bluuebunny/crossref_metadata_2025 huggingface dataset:
Democratic Traditions of the European Universities as the Development Assurance of Ukrainian Higher Education Institutions in Interwar Period
Authors: ANDRUSYSHYN BOHDAN , TOKARCHUK OLHA
Published: April 2021

The article deals with the study of the Ukrainian scientists’ activities in one of the largest and most notable centres of Ukrainian political emigration since the early twenties of the 20th century – in the Prague one. It has been pointed out that the Ukrainian intellectuals in foreign countries did not abandon their thoughts about the restoration of a united sovereign state. The Ukrainian state and legal thought development were associated both with the functioning of the Ukrainian Free University as well as other higher education institutions and with the broad involving of European democratic traditions during the emigration period.
The professors had to solve such important and difficult tasks as: to create independent university courses on many disciplines for Law Department which programmes had already been significantly expanded in Prague. Having a complicated scientific and methodological work the Ukrainian scientists performed a responsible task successfully; dozens of legal courses were compiled and partially published, most of the specializedcourses differed in originality and made a significant contribution to the development of legal thought and science. Regarding the teaching activity of scientists in emigration, and in the past many of them were lawyers-practitioners and statesmen, we should note that their reports and lecture materials are characterized by deep preparation, content, thoughtfulness and consistency of the basic idea development.
The training of Ukrainian youth in higher education institutions in Czechoslovakia was completely saturated not only with European worldview and methodological approaches, but also retained progressive national-state traditions.
The forced situation, in which legal scientists got, brought them to such a theoretical and practical level of training of legal staff, to which we are only approaching today.
This stage was viewed by young people as temporary and did not even imagine that they would remain in the West forever; prepared to “return home not empty-handed”.
Thus, modern legal education and science need advanced more thorough research on the legal refinement of legal scholars in exile. University students and postgraduate students should take an active part in events where scientists and students of law faculties of Ukrainian higher schools in Europe are popularized. It is advisable to organize discussions about state-legal, socio-political views, cultural activities of figures. It is also necessary to intensify the individual search for the scientific activities of Ukrainian emigration in certain areas of law.
Plasma membrane microparticles in angiogenesis: role in ischemic diseases and in cancer
Authors: Mostefai HA , Andriantsitohaina R , Martínez MC
Published: April 2021

Microparticles are small fragments of the plasma membrane
released by activated and/or apoptotic cells. In theory, all type of
cells can shed microparticles representing a physiological process
in the cell life. Mainly, microparticles generation has been studied
in different cardiovascular pathologies due to the facility to obtain
blood samples from individuals. Although microparticles have
been considered as simply markers of several diseases, in the
last decade, several studies support the hypothesis that they
participate in the regulation of the cardiovascular system function
by carrying biological messages between cells. Among the effects
of microparticles, recent data show that they can be implicated in
the modulation of neovascularization, an essential function of
cells from cardiovascular system during either ischemic diseases
or cancer development. Whereas during pathologies associated
with ischemia an increase of neovascularization may have
beneficial effects, anti-angiogenic strategies represent new
approaches for manipulation of tumor development. Here, we
give an overview of the mechanisms and factors involved in
neovascularization, and finally, we look at the role and the
consequences of the modulation of this process by microparticles
in pathological situations.
Preparation of Li-Doped Indium-Zinc Oxide Thin-Film Transistor at Relatively Low Temperature Using Inkjet Printing Technology
Authors: Choi Woon-Seop
Published: April 2021

Inkjet printing is a very attractive technology for printed electronics and a potential alternative to current high cost and multi-chemical lithography processes, for display and other applications in the electronics field. Inkjet technology can be employed to fabricate organic light emitting diodes (OLED), quantum dots displays, and thin-film transistors (TFTs). Among potential applications, metal oxide TFTs, which have good properties and moderate processing methods, could be prepared using inkjet printing in the display industry. One effective method of improving their electrical properties is via doping. Lithium doping an oxide TFT is a very delicate process, and difficult to get good results. In this study, lithium was added to indium-zinc oxide (IZO) for inkjet printing to make oxide TFTs. Electrical properties, transfer and output curves, were achieved using inkjet printing even at the relatively low annealing temperature of 200 oC. After optimizing the inkjet process parameters, a 0.01 M Li-doped IZO TFT at 400 oC showed a mobility of 9.08 ± 0.7 cm2/V s, a sub-threshold slope of 0.62 V/dec, a threshold voltage of 2.66 V, and an on-to-off current ratio of 2.83 × 108. Improved bias stability and hysteresis behavior of the inkjet-printed IZO TFT were also achieved by lithium doping.
Deconstruction: Speculative Materialism and its Other
Authors: Galetti Dino
Published: April 2021

