bluuebunny/crossref_metadata_2025 huggingface dataset:
The Use of Submerged Speleothems for Sea Level Research in the Mediterranean SeA: A New Perspective Using Glacial- and Hydro-Isostatic Adjustment (Gia)
Authors: antonioli fabrizio , Furlani Stefano , Montagna Paolo , Stocchi Paolo
Published: January 2021

The investigation of submerged speleothems for sea level studies has made significant contributions to the understanding of the global and regional sea level variations during the Middle and Late Quateranry. This has been especially the case for the Mediterranean Sea, where more than 300 submerged speleothems sampled in 32 caves have been analysed so far. Here, we present a comprehensive review of the results obtained from the study of submerged speleothems since 1978. The studied speleothems cover the last 1.4 Ma and are focused mainly on Marine Isotope Stages (MIS) 1, 2, 3, 5.1, 5.3, 5.5, 7.1, 7.2, 7.3 and 7.5. Results reveal that submerged speleothems represent extraordinary archives providing accurate information on former sea level changes, also considering that the Mediterranean Sea is devoid of any tropical corals since the Miocene. New results from a stalagmite collected at Palinuro (Campania, Italy) characterized by marine overgrowth are also reported. The measured elevations of speleothems are contaminated by the local response to glacial- and hydro-isostatic adjustment (GIA), and thus might significantly deviate from the global eustatic signal. Age and altitude comparation between Mediterranean speleothems, flowstone from Bahamas with local GIA provide a new scenario for MIS 5 and 7 sea level reconstrutions.
Interpretability in Convolutional Neural Networks for Building Damage Classification in Satellite Imagery
Authors: Chen Thomas
Published: January 2021

Natural disasters ravage the world's cities, valleys, and shores on a monthly basis. Having precise and efficient mechanisms for assessing infrastructure damage is essential to channel resources and minimize the loss of life. Using a dataset that includes labeled pre- and post- disaster satellite imagery, we train multiple convolutional neural networks to assess building damage on a per-building basis. In order to investigate how to best classify building damage, we present a highly interpretable deep-learning methodology that seeks to explicitly convey the most useful information required to train an accurate classification model. We also delve into which loss functions best optimize these models. Our findings include that ordinal-cross entropy loss is the most optimal loss function to use and that including the type of disaster that caused the damage in combination with a pre- and post-disaster image best predicts the level of damage caused. Our research seeks to computationally contribute to aiding in this ongoing and growing humanitarian crisis, heightened by climate change.
Investigation of the Surface Roughness in Infeed Centerless Grinding of SCM435 Steel
Authors: Trung Do Duc ,   Faculty of Mechanical Engineering, Hanoi University of Industry No.298, Cau Dien Street, Bac Tu Liem, Hanoi 100-000, Vietnam, Nguyen Nhu-Tung
Published: January 2021

This study was carried out to investigate the surface roughness in infeed centerless grinding process. The experiment was performed to determine the influence of several technological parameters on the surface roughness. The grinding wheel of Hai Duong Company, Vietnam, was used to machine the SCM435 steel. The experimental matrix was designed using central composite design (CCD). The machining parameters that were used as the input parameters in this study include the workpiece center height, dressing feed rate, regulating wheel velocity, and infeed rate. From the experimental data, an initial model of the surface roughness was built as a quadratic function. Further, a Box-Cox transformation was used to develop a new model from the initial surface roughness data with better accuracy than that of the initial model. The accuracy of the proposed model was verified by comparing the values of the mean absolute error, mean square error, and determination coefficients. This direct approach can be applied for the investigation of other factors during machining processes and can be used in the optimization of machining processes.
A raft or a pyramid: On the nature of intellectual courage
Authors:   Institute of Philosophy, Russian Academy of Sciences, Kasavin Ilya T.
Published: January 2021

The subject matter of the article is the problem of intellectual courage. Its origins can be traced from philosophical ethics, the psychology of morality, virtue epistemology, and the ethics of science. Intellectual courage represents the limit of reasonable fearlessness completing the continuum of “bravery – boldness – courage”. Intellectual courage is an epistemic virtue that ensures the development of knowledge (the discovery and justifica­tion of new theories, risky experiments and inventions) in the face of uncertainty and risk. The intellectual courage as an act of a selfless gift demonstrates the special epistemic sta­tus of the giver and his or her distance from the community. Being unreduced to the qual­ities of personal character, intellectual courage embodies a particular communicative phe­nomenon on the boundary of science and society: the creative loneliness.
Triviality and grammatical cor­rectess: contemporary issues in intensional semantics
Authors:   Institute of Philosophy, Russian Academy of Sciences, Vostrikova Ekaterina V. , Kusliy Petr S. ,   Institute of Philosophy, Russian Academy of Sciences
Published: January 2021

The article is devoted to the study of the semantics of embedded questions (interrogative subordinate clauses), as well as the nature of restrictions on the licensing of declarative and interrogative clauses as complements of propositional attitude verbs. The authors show that this topic goes back to the key aspects of the semantic and cognitive program of G. Frege and is of key importance for the philosophy of language. Using the analytical apparatus of contemporary semantics, the authors investigate this topic on the material of the most recent theoretical works. They show how the semantics of embedded questions contributes to the development of a new perspective on the structure of meaning and the cognitive potential of natural language users. The authors also identify a number of theoretical shortcomings and empirical limitations of several theories of the semantics of embedded questions and point at some directions for future research.
From Traditional the Ethics of Neighbor to the Ethics of Reverence for Life: The Unfinished Step (A. Schweitzer, H. Jonas, S. Donnelley)
Authors:   independent researcher, Gorbunov Svyatoslav Sergeevich , Pugacheva Natalya Petrovna ,   Penza State Agrarian University
Published: January 2021

