediated non-viral genome specific targeted CAR T cells achieve high safety and efficacy in relapsed/refractory B-cell non-Hodgkin lymphoma
Authors: Huang He , Zhang Jiqin , Hu Yongxian , Yang Jiaxuan , Li Wei , Zhang Mingming , Tian Yue , Wei Guoqing , Zhang Linjie , Zhao Kui , Tan Binghe , Cui Jiazhen , Qi Yalei , Li Yi , Tian Qiliang , Wang Qingcan , Wu Yuxuan , Li Dali , Du Bing , Liu Mingyao
Published: April 2021

In recent years, chimeric antigen receptor (CAR) T cell therapy has shown great promise in treating hematological malignancies. However, CAR T cell therapy currently has several limitations. Here we successfully developed a two-in-one approach to generate non-viral genome specific targeted CAR T cells through CRISPR/Cas9. Based on the optimized protocol, the feasibility was preliminarily demonstrated by a preclinical study inserting an anti-CD19 CAR cassette into the AAVS1 safe harbor locus. We found that non-viral AAVS1-knockin CAR T cells behave comparably to those conventionally produced by lentivirus. Furthermore, an innovative type of anti-CD19 CAR T cells with PD1-integration was constructed and shows a superior ability to eradicate tumor cells with high PD-L1 expression. In adoptive therapy for relapsed/refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL), we observed a high rate (87.5%) of complete remission (CR) and durable responses without serious adverse events in eight patients after treatment. Notably, these enhanced CAR T cells were effective even at a low infusion dose and with a low CAR percentage, which indicated that they have higher potency. No off-target events were found in the infusion product. Single-cell RNA sequencing analysis further validated the advantage of PD1 interference that results in fewer dysfunctional CAR T cells through this treatment. Collectively, our results demonstrate the outstanding safety and efficacy of non-viral genome specific integrated CAR T cells, thus providing a revolutionary technology for CAR T cell therapy.
Reduced fecal short-chain fatty acids levels and the relationship with gut microbiota in IgA nephropathy
Authors: Chai Lingxiong , Luo Qun , Cai Kedan , Wang Kaiyue , Xu Binbin
Published: April 2021

Background: IgA nephropathy(IgAN)) is the common pathological type of glomerular diseases. The role of gut microbiota in mediating "gut-IgA nephropathy" has not received sufficient attention in the previous studies. The purpose of this study was to investigate the changes of fecal short-chain fatty acids(SCFAs), a metabolite of the intestinal microbiota, in patients with IgAN and its correlation with intestinal flora and clinical indicators, and to further investigate the role of the gut-renal axis in IgAN.Methods: There were 29 patients with IgAN and 29 normal control subjects recruited from January 2018 to May 2018. The fresh feces were collected. The fecal SCFAs were measured by gas chromatography/mass spectrometry and gut microbiota was analysed by16S rDNA sequences, followed by estimation of α- and β-diversity. Correlation analysis was performed using the spearman’s correlation test between SCFAs and gut microbiota. Results:The levels of acetic acid, propionic acid, butyric acid, isobutyric acid and caproic acid in the IgAN patients were significantly reduced compared with control group(P<0.05). Butyric acid(r=-0.336, P=0.010) and isobutyric acid(r=-0.298, P=0.022) were negatively correlated with urea acid; butyric acid(r=-0.316, P=0.016) was negatively correlated with urea nitrogen; caproic acid(r=-0.415,P=0.025) showed negative correlation with 24-h urine protein level.Exemplified by the results of α-diversity and β-diversity, the intestinal flora of IgAN patients was significantly different from that of the control group. Acetic acid was positively associated with c_Clostridia(r=0.357, P=0.008), o_Clostridiales(r=0.357, P=0.008) and g_Eubacterium_coprostanoligenes_group(r=0.283, P=0.036). Butyric acid was positively associated with g_Alistipes (r=0.278, P=0.040). The relative abundance of those were significantly decreased in IgAN group compared to control group.Conclusion: The levels of fecal SCFAs in the IgAN patients were reduced, and correlated with clinical parameters and gut microbiota, which may be involved in the pathogenesis of IgAN, and this finding may provide a new therapeutic approach.
Evaluation of two Plasmodium vivax sexual-stage antigens as transmission-blocking vaccine candidates
Authors: Zhang Yongzhe , Liu Fei , Zhao Yan , Yang Fan , Bai Jie , Jia Xitong , Roobsoong Wanlapa , Sattabongkot Jetsumon , Cui Liwang , Cao Yaming , Luo Enjie , Wang Meilian
Published: April 2021