Since its inception in the late 2000s, supporters of Quentin Meillassoux tended to oppose the movement he founded, speculative materialism, to Derrida and the Derridean community. The arc of Meillassoux's later publications, however, did not support that opposition, especially when it became clear that he neither dismissed correlationism nor set aside literary concerns. These approaches might not be as incompatible as has been supposed. Still, if any affinity is to be established, a first need is to reassess the core of Meillassoux's argument in After Finitude, which has continued to influence his publications. In this article, I attempt not merely to comment upon Meillassoux's argument, but to justify it from within, and so to demonstrate its logic. Then, using a method of re-reading that will be familiar to many, I will attempt to show how that logic reveals speculative materialism and Derridean concerns to be better treated as logical affiliates. Doing so will not presuppose agreement, but will set the stage for more thorough comparisons in future.
Does Low-Magnitude High-Frequency Vibration (LMHFV) Worth for Clinical Trial on Dental Implant? A Systematic Review and Meta-Analysis on Animal Studies
Authors: Ye Xinjian , Gu Ying , Bai Yijing , Xia Siqi , Zhang Yujia , Lou Yuwei , Zhu Yuchi , Dai Yuwei , Tsoi James Kit-Hon , Wang Shuhua
Published: April 2021

Being as a non-pharmacological medical intervention, low-magnitude high-frequency vibration (LMHFV) has shown a positive effect on bone induction and remodeling for various muscle diseases in animal studies, among which dental implants osteointegration were reported to be improved as well. However, whether LMHFV can be clinically used in dental implant is still unknown. In this study, efficacy, parameters and side effects of LMHFV were analyzed via data before 15th July 2020, collecting from MEDLINE/PubMed, Embase, Ovid and Cochrane Library databases. In the screened 1,742 abstracts and 45 articles, 15 animal studies involving 972 implants were included. SYRCLE's tool was performed to assess the possible risk of bias for each study. The GRADE approach was applied to evaluate the quality of evidence. Random effects meta-analysis detected statistically significant in total BIC (P < 0.0001) and BV/TV (P = 0.001) upon loading LMHFV on implants. To conclude, LMHFV played an active role on BIC and BV/TV data according to the GRADE analysis results (medium and low quality of evidence). This might illustrate LMHFV to be a worthy way in improving osseointegration clinically, especially for osteoporosis.

Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO, identifier: NCT02612389
Staging Encystation Progression in Giardia lamblia Using Encystation-Specific Vesicle Morphology and Associating Molecular Markers
Authors: Thomas Elizabeth B. , Sutanto Renaldo , Johnson Richard S. , Shih Han-Wei , Alas Germain C. M. , Krtková Jana , MacCoss Michael J. , Paredez Alexander R.
Published: April 2021

Differentiation into environmentally resistant cysts is required for transmission of the ubiquitous intestinal parasite Giardia lamblia. Encystation in Giardia requires the production, processing and transport of Cyst Wall Proteins (CWPs) in developmentally induced, Golgi-like, Encystation Specific Vesicles (ESVs). Progress through this trafficking pathway can be followed by tracking CWP localization over time. However, there is no recognized system to distinguish the advancing stages of this process which can complete at variable rates depending on how encystation is induced. Here, we propose a staging system for encysting Giardia based on the morphology of CWP1-stained ESVs. We demonstrate the molecular distinctiveness of maturing ESVs at these stages by following GlRab GTPases through encystation. Previously, we established that Giardia’s sole Rho family GTPase, GlRac, associates with ESVs and has a role in regulating their maturation and the secretion of their cargo. As a proof of principle, we delineate the relationship between GlRac and ESV stages. Through proteomic studies, we identify putative interactors of GlRac that could be used as additional ESV stage markers. This staging system provides a common descriptor of ESV maturation regardless of the source of encysting cells. Furthermore, the identified set of molecular markers for ESV stages will be a powerful tool for characterizing trafficking mutants that impair ESV maturation and morphology.
Fibrocartilage Stem Cells in the Temporomandibular Joint: Insights From Animal and Human Studies
Authors: Fan Yi , Cui Chen , Li Peiran , Bi Ruiye , Lyu Ping , Li Yanxi , Zhu Songsong
Published: April 2021

Temporomandibular disorders (TMD) are diseases involving the temporomandibular joint (TMJ), masticatory muscles, and osseous components. TMD has a high prevalence, with an estimated 4.8% of the U.S. population experiencing signs and symptoms, and represents a financial burden to both individuals and society. During TMD progression, the most frequently affected site is the condylar cartilage. Comprising both fibrous and cartilaginous tissues, condylar cartilage has restricted cell numbers but lacks a vascular supply and has limited regenerative properties. In 2016, a novel stem cell niche containing a reservoir of fibrocartilage stem cells (FCSCs) was discovered in the condylar cartilage of rats. Subsequently, FCSCs were identified in mouse, rabbit, and human condylar cartilage. Unlike mesenchymal stem cells or other tissue-specific stem/progenitor cells, FCSCs play a unique role in the development and regeneration of fibrocartilage. More importantly, engraftment treatment of FCSCs has been successfully applied in animal models of TMD. In this context, FCSCs play a major role in the regeneration of newly formed cartilage. Furthermore, FCSCs participate in the regeneration of intramembranous bone by interacting with endothelial cells in bone defects. This evidence highlights the potential of FCSCs as an ideal stem cell source for the regeneration of oral maxillofacial tissue. This review is intended to detail the current knowledge of the characteristics and function of FCSCs in the TMJ, as well as the potential therapeutic applications of FCSCs. A deep understanding of the properties of FCSCs can thus inform the development of promising, biologically based strategies for TMD in the future.
Ce-Doped PANI/Fe3O4 Nanocomposites: Electrode Materials for Supercapattery
Authors: Pandey Subash , Neupane Shova , Gupta Dipak Kumar , Das Anju Kumari , Karki Nabin , Singh Sanjay , Yadav Ram Jeewan , Yadav Amar Prasad
Published: April 2021