This is a preface to the translation of one of Albert Schweitzer’s major works, Philosophy and Animal Welfare Movement (Philosophie und Tierschutzbewegung), included in the modern “canon” of Schweitzer’s texts on the reverence for life. We analyzed the development of the ethical thought from the traditional ethics of attitude towards fellow beings through the principle of reverence for life to the modern ethics of life, as outlined in Schweitzer’s works and those of his followers. Our main tasks were to comprehend modern versions of human­ism, the ethics of responsibility and the ethics of life itself, as well as to confirm the relevance of Schweitzer’s ideas through the concepts of life developed by his followers, using com­parative analysis as the main research method. As a result, we showed the continuity and relevance of Schweitzer’s ideas in the new moral realities of the 21st century. The traditional ethics of attitude towards fellow beings is naturally expanded, recognizing living creatures and life in general as the objects of a moral, humane attitude. In addition to the principle of reverence for life, examples of a new ethics are H. Jonas’s ethics of responsibility and onto­logical axiology, as well as S. Donnelley’s ethics of the living, which, in particular, rises the issue of the animals’ individuality. The man’s need to use animals for his own purposes and choose between different life forms, as well as his ability to destroy life itself remains a ma­jor moral problem of the new ethics. Albert Schweitzer paid particular attention to this in his works, one of which was translated by the authors of the article into Russian.
Ethical Interpretation of the Concept of Natural Slavery in Aristotle’s Philosophy
Authors:   Institute of Philosophy, Russian Academy of Sciences, Platonov Roman S.
Published: January 2021

The article examines the interpretation of Aristotle’s conception of natural slavery, which is based on his ethical doctrine. The article sets a goal to show the features of this interpreta­tion and its advantages over more popular interpretation, which is based on Aristotle’s polit­ical doctrine. To do this, we analyze the so-called “aporia of slavery” as one of the main problems of the conception – the incompatibility of defining a slave as a person and as a tool. In Aristotle’s description, the dependent position of the slave is formed due to the limitations of his intellectual activity, primarily the virtue “prudence”, which makes him in­capable of governing in general and of governing himself in particular. In this situation, his activities are limited to craft/art (teсhne), like that of the craftsman, but since he is incapable of governing himself, it is necessary to limit personal freedom. However, Aristotle also li­mits the power of the master, as a result, it becomes possible to communicate between the slave and the master. This communication has a moral goal – the moral development of the slave and the realization of master’s virtues. Not every free, i.e. morally independent, person can be a master, i.e. morally developed enough to guide the development of another person. Thus, the slave becomes a subject of morality – the master has moral obligations to­wards him and only the fulfillment of these obligations is a basis of his power, not the law or origin. In other words, the point is not the exploitation of a person by a person, but is a fair and mutual morally binding distribution of communicative roles, i.e. Aristotle calls a morally dependent person “natural slavery”. All social limitations are secondary and derived from this feature, and this eliminates aporia. Aristotle’s ideas do not correspond to classical or pa­triarchal slavery, they are a unique conception of moral communication.
Religion not only within the Bounds of Bare Reason
Authors:   Institute of Philosophy, Russian Academy of Sciences, Berdnikova Aleksandra Yuryevna
Published: January 2021

The review is devoted to the analysis of the monograph by K.M. Antonov, which represents a fundamentally new and original methodological approach that allows you to look at the history of Russian philosophy of the late XVIII – early XX centuries as a “secular alternative” to the traditional theology. Because of this new methodology it becomes possible to correlate the ideas of Russian thinkers of that era with the problems of modern religious studies, philosophy of religion and philosophical theology. The work of Antonov in this regard can rightfully be called the "continuation" of classical works on the history of Russian religious philosophy by V.V. Zenkovsky, N.O. Lossky and G.V. Florovsky.
The Aristotelian Paradigm of Participation in Byzantine Theology: Gregory of Nyssa on Human Nature as a Monad and Gregory of Palamas on Impossibility of Participation in the Divine Essence
Authors:   National Research University Higher School of Economics, Biriukov Dmitry Sergeyevich ,   Institute of Philosophy and Law of the Siberian Branch of the RAS
Published: January 2021

The article examines how the Aristotelian paradigm of participation works in Gregory of Nyssa’s and Gregory of Palamas’ teachings. Gregory of Nyssa uses this paradigm while developing his teaching on human nature as a monad in the treatise “To Ablabius” and relies in this regard on the “Isagoga” by Porphyry. This version of the Aristotelian paradigm of participation, which is present in Porphyry and Gregory of Nyssa, includes, first, the discourse of the participation of hypostases in their own essence, and, second, the discourse of divisibility of the participating whereas the participated remains indivisible. Gregory Palamas also uses the Aristotelian paradigm of participation in his argumentation on nonparticibility of the divine essence, and, as I suggest in the article, borrows it from Gregory of Nyssa. At the same time, Palamas transforms this discourse and associates the category of divisibility with the situation of participation as such, so that the participated appears divisible. This allows him to assert that in God the energies are participable and not the Divine essence.
The Existence of God and the Resources of Metaphysical Personalism
Authors:   Voronezh Theological Seminary, Prasolov Mikhail Alexeyevich
Published: January 2021