Background: Plasmodium vivax transmission-blocking vaccines (TBVs) have received high attention. PVX_098655 (PvPH) and PVX_101120 (PvSOP26) were predicted to be potential TBV antigens based on the studies of their orthologs in Plasmodium berghei. Methods: Fragments of PvPH (amino acids 22–304) and PvSOP26 (amino acids 30–272) were expressed in the yeast expression system. The recombinant proteins were used to immunize mice to obtain the antisera. The transmission-reducing activities of these antisera were evaluated using the standard membrane feeding assay (SMFA) using Anopheles dirus mosquitoes and P. vivax clinical isolates. Results: The recombinant proteins PvPH and PvSOP26 induced robust antibody responses in mice. With SMFA, the anti-PvSOP26 sera significantly reduced oocyst densities by 92.0% and 84.1% in two parasite isolates, while the anti-PvPH sera did not show evident transmission-reducing activity. Both PvPH and PvSOP26 showed limited gene polymorphisms in the clinical P. vivax isolates. Conclusion: PvSOP26 could be a promising TBV candidate for P. vivax.
Structure elucidation of the novel carotenoid gemmatoxanthin from the photosynthetic complex of Gemmatimonas phototrophica AP64
Authors: Nupur  , Kuzma Marek , Hájek Jan , Hrouzek Pavel , Gardiner Alastair T. , Lukeš Martin , Moos Martin , Šimek Petr , Koblížek Michal
Published: April 2021

Gemmatimonas phototrophica AP64 is the first phototrophic representative of bacterial phylum Gemmatimonadetes. The cells contain photosynthetic complexes with bacteriochlorophyll a as the main light-harvesting pigment. In addition, the complexes contain a carotenoid with a single broad absorption band at 490 nm in methanol. A combination of nuclear magnetic resonance, high-resolution mass spectroscopy and Fourier-transformed infra-red spectroscopy was used to determine the chemical structure of G. phototrophica light-harvesting carotenoid that we have named gemmatoxanthin. It is a novel linear carotenoid containing 11 conjugated double bonds and further substituted by methoxy, carboxyl and aldehyde group. Its IUPAC-IUBMB semi-systematic name is 1’-Methoxy-19’-oxo-3’,4’-didehydro-7,8,1’,2’-tetrahydro- Ψ, Ψ carotene-16-oic acid. To our best knowledge, the presence of the carboxyl, methoxy and aldehyde groups on a linear C40 carotenoid backbone is reported here for the first time.
Retrospective and cross-sectional study on the prevalence of malaria in selected areas under elimination program in Dembiya district, North-western Ethiopia
Authors: Tarekegn Mihretu , Tekie Habte , Dugassa Sisay , Wolde-hawariat Yitbarek
Published: April 2021

Background: Ethiopia embarked on combating malaria with an aim to eliminate malaria from low transmission districts by 2030. This involves malaria vector interventions by implementing mainly indoor residual spraying (IRS) and long-lasting insecticidal nets (LLINs) against endophilic and endophagic female Anopheles mosquitoes. Limited published reports are available about the status of malaria in areas under malaria elimination program in Ethiopia. This study intended to assess the prevalence of malaria in selected areas with a long history of implementing malaria prevention and elimination strategies. Methods: A cross-sectional parasitological survey was conducted in two selected malaria endemic areas in Dembiya District, Northwest Ethiopia. Thin and thick blood smears collected from 735 randomly selected individuals were microscopically examined for malaria parasites. Six years retrospective malaria data was also collected from the medical records of the health centres. Structured questionnaires were prepared to collect information about the socio-economic data of the population. The data were analysed using SPSS version 20 and p ≤0.05 were considered statistically significant. Results: The six-year retrospective malaria prevalence trend indicates an overall malaria prevalence of 22.4%, out of which Plasmodium falciparum was the dominant species. From a total of 735 slides examined for the presence of malaria parasites, 3.5% (n=26) were positive for malaria parasites, in which P. falciparum was more prevalent (n=17; 2.3%), P. vivax (n=5; 0.7%), and mixed infections (n=4; 0.5%). Males were 2.6 times more likely to be infected with malaria than females (AOR = 2.6; 95% CI: 1.0, 6.4), and individuals with frequent outdoor activity were 16.4 times more vulnerable than individuals with limited outdoor activities (AOR= 16.4, 95% CI: 1.8, 147.9). Furthermore, awareness about malaria transmission was significantly associated with the prevalence of malaria.Conclusions: Malaria is still a public health problem in Dembiya district irrespective of the past and existing vector control interventions. A malaria elimination plan might not be successful unless other alternative intervention tools targeting outdoor malaria transmission are included. For this, continuous monitoring of vectors’ susceptibility, density, and behaviour is very important in such areas.