In this study, we report on a combined approach to preparing an active electrode material for supercapattery application by making nanocomposites of Polyaniline/Cerium (PANI/Ce) with different weight percentages of magnetite (Fe3O4). Fourier-transform infrared spectroscopy (FTIR) and x-ray diffraction (XRD) analyses supported the interaction of PANI with Ce and the formation of the successful nanocomposite with magnetite nanoparticles. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses showed the uniform and porous morphology of the composites. Cyclic voltammetry (CV) and galvanostatic charge–discharge (GCD) were used to test the supercapattery behavior of the nanocomposite electrodes in 1.0 M H2SO4. It was found that the supercapattery electrode of PANI/Ce+7 wt.% Fe3O4 exhibited a specific capacity of 171 mAhg−1 in the potential range of −0.2 to 1.0 V at the current density of 2.5 Ag−1. Moreover, PANI/Ce+7 wt.% Fe3O4 revealed a power density of 376.6 Wkg−1 along with a maximum energy density of 25.4 Whkg−1 at 2.5 Ag−1. Further, the cyclic stability of PANI/Ce+7 wt.% Fe3O4 was found to be 96.0% after 5,000 cycles. The obtained results suggested that the PANI/Ce+Fe3O4 nanocomposite could be a promising electrode material candidate for high-performance supercapattery applications.
Identification of Zoophilic Dermatophytes Using MALDI-TOF Mass Spectrometry
Authors: Baumbach Christina-Marie , Müller Stefanie , Reuschel Maximilian , Uhrlaß Silke , Nenoff Pietro , Baums Christoph Georg , Schrödl Wieland
Published: April 2021

Dermatophytosesrepresent a major health burden in animals and man. Zoophilic dermatophytes usually show a high specificity to their original animal host but a zoonotic transmission is increasingly recorded. In humans, these infections elicit highly inflammatory skin lesions requiring prolonged therapy even in the immunocompetent patient. The correct identification of the causative agent is often crucial to initiate a targeted and effective therapy. To that end, matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) represents a promising tool. The objective of this study was to evaluate the reliability of species identification of zoophilic dermatophytes using MALDI-TOF MS. The investigation of isolates from veterinary clinical samples suspicious of dermatophytoses suggests a good MALDI-TOF MS based identification of the most common zoophilic dermatophyteMicrosporum canis. Trichophyton (T.)spp. usually achieved scores only around the cutoff value for secure species identification because of a small number of reference spectra. Moreover, these results need to be interpreted with caution due to the close taxonomic relationship of dermatophytes being reflected in very similar spectra. In our study, the analysis of 50 clinical samples of hedgehogs revealed no correct identification using the provided databases, nor for zoophilic neither for geophilic causative agents. After DNA sequencing, adaptation of sample processing and an individual extension of the in-house database, acceptable identification scores were achieved (T. erinaceiandArthrodermaspp., respectively). A score-oriented distance dendrogram revealed clustering of geophilic isolates of four different species of the genusArthrodermaand underlined the close relationship of the important zoophilic agentsT. erinacei, T. verrucosumandT. benhamiaeby forming a subclade within a larger cluster including different dermatophytes. Taken together, MALDI-TOF MS proofed suitable for the identification of zoophilic dermatophytes provided fresh cultures are used and the reference library was previously extended with spectra of laboratory-relevant species. Performing independent molecular methods, such as sequencing, is strongly recommended to substantiate the findings from morphologic and MALDI-TOF MS analyses, especially for uncommon causative agents.
Amylases: Biofilm Inducer or Biofilm Inhibitor?
Authors: Lahiri Dibyajit , Nag Moupriya , Banerjee Ritwik , Mukherjee Dipro , Garai Sayantani , Sarkar Tanmay , Dey Ankita , Sheikh Hassan I. , Pathak Sushil Kumar , Edinur Hisham Atan , Pati Siddhartha , Ray Rina Rani
Published: April 2021

Biofilm is a syntrophic association of sessile groups of microbial cells that adhere to biotic and abiotic surfaces with the help of pili and extracellular polymeric substances (EPS). EPSs also prevent penetration of antimicrobials/antibiotics into the sessile groups of cells. Hence, methods and agents to avoid or remove biofilms are urgently needed. Enzymes play important roles in the removal of biofilm in natural environments and may be promising agents for this purpose. As the major component of the EPS is polysaccharide, amylase has inhibited EPS by preventing the adherence of the microbial cells, thus making amylase a suitable antimicrobial agent. On the other hand, salivary amylase binds to amylase-binding protein of plaque-forming Streptococci and initiates the formation of biofilm. This review investigates the contradictory actions and microbe-associated genes of amylases, with emphasis on their structural and functional characteristics.
Prenatal Management Strategy for Immune-Associated Congenital Heart Block in Fetuses
Authors: Liao Hongyu , Tang Changqing , Qiao Lina , Zhou Kaiyu , Hua Yimin , Wang Chuan , Li Yifei
Published: April 2021