The article analyses and assesses metaphysical personalism – a group of personalists including both Russian (L.M. Lopatin, A.A. Kozlov, P.E. Astaf’ev, S.A. Askol’dov, E.A. Bobrov) and German (G. Teichmüller) philosophers – in the context of modern discussions about the existence of God. The importance and potential of metaphysical personalism stems from its specific features: a conscious task of creating a personalistic metaphysics as a system, understanding of metaphysics as a rational philosophy, critical attitude to its own methods, use of rational controversial arguments in polemics, pursuance of metaphysical substantiation of the Christian theism. The article studies how metaphysical personalism sets and solves the problem of the reality of substance as the concept required to substantiate the existence of God. The concept of substance is given within the Aristotelian tradition as a real self-identical unity, the source and centre of active power. Personalism is particularly focused on proving the equal reality of both the substance and its actions. The concept of substance is substantiated based on the grounds of immediate consciousness (“inner experience”). Only the reality of spiritual, self-conscious individual substances is accepted. Other substances can be conceived by the analogy with the substance of a human subject. However, the criterion of differentiation of the substances of various ontological statuses remains unclear. The ontological argument requires to analyse the concept of being, which is also based on the structure of consciousness, including the substance of the self, its activity and the content of the activity. The immediate consciousness of a man is an archetype of any being. A man can directly access the reality of God in the consciousness of the own being. Therefore, the evidence of the existence of God results from the self-evidence of the consciousness of a substantial subject. Metaphysical personalism using the resources of the rational metaphysics has substantiated the existence of God through the structures and immediate experience of the consciousness of the subject.
Metaphysics of the Divine Intellection in Marius Victorinus and its Possible Philosophical Sources
Authors:   Institute of Philosophy, Russian Academy of Sciences, Fokin Alexey Ruslanovych
Published: January 2021

The article deals with the doctrine of Marius Victorinus (ca. 281/291‒382/386) on the Divine thinking or intellection, and provides a reconstruction of its possible philosophical sources. In the beginning the author after a breaf mentioning of Aristotle’s noetic theory in his “Metaphysica” emphasizes an important role of the neoplatonic doctrine of the “intelligible triad” in the Trinitarian doctrine of Victorinus, in which God is seen as the unity of the three Divine attributes, potencies or acts: being, life and thought, which correspond to the persons of the Christian Trinity. It is noted that the relationship between these Divine acts has a dynamic character, based on the logic of the eternal process of self-determination of God as the pure Being (Father), which defines himself as the Life (Son) and returns to himself as the Intellect (Holy Spirit), by which the fullness of Divine self-knowledge is achieved. This process Victorinus also connects with the idea of God as an absolute Spirit –a Substance that exists, lives and thinks of itself. Further the author consideres Victorinus’ concept of two actions and movements in God: one is internal, characterizing God the Father, the other is external, characterizing the Son-Logos. It has been argued that this doctrine goes back to the similar doctrine of Plotinus, which he applies to the One and the Intellect. It is noted that Victorinus in the light of the Neo-Platonic dialectics of the One and the Intellect reconsidered an Aristotelian theory of Divine intellect, which thinks of itself. He not only applies it to the Son-Logos, but also joins to it a Plotinian-Porphyrian conception of the “super-thinking” of the One, as a result of which Divine thinking according to Victorinus has two different forms: an internal, potential, hidden and unmanifest thinking (or “super-thinking”) of God the Father, and an external, actual and manifested thinking (or “self-thinking”) of the Son-Logos; the latter initially dwells in the internal thinking of the Father, and then was genereted from it as a Divine thinking that thinks both of the Father and of itself, becoming self-knowledge or self-thinking.
Factors associated with work-private life conflict and leadership qualities among line managers of health professionals in Swiss acute and rehabilitation hospitals – a cross-sectional study
Authors: Peter Karin Anne , Halfens Ruud JG , Hahn Sabine , Schols Jos MGA
Published: January 2021

Background: The workforce shortage of health professionals is a matter of global concern. Among possible causative factors in this shortage are work-private life conflicts related to increased stress and burnout symptoms, job dissatisfaction and a higher intention to leave the profession prematurely. Also, poor leadership qualities among direct line managers (e.g. clinic directors, leading physicians, ward managers, team leaders) have been associated with health professionals’ job dissatisfaction and intention to leave in previous studies. Therefore, this study aimed to identify key associated factors of work-private life conflicts and managerial leadership quality among health professionals.Methods: The study is based on a cross-sectional survey in 26 Swiss acute and rehabilitation hospitals, consisting of 3398 health professionals from various disciplines. For data analysis, multilevel models (with hospitals as the second level variable) were performed for ‘work-private life conflict’ and ‘quality of leadership’, considering significant main effects (using AIC) and significant interactions (using BIC) of potential explanatory variables.Results: The main findings reveal that the compatibility of health professionals’ work and private life is associated with topics of shift planning, in particular workers’ influence on shift planning (possibility of exchanging shifts, B=-2.87, p<0.01), the extent to which their individual preferences are considered (e.g. working on one specific shift only, B=6.31, p<0.01), number of shifts per weekend (B=1.38, p<0.01) and number of hours per week (B=0.13, p<0.01) that they had to work. In addition, high quantitative demands (B=0.25, p<0.01), being required to hide their emotions (B=0.16, p<0.01) and poor social community support at work (B=-0.12, p<0.01) were also related to severe work-private life conflict. Regarding managerial leadership, health professionals perceived the leadership qualities of their direct line manager as being better if they received more social support (B=0.61, p<0.01) and rewards (B=0.41, p<0.01) at work. Conclusions: The results show key components of improving the compatibility of work and private life as well as managerial leadership qualities among health professionals and may help health care leaders working in acute or rehabilitation hospitals to develop appropriate interventions.
Quality of Life and its Related Factors in Women with Substance Use Disorders Referring to Substance Abuse Treatment Centers
Authors: Barati Majid , Bandehelahi Khadijeh , Nopasandasil Tahereh , Jormand Hanieh , Keshavarzi Amir
Published: January 2021

Background: Substance-Related Disorders are among the most common social problems caused by using legal and illegal substances. Therefore, this study aimed at determining the quality of life (QoL) and its related factors among women with substance use disorders referring to substance abuse treatment centers in Hamadan, west of Iran.Methods: This cross-sectional study was carried out on 120 Iranian female substance users recruited through the census sampling method in 2018. Data collection tools consisted of demographic characteristics and QoL assessment (SF-36). Data were analyzed using SPSS-16 via one-way analysis of variance (ANOVA) and chi-square tests.Results: The mean age of the participants was 33.2±12.1 years and the mean score of their total QoL was 35.35±13.5. The results of multiple linear regression analysis indicated that using methamphetamine (β=-6.62) was the predictor of QoL in women. Moreover, there was a significant association between QoL and age (p <0.001), educational level (p = 0.011), and age at first use (p <0.001).Conclusion: According to the results, the participants’ QoL was found to be at an unsatisfactory level. So, it is essential to implement educational help-seeking behavior for treatment and effectiveness educational, as well as holding mental health intervention, school-based substance abuse prevention, and harm reduction programs of substance use. This is especially important in adolescents, young, low-educated, early drug use, and methamphetamine user women, as it may increase the QoL
Active constituents of Zanthoxylum nitidum from Yunnan Province against leukemia cells in vitro
Authors: Deng Ying , Ding Tongtong , Deng Lulu , Hao Xiaojiang , Mu Shu Zhen
Published: January 2021

Zanthoxylum nitidium (Roxb.) DC (Rutaceae) is well known for inhibiting the proliferation of human gastric, liver, kidney and lung cancer cells, though research on its potential use in treating leukaemia is relatively rare. Twenty-six compounds were isolated from the chloroform and petroleum ether extracts of the roots and leaves of Z. nitidium (Zanthoxylum nitidium). They were (+)-9′-O-transferuloyl-5, 5′-dimethoxylaricriresinol (1), 8-(3′-oxobut-1′-en-1′-yl)-5, 7-dimethoxy-coumarin (2), 5, 7, 8-trimethoxy-coumarin (3), 5-(3′, 3′-dimethyl-2′-butenyloxy)-7, 8-dimethoxy-coumarin (4), 2-(5-methoxy-2-methyl-1H-indol-3-yl) methyl acetate (5), 2′-(5, 6-dihydrochleletrythrine-6-yl) ethyl acetate (6), 6-acetonyldi-hydrochelerythrine (7), 6β-hydroxymethyldihydronitidine (8), bocconoline (9), zanthoxyline (10), O-methylzanthoxyline (11), rhoifoline B (12), N-nornitidine (13), nitidine (14), chelerythrine (15), 4-hydroxyl-7,8-dimethoxy-furoquinoline (16), dictamnine (17), γ-fagarine (18), skimmianine (19), robustine (20), R-(+)-platydesmine (21), 4-methoxyl-1-methyl-2-quinoline (22), 4-methoxy-2-quinolone (23), liriodenine (24), aurantiamide acetate (25), 10-O-demethyl-12-O-methylarnottianamide (26). Four among them, compounds 4-6 and 16, were first confirmed in this study by UV, IR, 1D, 2D NMR and HR-ESI-MS spectra. Compounds 1-2 and 11 were isolated from Z. nitidium for the first time. Of the assayed compounds, 1, 2, 9, 10, 14, 15 and 24, exhibited good inhibitory activities in the leukaemia cell line HEL, whereas compound 14 (IC50: 3.59 µM) and compound 24 (IC50: 15.95 µM) exhibited potent inhibitory activities. So, to further investigate the possible mechanisms, cell cycle and apoptosis assays were performed, which indicated that compound 14 causes obvious S-phase arrest in HEL cells and induced apoptosis, whereas compound 24 only induced apoptosis. The present results suggested both compounds 14 and 24 are promising potential anti-leukaemia drug candidates.
A novel tumour-on-chip microfluidic platform advances assessment of drug pharmacokinetics and treatment response
Authors: Petreus Tudor , Cadogan Elaine , Hughes Gareth , Smith Aaron , Reddy Venkatesh , Lau Alan , O'Connor Mark , Critchlow Susan , Ashford Marianne , O'Connor Lenka Oplustil
Published: January 2021