Fetal congenital heart block (CHB) is the most commonly observed type of fetal bradycardia, and is potentially life-threatening. More than 50% of cases of bradycardia are associated with maternal autoimmunity, and these are collectively termed immune-associated bradycardia. Several methods have been used to achieve reliable prenatal diagnoses of CHB. Emerging data and opinions on pathogenesis, prenatal diagnosis, fetal intervention, and the prognosis of fetal immune-associated CHB provide clues for generating a practical protocol for clinical management. The prognosis of fetal immune-associated bradycardia is based on the severity of heart blocks. Morbidity and mortality can occur in severe cases, thus hieratical management is essential in such cases. In this review, we mainly focus on optimal strategies pertaining to autoimmune antibodies related to CHB, although the approaches for managing autoimmune-mediated CHB are still controversial, particularly with regard to whether fetuses benefit from transplacental medication administration. To date there is still no accessible clinical strategy for autoimmune-mediated CHB. This review first discusses integrated prenatal management strategies for the condition. It then provides some advice for clinicians involved in management of fetal cardiovascular disorder.
Case Report: Are We Witnessing an Increase of Chronic Ascending Aortic Dissection as a Collateral Effect to the COVID-19 Pandemic?
Authors: Lyon Arnaud , Gunga Ziyad , Niclauss Lars , Rancati Valentina , Tozzi Piergiorgio
Published: April 2021

Background: The COVID-19 (coronavirus disease 2019) pandemic is reducing health care accessibility to non–life-threatening diseases, thus hiding their real incidence. Moreover, the incidence of potentially fatal conditions such as acute type A aortic dissection seems to have decreased since the pandemic began, whereas the number of cases of chronic ascending aortic dissections dramatically increased. We present two patients whose management has been affected by the exceptional sanitary situation we are dealing with.

Case report: A 70-year-old man with chest pain and an aortic regurgitation murmur had his cardiac workup delayed (4 months) because of sanitary restrictions. He was then diagnosed with chronic type A aortic dissection and underwent urgent replacement of ascending aorta and aortic root. The delay in surgical treatment made the intervention technically challenging because the ascending aorta grew up to 80 mm inducing strong adhesions and chronic inflammation. The second case report concerns a 68-year-old woman with right lower-limb pain who was diagnosed with deep vein thrombosis. However, a CT scan to exclude a pulmonary embolism could not be realized until 5 months later because of sanitary restrictions. When she eventually got the CT scan, it fortuitously showed a chronic dissection of the ascending aorta. She underwent urgent surgery, and the intervention was challenging because of adhesions and severe inflammation.

Conclusion: Delayed treatment due to sanitary restrictions related to COVID-19 pandemic is having a significant impact on the management of potentially life-threatening conditions including type A aortic dissection. We should remain careful to avoid COVID-19 also hitting patients who are not infected with the virus.
Correlation Analysis of Influencing Factors and the Monthly Displacement Increment of a Hydrodynamic Landslide Using a Pseudo-Maximum-Likelihood-Estimation-Mixed-Copula Approach
Authors: Wang Rubin , Zhang Kun , Qi Jian , Xu Weiya , Wang Huanling , Huang Haifeng
Published: April 2021

Heavy rainfall and changes in the water levels of reservoirs directly affect the degree of landslide disasters in major hydropower project reservoir areas. Correlation analyses of rainfall- and water-level fluctuations with landslide displacement changes can provide a scientific basis for the prevention and early warning of landslide disasters in reservoir areas. Because of the shortcomings of the traditional correlation analysis based on linear assumptions, this study proposed the use of a pseudo-maximum-likelihood-estimation-mixed-Copula (MLE-M-Copula) method instead of linear assumptions. We used the Bazimen landslide in the Three Gorges Reservoir Area as a case study to carry out the correlation analysis of the rainfall, water-level fluctuations, and landslide displacement. First, we selected several appropriate influencing factors to construct four candidate Copula models and estimated the parameters using the pseudo-MLE method. After the goodness-of-fit test, we selected the M-Copula model as the optimal model and used this model to study correlations between the monthly displacement increment of the landslide and influencing factors. We then established the joint distribution functions of these correlations. We computed and analyzed the overall and tail correlations between the displacement increment and the influencing factors, and we constructed the conditional probability distribution of the monthly displacement increment for different given conditions. The results showed that the pseudo-MLE-M-Copula method effectively quantified the correlation between the rainfall, reservoir-level fluctuations, and landslide displacement changes, and we obtained the return periods and value at risk of the influencing factors of the Bazimen landslide under different rainfall conditions and reservoir-level changes. Furthermore, the tail correlations between the monthly displacement increment of the landslide and the rainfall- and reservoir-level changes were higher than the overall correlations.
A Bibliometric Analysis of Primary Aldosteronism Research From 2000 to 2020
Authors: Wang Chengyuan , Jing Hongwei , Sun Zuyu , Yao Jiaxi , Zhang Xinyu , Liu Tao , Wu Ying
Published: April 2021