Microphysiological in vitro systems are platforms for preclinical evaluation of drug effects and significant advances have been made in recent years. However, existing microfluidic devices are not yet able to deliver compounds to cell models in a way that reproduces the real physiological drug exposure. Here, we introduce a novel tumour-on-chip microfluidic system that mimics the pharmacokinetic profile of compounds on 3D tumour spheroids to evaluate their response to the treatments. We used this platform to test the response of SW620 colorectal cancer spheroids to irinotecan (SN38) alone and in combination with the ATM inhibitor AZD0156, using concentrations mimicking mouse plasma exposure profiles of both agents. We explored spheroid volume and viability as a measure of cancer cells response and changes in mechanistically relevant pharmacodynamic biomarkers (γH2AX, cleaved-caspase 3 and Ki67). We demonstrate here that our microfluidic tumour-on-chip platform can successfully predict the efficacy from in vivo studies and therefore represents an innovative tool to guide drug dose and schedules for optimal efficacy and pharmacodynamic assessment, while reducing the need for animal studies.
Bioinformatics analysis of expression profiling by high throughput sequencing for identification of potential key genes among SARS-CoV-2/COVID 19
Authors: Vastrad Basavaraj Mallikarjunayya , Vastrad Chanabasayya Mallikarjunayya
Published: January 2021

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is pandemic recently emerged and is rapidly spreading in humans. However, the precise molecular mechanisms of the advancement and progression of SARS-CoV-2 infection remain unclear. The current investigation attempted to identify and functionally analyze the differentially expressed genes (DEGs) between SARS-CoV-2 infection and mock by using comprehensive bioinformatics analyses. The GSE148729 expression profiling by high throughput sequencing was downloaded from the Gene Expression Omnibus (GEO) and analyzed using the limma package in R software to identify DEGs. Pathway and gene ontology (GO) enrichment analysis of the up and down regulated genes were performed in ToppGene. The HIPPIE database was used to evaluate the interactions of up and down regulated genes and to construct a protein-protein interaction (PPI) network using Cytoscape software. Hub genes were selected using the Network Analyzer plugin. Subsequently, extensive target prediction and network analyses methods were used to assess, target gene - miRNA regulatory network and target gene - TF regulatory network. Receiver operating characteristic (ROC) analysis was utilized for validation. A total of 928 DEGs (461 up regulated genes and 467 down regulated genes) were identified between SARS-CoV-2 infection and mock samples. The Pathway enrichment analysis results showed that these up and down regulated genes were significantly enriched in cytokine-cytokine receptor interaction, and ascorbate and aldarate metabolism. Several significant GO terms, including the response to biotic stimulus and oxoacid metabolic process, were identified as being closely associated with these up and down regulated genes. The top hub genes and target genes were screened and included JUN, FBXO6, PCLAF, CFTR, TXNIP, PMAIP1, BRI3BP, FAHD1, PROX1, CXCL11, SERHL2 and CFI. ROC curve analysis showed that messenger RNA levels of these ten genes (DDX58, IFITM2, IRF1, PML, SAMHD1, ACSS1, CYP2U1, DDC, PNMT and UGT2A3) exhibited better diagnostic efficiency for SARS-CoV-2 infection and mock. The current investigation identified a series of key genes and pathways that may be involved in the progression of SARS-CoV-2 infection, providing a new understanding of the underlying molecular mechanisms of SARS-CoV-2 infection.
Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma
Authors: Nolan Garry , Phillips Darci , Matusiak Magdalena , Gutierrez Belén , Bhate Salil , Barlow Graham , Jiang Sizun , Demeter Janos , Smythe Kimberly , Pierce Robert , Fling Steven , Ramchurren Nirasha , Cheever Martin , Goltsev Yury , West Robert , Khodadoust Michael , Kim Youn , Schürch Christian
Published: January 2021

Anti-PD-1 immunotherapies have transformed cancer treatment, yet the determinants of clinical response are largely unknown. We performed CODEX multiplexed tissue imaging and RNA sequencing on 70 tumor regions from 14 advanced cutaneous T cell lymphoma (CTCL) patients enrolled in a clinical trial of pembrolizumab therapy. Clinical response was not associated with the frequency of tumor-infiltrating T cell subsets, but rather with striking differences in the spatial organization and functional immune state of the tumor microenvironment (TME). After treatment, pembrolizumab responders had a localized enrichment of tumor and CD4+ T cells, which coincided with immune activation and cytotoxic PD-1+ CD4+ T cells. In contrast, non-responders had a localized enrichment of Tregs pre- and post-treatment, consistent with a persistently immunosuppressed TME and exhausted PD-1+ CD4+ T cells. Integrating these findings by computing the physical distances between PD-1+ CD4+ T cells, tumor cells, and Tregs revealed a spatial biomarker predictive of pembrolizumab response. Finally, the chemokine CXCL13 was upregulated in tumor cells in responders post-treatment, suggesting that chemoattraction of PD-1+ CD4+ T cells towards tumor cells facilitates a positive outcome. Together, these data show that T cell topography reflects the balance of effector and suppressive activity within the TME and predicts clinical response to PD-1 blockade in CTCL.
Petabyte-Scale Multi-Morphometry of Single Neurons for Whole Brains
Authors: Jiang Shengdian , Wang Yimin , Liu Lijuan , Zhao Sujun , Chen Mengya , Zhao Xuan , Xie Peng , Ding Liya , Ruan Zongcai , Dong Hongwei , Ascoli Giorgio , Hawrylycz Michael , Zeng Hongkui , Peng Hanchuan
Published: January 2021

Recent advances in brain imaging allow producing large amounts of 3-D volumetric data from which morphometry data is reconstructed and measured. Fine detailed structural morphometry of individual neurons, including somata, dendrites, axons, and synaptic connectivity based on digitally reconstructed neurons, is essential for cataloging neuron types and their connectivity. To produce quality morphometry at large scale, it is highly desirable but extremely challenging to efficiently handle petabyte-scale high-resolution whole brain imaging database. Here, we developed MorphoHub to address this challenge by optimizing both the data and workflow management. In particular, this work presents a multi-level method to produce high quality somatic, dendritic, axonal, and potential synaptic morphometry. Our method also boosts data sharing and remote collaborative validation. We applied MorphoHub to a petabyte application dataset involving 62 whole mouse brains, and identified 50,233 somata of individual neurons, profiled the dendrites of 11,322 neurons, reconstructed the full 3-D morphology of 1,050 neurons including their dendrites and full axons, and detected 1.9 million putative synaptic sites derived from axonal boutons. Analysis and simulation of these data indicate the promise of this approach for modern large-scale morphology applications.
Mealtime Caregiving Approaches and Behavioral Symptoms in Persons Living With Dementia: A Longitudinal, Observational Study
Authors: Lee Ji Yeon , Lee Kyung Hee , McConnell Eleanor
Published: January 2021

Background: Behavioral symptoms during mealtime can prohibit persons living with dementia from obtaining sufficient nutrition. However, little research has examined the relationship between behavioral symptoms and caregiving approaches. This study examines this relationship and further explores which specific caregiver behaviors were related to behavioral symptoms among persons living with dementia. Methods: A secondary data analysis was performed using 86 mealtime videos from a longitudinal, observational study. The videos were repeatedly taken at months 0, 3, and 6 with 30 persons living with dementia in one of four long-term care facilities. Video coding was performed using coding schemes modified from the Cohen-Mansfield Agitation Inventory for behavioral symptoms and the Person-/Task-Centered Behavior Inventory for caregiving approaches. Coding schemes for behavioral symptoms consisted of four categories: total duration, aggressive behavior, physically nonaggressive behavior, and verbally agitated behavior. Caregiving approaches consisted of ten-verbal/seven-nonverbal person-centered behavior codes, four-verbal/four-nonverbal task-centered behavior codes, and no-verbal/no-nonverbal interaction codes. A mixed-effect model was conducted using variables such as demographics, medical information, cognitive status, depression, function, and caregiving approaches as fixed effects, participant as a random effect, and four categories of behavioral symptoms as dependent variables. Results: The total duration of the Cohen-Mansfield Agitation Inventory was associated with no verbal response (β = 9.09) and task-centered verbal behavior (β = 8.43), specifically verbal controlling (β = 7.87). Physically nonaggressive behavior was associated with no verbal response (β = 9.36). Verbally agitated behavior was associated with task-centered nonverbal behavior (β = 51.29), and specifically inappropriate touch (β = 59.05). Conclusions: Mealtime is indispensable to dementia care, but best practices for mealtime have not been suggested when behavioral symptoms are present. Our findings revealed caregivers’ task-centered behaviors and no interaction were related to behavioral symptoms of persons living with dementia. When caregivers encounter behavioral symptoms during mealtime, it is recommended to avoid no response and task-centered behaviors, especially verbal controlling and inappropriate touch, and to promote person-centered behaviors.
Serum Albumin Levels as a Predictive Biomarker for Low-Load Resistance Training Programs’ Effects on Muscle Thickness in the Community-Dwelling Elderly Japanese Population: Results From the Interventional Study
Authors: Sawada Shuji , Ozaki Hayao , Natsume Toshiharu , Nakano Daiki , Deng Pengyu , Yoshihara Toshinori , Osawa Takuya , Kobayashi Hiroyuki , Machida Shuichi , Naito Hisashi
Published: January 2021

Background Resistance training has been recommended as an effective measure against age-related loss of muscle mass and muscle strength, called sarcopenia, even in older adults. However, despite subjecting each participant to the same training program, the training effect solely depended on the individual. This study aimed to evaluate whether certain blood parameters influenced the effect of a low-load resistance training program on muscle thickness in the community-dwelling elderly population.Methods Sixty-nine community-dwelling Japanese (49 women and 20 men) subjects aged 69.4±6.5 years were included. Low-load resistance training was performed twice a week for 12 weeks. Muscle thickness at the anterior aspects of the thigh (AT) was measured using a B-mode ultrasound device, and 22 blood parameter levels were assessed before and after the program. We checked the first quartile value of each parameter to establish cutoff values, and participants were divided into low or normal groups for each parameter.Results A low-load resistance training program significantly increased muscle thickness at the AT. The interaction between time and groups was examined at low (<4.1 g/dL) versus normal (≥4.1 g/dL) serum albumin (Alb) levels. Although there was no difference in muscle thickness at the AT before the training intervention, the hypertrophic effects were higher in the normal serum Alb level group than in the low serum Alb level group. The binomial logistic regression analysis showed that participants in the low serum Alb group had an odds ratio of 7.08 for decreased muscle thickness at the AT. The effect of a low-load resistance training program on lower limb muscle thickness appears to be limited in participants with low serum Alb levels before training interventions.Conclusions Serum Alb level may act as a biomarker to predict the effects of low-load resistance training programs on muscle hypertrophy in elderly individuals.Trial registration This study was retrospectively registered in UMIN-Clinical Trial Registry (CTR), ID: UMIN000042759. Date of registration: 14/12/2020.
Th Cytokine Profile in Childhood-Onset Systemic Lupus Erythematosus
Authors: Quan Wei , An Jingnan , Li Gang , Qian Guanghui , Jin Meifang , Feng Chenxi , Li Si , Li Xiaozhong , Xu Yunyun , Hu Xiaohan
Published: January 2021