Thousands of papers on primary aldosteronism (PA) have been published in the last two decades. This study aimed to evaluate the research hotspots and future trends in PA research using bibliometric analysis. A total of 2,365 PA research papers between 2000 and 2020 were included. The dominant position of the United States in global PA research throughout this 20-year period was evident, and it was also the country most frequently involved in international cooperation. The University of Padua was the most productive institution and a leader in research collaboration. The Journal of Clinical Endocrinology & Metabolism was the most productive journal in terms of the number of publications on PA. Further, Mulatero P, Reincke M, Beuschlein F and Wu VC all made significant contributions to PA research. Five hotspots have been identified: (1) metabolic syndrome associated with PA; (2) molecular mechanisms of PA; (3) adrenal adenoma and adrenal cortex; (4) hypertension associated with PA; and (5) clinical monitoring parameters and diagnosis in patients with PA. Our results suggest that the molecular mechanisms of PA will remain research hotspots in the future. International collaboration is also expected to widen and deepen in the field of PA research.
Effects of Heterogeneous Environment After Deforestation on Plant Phenotypic Plasticity of Three Shrubs Based on Leaf Traits and Biomass Allocation
Authors: Wang Jinniu , Gao Jing , Wu Yan , Xu Bo , Shi Fusun , Zhou Haiyan , Bisht Neha , Wu Ning
Published: April 2021

Phenotypic plasticity among natural plant populations is a species-specific ecological phenomenon of paramount importance that depends on their life forms, development stages, as well as environmental factors. While this phenomenon is broadly understood, it has hardly been observed in nature. This study aimed at understanding phenotypic plasticity and ecological adaptability in three shrubs (Salix etosia,Rubus setchuenensis, andHydrangea aspera) affected by potential environmental variables after deforesting in sparseLarixspp. forest and tall shrub mixed secondary forests. Soil organic carbon content, total nitrogen content, and available nitrogen content were greater outside the forests, contrary to other measured factors whose availability was higher in the forest interiors. In case of leaf traits and stoichiometric indicators, there were significant interactions of leaf area (LA), leaf dry matter (DW), specific leaf area (SLA), and leaf phosphorus content (LPC) between shrub species and heterogeneous environments (P< 0.05) but not for leaf C/N, N/P, and C/P. Principal components analysis (PCA) indicated that soil temperature, pH value, soil carbon content, soil nitrogen content, and MBC and MBN mainly constituted the first component. Summarized results indicated that TB and leaf C/P ofS. etosiawere significantly correlated with three principal components, but only marginal significant correlations existed between R/S and relevant components. SLA and R/S ofR. setchuenensishad marginal significant relationships with independent variables. Both SLA and TB ofH. asperawere significantly correlated with three principal components. Based on the pooled values of leaf functional traits and leaf stoichiometric indicators,R. setchuenensis(vining type) had better leaf traits plasticity to adapt to a heterogeneous environment. In descending order, the ranks of biomass allocation plasticity index of three shrubs wereH. aspera(bunch type),R. setchuenensis (vining type), andS. etosia(erect type). The highest integrated plasticity values of leaf traits and biomass allocation was observed inH. aspera(bunch type), followed byR. setchuenensis, and byS. etosiawith less adaptive plasticity in heterogeneous environments.
The Hallmarks of Cancer as Ecologically Driven Phenotypes
Authors: Somarelli Jason A.
Published: April 2021

Ecological fitness is the ability of individuals in a population to survive and reproduce. Individuals with increased fitness are better equipped to withstand the selective pressures of their environments. This paradigm pertains to all organismal life as we know it; however, it is also becoming increasingly clear that within multicellular organisms exist highly complex, competitive, and cooperative populations of cells under many of the same ecological and evolutionary constraints as populations of individuals in nature. In this review I discuss the parallels between populations of cancer cells and populations of individuals in the wild, highlighting how individuals in either context are constrained by their environments to converge on a small number of critical phenotypes to ensure survival and future reproductive success. I argue that the hallmarks of cancer can be distilled into key phenotypes necessary for cancer cell fitness: survival and reproduction. I posit that for therapeutic strategies to be maximally beneficial, they should seek to subvert these ecologically driven phenotypic responses.
A Novel Analysis Method for Evaluating the Interplay of Oxygen and Ionizing Radiation at the Gene Level
Authors: Jansen Jeannette , Vieten Patricia , Pagliari Francesca , Hanley Rachel , Marafioti Maria Grazia , Tirinato Luca , Seco Joao
Published: April 2021

Whilst the impact of hypoxia and ionizing radiations on gene expression is well-understood, the interplay of these two effects is not. To better investigate this aspect at the gene level human bladder, brain, lung and prostate cancer cell lines were irradiated with photons (6 Gy, 6 MV LINAC) in hypoxic and normoxic conditions and prepared for the whole genome analysis at 72 h post-irradiation. The analysis was performed on the obtained 20,000 genes per cell line using PCA and hierarchical cluster algorithms to extract the most dominant genes altered by radiation and hypoxia. With the help of the introduced novel radiation-in-hypoxia and oxygen-impact profiles, it was possible to overcome cell line specific gene regulation patterns. Based on that, 37 genes were found to be consistently regulated over all studied cell lines. All DNA-repair related genes were down-regulated after irradiation, independently of the oxygen state. Cell cycle-dependent genes showed up-regulation consistent with an observed change in cell population in the S and G2/M phases of the cell cycle after irradiation. Genes behaving oppositely in their regulation behavior when changing the oxygen concentration and being irradiated, were immunoresponse and inflammation related genes. The novel analysis method, and by consequence, the results presented here have shown how it is important to consider the two effects together (oxygen and radiation) when analyzing gene response upon cancer radiation treatment. This approach might help to unrevel new gene patterns responsible for cancer radioresistance in patients.
Clinical Insights Into Heritable Cardiomyopathies
Authors: Martinez Hugo R. , Beasley Gary S. , Miller Noah , Goldberg Jason F. , Jefferies John L.
Published: April 2021

Cardiomyopathies (CMs) encompass a heterogeneous group of structural and functional abnormalities of the myocardium. The phenotypic characteristics of these myocardial diseases range from silent to symptomatic heart failure, to sudden cardiac death due to malignant tachycardias. These diseases represent a leading cause of cardiovascular morbidity, cardiac transplantation, and death. Since the discovery of the first locus associated with hypertrophic cardiomyopathy 30 years ago, multiple loci and molecular mechanisms have been associated with these cardiomyopathy phenotypes. Conversely, the disparity between the ever-growing landscape of cardiovascular genetics and the lack of awareness in this field noticeably demonstrates the necessity to update training curricula and educational pathways. This review summarizes the current understanding of heritable CMs, including the most common pathogenic gene variants associated with the morpho-functional types of cardiomyopathies: dilated, hypertrophic, arrhythmogenic, non-compaction, and restrictive. Increased understanding of the genetic/phenotypic associations of these heritable diseases would facilitate risk stratification to leveraging appropriate surveillance and management, and it would additionally provide identification of family members at risk of avoidable cardiovascular morbidity and mortality.
The Peripheral Blood Transcriptome Is Correlated With PET Measures of Lung Inflammation During Successful Tuberculosis Treatment
Authors: Odia Trust , Malherbe Stephanus T. , Meier Stuart , Maasdorp Elizna , Kleynhans Léanie , du Plessis Nelita , Loxton Andre G. , Zak Daniel E. , Thompson Ethan , Duffy Fergal J. , Kuivaniemi Helena , Ronacher Katharina , Winter Jill , Walzl Gerhard , Tromp Gerard ,   the Catalysis TB-Biomarker Consortium
Published: April 2021

Pulmonary tuberculosis (PTB) is characterized by lung granulomas, inflammation and tissue destruction. Here we used within-subject peripheral blood gene expression over time to correlate with the within-subject lung metabolic activity, as measured by positron emission tomography (PET) to identify biological processes and pathways underlying overall resolution of lung inflammation. We used next-generation RNA sequencing and [18F]FDG PET-CT data, collected at diagnosis, week 4, and week 24, from 75 successfully cured PTB patients, with the [18F]FDG activity as a surrogate for lung inflammation. Our linear mixed-effects models required that for each individual the slope of the line of [18F]FDG data in the outcome and the slope of the peripheral blood transcript expression data correlate, i.e., the slopes of the outcome and explanatory variables had to be similar. Of 10,295 genes that changed as a function of time, we identified 639 genes whose expression profiles correlated with decreasing [18F]FDG uptake levels in the lungs. Gene enrichment over-representation analysis revealed that numerous biological processes were significantly enriched in the 639 genes, including several well known in TB transcriptomics such as platelet degranulation and response to interferon gamma, thus validating our novel approach. Others not previously associated with TB pathobiology included smooth muscle contraction, a set of pathways related to mitochondrial function and cell death, as well as a set of pathways connecting transcription, translation and vesicle formation. We observed up-regulation in genes associated with B cells, and down-regulation in genes associated with platelet activation. We found 254 transcription factor binding sites to be enriched among the 639 gene promoters. In conclusion, we demonstrated that of the 10,295 gene expression changes in peripheral blood, only a subset of 639 genes correlated with inflammation in the lungs, and the enriched pathways provide a description of the biology of resolution of lung inflammation as detectable in peripheral blood. Surprisingly, resolution of PTB inflammation is positively correlated with smooth muscle contraction and, extending our previous observation on mitochondrial genes, shows the presence of mitochondrial stress. We focused on pathway analysis which can enable therapeutic target discovery and potential modulation of the host response to TB.
The Iron Curtain: Macrophages at the Interface of Systemic and Microenvironmental Iron Metabolism and Immune Response in Cancer
Authors: DeRosa Angela , Leftin Avigdor
Published: April 2021

Macrophages fulfill central functions in systemic iron metabolism and immune response. Infiltration and polarization of macrophages in the tumor microenvironment is associated with differential cancer prognosis. Distinct metabolic iron and immune phenotypes in tumor associated macrophages have been observed in most cancers. While this prompts the hypothesis that macroenvironmental manifestations of dysfunctional iron metabolism have direct associations with microenvironmental tumor immune response, these functional connections are still emerging. We review our current understanding of the role of macrophages in systemic and microenvironmental immune response and iron metabolism and discuss these functions in the context of cancer and immunometabolic precision therapy approaches. Accumulation of tumor associated macrophages with distinct iron pathologies at the invasive tumor front suggests an “Iron Curtain” presenting as an innate functional interface between systemic and microenvironmental iron metabolism and immune response that can be harnessed therapeutically to further our goal of treating and eliminating cancer.
A Structural Landscape of Neutralizing Antibodies Against SARS-CoV-2 Receptor Binding Domain
Authors: Niu Ling , Wittrock Kathryn N. , Clabaugh Gage C. , Srivastava Vikram , Cho Michael W.
Published: April 2021