Background: Childhood-onset systemic lupus erythematosus (cSLE) is a kind of chronic inflammatory disease characterized by a highly abnormal immune system. This study aimed to detect expression of the Th cytokines IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-21, IL-22, IFN-γ and TNF-α in the peripheral blood of children with cSLE; clinical symptoms; and a disease index and discuss the relationship between the Th cell cytokine regulatory network and onset of systemic lupus erythematosus (SLE) in children and disease outcome.Methods: A total of 33 children with cSLE and 30 healthy children were enrolled in this study. Children in the cSLE group were classified into the inactive cSLE group or active cSLE group according to their SLE disease activity index 2000 (SLEDAI-2K). Th cytokine profiles in peripheral blood of different groups were detected and analyzed.Results: The levels of IL-2, IL-10 and IL-21 in the cSLE group were significantly higher than those in the healthy control group (P < 0.05, P<0.01 and P<0.01, respectively). The expression of IL-2, IL-10 and IL-21 in the active cSLE group was significantly higher than that in the healthy control group (P<0.05, P<0.01 and P<0.05, respectively), but IL-22 expression was remarkably lower in the active cSLE group than in the healthy control group (P<0.001). IL-21 in the inactive SLE group was significantly higher than that in the healthy control group (P<0.05). The levels of IL-2 and IL-10 in the active cSLE group were significantly higher than those in the inactive cSLE group (P<0.01 and P<0.05). In-depth analysis showed that the expression levels of IL-2 (r=0.382, P=0.028), IL-6 (r=0.514, P=0.002) and IL-10 (r=0.429, P=0.016) were positively correlated with disease activity. Conclusion: This study provides a theoretical basis for the discovery of effective methods to regulate imbalance in T lymphocyte subsets in cSLE, which may open up potential new approaches for the diagnosis of cSLE.
Bayesian Spatial Modeling of Anemia among children under 5 years in Guinea
Authors: Barry Thierno Souleymane , Ngesa Oscar , Onyango Nelson Owuor , Mwambi Henry
Published: January 2021

Bacground: Anemia is a major public health problem in Africa with an increasing number of children under 5years getting infected. Guinea is one of the most affected countries. In 2018, the prevalence rate was 75% inchildren under 5 years. This study sought to identify the factors associated with anemia and to map spatialvariation of anemia across the eight (8) regions in Guinea for children under 5 years, which can provideguidance for control programs for the reduction of the disease.Methods: Data from the Guinea Multiple Indicator Cluster Survey (MICS5) 2016 was used for this study. Atotal of 2609 children under 5 years who had full covariate information were used in the analysis. Spatialbinomial logistic regression methodology was undertaken via Bayesian estimation based on Markov chainMonte Carlo (McMC) using WinBUGS software version 1.4. Results: Our findings revealed that 77% of children under 5 years in Guinea had anemia and the prevalence inthe regions ranged from 70.32% (Conakry) to 83.60% (N’Zerekore) across the country. After adjusting for nonspatial and spatial random effects in the model, older children (48–59 months) (OR: 0.47, CI [0.29 0.70]) were less likely to be anemic compared to those who are younger (0-11 months). Children whose mothers havecompleted secondary education or more had a reduced chance of anemia infection by 33% (OR: 0.67, CI [0.490.90]) and Children from household heads from Kissi ethnic group are less likely to have anemia than theircounterparts whose leader is from Soussou (OR: 0.48, CI [0.22 0.91]). Conclusion: The spatial analysis allowed the identification of high-risk areas as well as the identification ofsocio-economic and demographic factors associated with anemia among children under 5 years. Such ananalysis is important in helping policy makers and health practitioners in developing programs geared towardscontrol and management of anemia among children under 5 years in the country.
Identifying Serum Exosomal-Associated lncRNA/circRNA-miRNA-mRNA Network in Coronary Heart Disease
Authors: Mao Jia , Zhou Yufei , Lu Licheng , Zhang Ping , Ren Runhua , Wang Yaqiong , Wang Jing
Published: January 2021