SARS-CoV-2, the novel coronavirus responsible for the ongoing COVID-19 pandemic, has been spreading rampantly. The global scientific community has responded rapidly to understand immune correlates of protection to develop vaccines and immunotherapeutics against the virus. The major goal of this mini review is to summarize current understanding of the structural landscape of neutralizing antibodies (nAbs) that target the receptor binding domain (RBD) of viral spike (S) glycoprotein. The RBD plays a critical role in the very first step of the virus life cycle. Better understanding of where and how nAbs bind the RBD should enable identification of sites of vulnerability and facilitate better vaccine design and formulation of immunotherapeutics. Towards this goal, we compiled 38 RBD-binding nAbs with known structures. Review of these nAb structures showed that (1) nAbs can be divided into five general clusters, (2) there are distinct non-neutralizing faces on the RBD, and (3) maximum of potentially four nAbs could bind the RBD simultaneously. Since most of these nAbs were isolated from virus-infected patients, additional analyses of vaccine-induced nAbs could facilitate development of improved vaccines.
The Role of Tumor Necrosis Factor in Manipulating the Immunological Response of Tumor Microenvironment
Authors: Laha Dipranjan , Grant Robert , Mishra Prachi , Nilubol Naris
Published: April 2021

The tumor microenvironment (TME) is an intricate system within solid neoplasms. In this review, we aim to provide an updated insight into the TME with a focus on the effects of tumor necrosis factor-α (TNF-α) on its various components and the use of TNF-α to improve the efficiency of drug delivery. The TME comprises the supporting structure of the tumor, such as its extracellular matrix and vasculature. In addition to cancer cells and cancer stem cells, the TME contains various other cell types, including pericytes, tumor-associated fibroblasts, smooth muscle cells, and immune cells. These cells produce signaling molecules such as growth factors, cytokines, hormones, and extracellular matrix proteins. This review summarizes the intricate balance between pro-oncogenic and tumor-suppressive functions that various non-tumor cells within the TME exert. We focused on the interaction between tumor cells and immune cells in the TME that plays an essential role in regulating the immune response, tumorigenesis, invasion, and metastasis. The multifunctional cytokine, TNF-α, plays essential roles in diverse cellular events within the TME. The uses of TNF-α in cancer treatment and to facilitate cancer drug delivery are discussed. The effects of TNF-α on tumor neovasculature and tumor interstitial fluid pressure that improve treatment efficacy are summarized.
ARTEMIS: A Novel Mass-Spec Platform for HLA-Restricted Self and Disease-Associated Peptide Discovery
Authors: Finton Kathryn A. K. , Brusniak Mi-Youn , Jones Lisa A. , Lin Chenwei , Fioré-Gartland Andrew J. , Brock Chance , Gafken Philip R. , Strong Roland K.
Published: April 2021

Conventional immunoprecipitation/mass spectroscopy identification of HLA-restricted peptides remains the purview of specializing laboratories, due to the complexity of the methodology, and requires computational post-analysis to assign peptides to individual alleles when using pan-HLA antibodies. We have addressed these limitations with ARTEMIS: a simple, robust, and flexible platform for peptide discovery across ligandomes, optionally including specific proteins-of-interest, that combines novel, secreted HLA-I discovery reagents spanning multiple alleles, optimized lentiviral transduction, and streamlined affinity-tag purification to improve upon conventional methods. This platform fills a middle ground between existing techniques: sensitive and adaptable, but easy and affordable enough to be widely employed by general laboratories. We used ARTEMIS to catalog allele-specific ligandomes from HEK293 cells for seven classical HLA alleles and compared results across replicates, against computational predictions, and against high-quality conventional datasets. We also applied ARTEMIS to identify potentially useful, novel HLA-restricted peptide targets from oncovirus oncoproteins and tumor-associated antigens.
Snakebite Envenoming Diagnosis and Diagnostics
Authors: Knudsen Cecilie , Jürgensen Jonas A. , Føns Sofie , Haack Aleksander M. , Friis Rasmus U. W. , Dam Søren H. , Bush Sean P. , White Julian , Laustsen Andreas H.
Published: April 2021

Snakebite envenoming is predominantly an occupational disease of the rural tropics, causing death or permanent disability to hundreds of thousands of victims annually. The diagnosis of snakebite envenoming is commonly based on a combination of patient history and a syndromic approach. However, the availability of auxiliary diagnostic tests at the disposal of the clinicians vary from country to country, and the level of experience within snakebite diagnosis and intervention may be quite different for clinicians from different hospitals. As such, achieving timely diagnosis, and thus treatment, is a challenge faced by treating personnel around the globe. For years, much effort has gone into developing novel diagnostics to support diagnosis of snakebite victims, especially in rural areas of the tropics. Gaining access to affordable and rapid diagnostics could potentially facilitate more favorable patient outcomes due to early and appropriate treatment. This review aims to highlight regional differences in epidemiology and clinical snakebite management on a global scale, including an overview of the past and ongoing research efforts within snakebite diagnostics. Finally, the review is rounded off with a discussion on design considerations and potential benefits of novel snakebite diagnostics.
The Potential of Harnessing IL-2-Mediated Immunosuppression to Prevent Pathogenic B Cell Responses
Authors: Papillion Amber , Ballesteros-Tato André
Published: April 2021

Immunosuppressive drugs can partially control Antibody (Ab)-dependent pathology. However, these therapeutic regimens must be maintained for the patient’s lifetime, which is often associated with severe side effects. As research advances, our understanding of the cellular and molecular mechanisms underlying the development and maintenance of auto-reactive B cell responses has significantly advanced. As a result, novel immunotherapies aimed to restore immune tolerance and prevent disease progression in autoimmune patients are underway. In this regard, encouraging results from clinical and preclinical studies demonstrate that subcutaneous administration of low-doses of recombinant Interleukin-2 (r-IL2) has potent immunosuppressive effects in patients with autoimmune pathologies. Although the exact mechanism by which IL-2 induces immunosuppression remains unclear, the clinical benefits of the current IL-2-based immunotherapies are attributed to its effect on bolstering T regulatory (Treg) cells, which are known to suppress overactive immune responses. In addition to Tregs, however, rIL-2 also directly prevent the T follicular helper cells (Tfh), T helper 17 cells (Th17), and Double Negative (DN) T cell responses, which play critical roles in the development of autoimmune disorders and have the ability to help pathogenic B cells. Here we discuss the broader effects of rIL-2 immunotherapy and the potential of combining rIL-2 with other cytokine-based therapies to more efficiently target Tfh cells, Th17, and DN T cells and subsequently inhibit auto-antibody (ab) production in autoimmune patients.
SalaciaML: A Deep Learning Approach for Supporting Ocean Data Quality Control
Authors: Mieruch Sebastian , Demirel Serdar , Simoncelli Simona , Schlitzer Reiner , Seitz Steffen
Published: April 2021

We present a skillful deep learning algorithm for supporting quality control of ocean temperature measurements, which we name SalaciaML according to Salacia the roman goddess of sea waters. Classical attempts to algorithmically support and partly automate the quality control of ocean data profiles are especially helpful for the gross errors in the data. Range filters, spike detection, and data distribution checks remove reliably the outliers and errors in the data, still wrong classifications occur. Various automated quality control procedures have been successfully implemented within the main international and EU marine data infrastructures (WOD, CMEMS, IQuOD, SDN) but their resulting data products are still containing data anomalies, bad data flagged as good and vice-versa. They also include visual inspection of suspicious measurements, which is a time consuming activity, especially if the number of suspicious data detected is large. A deep learning approach could highly improve our capabilities to quality assess big data collections and contemporary reducing the human effort. Our algorithm SalaciaML is meant to complement classical automated quality control procedures in supporting the time consuming visually inspection of data anomalies by quality control experts. As a first approach we applied the algorithm to a large dataset from the Mediterranean Sea. SalaciaML has been able to detect correctly more than 90% of all good and/or bad data in 11 out of 16 Mediterranean regions.
Tumor-Derived Exosomes Enriched by miRNA-124 Promote Anti-tumor Immune Response in CT-26 Tumor-Bearing Mice
Authors: Rezaei Ramazan , Baghaei Kaveh , Hashemi Seyed Mahmoud , Zali Mohammad Reza , Ghanbarian Hossein , Amani Davar
Published: April 2021

Exosomes have been introduced as a new alternative delivery system for the transmission of small molecules. Tumor-derived exosomes (TEXs) not only contain tumor-associated antigens to stimulate antitumor immune responses but also act as natural carriers of microRNAs. The aim of the current study was to evaluate the efficacy of miR-124-3p-enriched TEX (TEXomiR) as cell-free vaccine in the induction of antitumor immune responses in a mouse model of colorectal cancer. Briefly, the exosomes were isolated from cultured CT-26 cell line, and modified calcium chloride method was used to deliver miR-124-3p mimic into the exosomes. We used a CT-26-induced BALB/c mouse model of colorectal cancer and analyzed the effect of TEXomiR on survival, tumor size, spleen and tumor-infiltrated lymphocytes, and splenocyte proliferation. Furthermore, intra-tumor regulatory T cells, cytotoxic activity of the splenocytes, and cytokine secretion was also evaluated to describe the anti-tumor immune response. When the tumor size reached 100 mm3, the mice were injected with TEXomiR, TEX, and/or phosphate-buffered saline (PBS) subcutaneously three times with 3-day interval, and then tumor size was monitored every 2 days. Thein vitroresults indicated that TEXs could efficiently deliver functional miR-124-3p mimic. Thein vivoevaluation in tumor-bearing mice showed that treatment with TEXomiR can elicit a stronger anti-tumor immune response than unloaded TEX and PBS. Significant tumor growth inhibition and increased median survival time was achieved in tumor-bearing mice treated with TEXomiR. A significant decrease in CD4/CD8 and Treg/CD8 ratio in tumor tissue was demonstrated. Moreover, increased cytotoxicity and proliferation of splenocytes in the TEXomiR group compared to the TEX and PBS groups were identified. Taken together, our data demonstrated that tumor-derived exosomes efficiently deliver miR-124-3p mimic, and TEXomiR promotes anti-tumor immune responses.