Background: Accumulating evidence has indicated that the importance of noncoding RNAs and exosomes in coronary heart disease (CHD). However, the exosomal-associated competing endogenous RNA (ceRNA)-mediated regulatory mechanism in CHD is still unknown. The present study aimed to explore exosomal-associated ceRNA network in CHD.Methods: The dataset, including 6 CHD patients and 32 normal controls, were downloaded from the ExoRBase database. Differentially expressed mRNAs (DEMs), lncRNAs (DELs) and circRNAs (DECs) in the serum exosomes between CHD and normal controls were screened. MicroRNAs (miRNAs) targeting DEMs were predicted by Targetscan and miRanda, miRNAs targeting DELs and DECs were predicted with miRcode and starBase, respectively. The biological functions and related signal pathways of DEMs were analyzed using David and KOBAS database. Subsequently, the protein-protein interaction (PPI) network was established to screen out hub genes, enrichment analyses of hub genes were performed and the ceRNA network (lncRNA/circRNA-miRNA-mRNA) was constructed to elucidate ceRNA axes in CHD.Results: A total of 312 DEMs, 43 DELs and 85 DECs were identified between CHD patients and normal controls. Functional enrichment analysis showed that DEMs were significantly enriched in “chromatin silencing at rDNA”, “telomere organization”, “negative regulation of gene expression, epigenetic”. The PPI network analysis showed that 25 hub DEMs were closely related to CHD, of which, ubiquitin C (UBC) was the most important. The biological function of hub genes showed that they were mainly enriched in “cellular protein metabolic process”. The exosomal-associated ceRNA regulatory network incorporated 48 DEMs, 72 predicted miRNAs, 10 DELs and 15 DECs. LncRNA/circRNA-miRNA-mRNA interaction axes (RPL7AP11/hsa-miR-17-5p/UBC, RPL7AP11/hsa-miR-20b-5p/UBC) were obtained from the network. Conclusions: Our findings have provided a novel perspective on the potential roles of exosomal-associated ceRNA network regulating the pathogenesis of CHD.
Frequency of metabolic syndrome and insulin resistance in epileptic patients treated with sodium valproate or carbamazepine monotherapy: A Case-Control Study
Authors: Bayat Mahnaz , Jalali Nasrin , Poursadeghfard Maryam , Nazeri Masomeh , Dabbaghmanesh Mohammad Hossein , Ashjazadeh Nahid
Published: January 2021

Background

Metabolic syndrome (MetS) represents a collection of metabolic risk factors such as obesity, dyslipidemia, hyperglycemia, and hypertension. Medications can increase the incidence rate of MetS and insulin resistance (IR).
Objective

This study aims to evaluate the effects of Carbamazepine (CBZ) or Valproate (VPA) as monotherapy on the development of MetS and IR in the adult Iranian epileptic patients.
Methods

In this observational analytic case-control study, 80 epileptic patients were treated with VPA (40 patients) or CBZ (40 patients) monotherapies for more than 6 months and 45 age and sex matched controls were included. MetS was assessed based on International Diabetes Federation (IDF) and National Cholesterol Education Program (NCEP) criteria.
Results

In the multiple regression analysis, in VPA-treated patients the risk of MetS (by IDF criteria) was increased 19 times higher than controls (OR = 19.20; 95% CI = 2.62-140.23, P = 0. 004) and risk of IR (by HOMA and QUICKI) was increased 15 and 9 times more than controls (OR = 14.83; 95% CI = 3.03–72.56, P = 0.001) and (OR = 9.13; 95% CI = 2.55–32.65, P = 0.001) respectively. Increase in waist, DBP, and insulin level were also showed as important factors in risk of MetS. In CBZ therapy, the risk of MetS (by IDF) depressed by 17% less than controls and the risk of IR (by HOMA) increased 7 times more than controls.
Conclusion

Treatment with VPA can increase the likelihood of developing MetS and IR while, CBZ therapy could decrease the risk of MetS and increase risk of IR in the epileptic patients in Iran compared to the general population.
An Innovative Approach to Improve the Detection and Treatment of Risk Factors in Poor Urban Settings: A Feasibility Study in Argentina
Authors: Poggio Rosana , Danaei Goodarz , Gutierrez Laura , Cavallo Ana , Lopez María , Irazola Vilma
Published: January 2021

Background The effective management of cardiovascular (CVD) prevention among the uninsured population in Argentina is low since less than 30% of the individuals with predicted 10-year CVD risk ≥10% attend a clinical visit for CVD risk factors control in the primary care clinics (PCCs). Methods We conducted a non-controlled feasibility study using a mixed methods approach to evaluate acceptability, adoption and fidelity of a multi-component intervention implemented in the public healthcare system. The eligibility criteria were being uninsured, age ≥ 40 years, residence in the PCC´s catchment area and 10-year CVD risk ≥ 10%. The multi-component intervention addressed (1) system barriers through task shifting among the PCC´s staff, protected medical appointments slots and a new CVD form and (2) Provider barriers through training for primary care physicians and CHW and individual barriers through a home-based intervention delivered by community health workers (CHWs).Results A total of 185 participants were included in the study. Of the total number of the eligible participants, 82.2% of eligible participants attended to at least one clinical visit for risk factor control. Physicians intensified drug treatment in 77% of participants with BP ≥140/90 mmHg and 79.5% of participants with diabetes, increased the proportion of participants treated according to GCP from 21% to 32.6% in hypertensive participants, 7.4% to 33.3% in high CVD risk and 1.4% to 8.7% in very high CVD risk groups. Mean systolic and diastolic blood pressure were lower at the end of follow up (156.9 to 145.4 mmHg and 92.9 to 88.9 mmHg, respectively) and control of hypertension (BP<140/90 mmHg) increased from 20.3% to 35.5%.Conclusion The proposed CHWs-led intervention was feasible and well accepted in improving the detection and treatment of risk factors in the uninsured and poor population with moderate or high CVD risk at the primary care setting in Argentina. Task sharing activities with CHWs not only stimulated teamwork among PCC staff, but it also improved quality of care. This study showed that community health workers could have a more active role in the detection and clinical management of CVD risk factors in low-income communities.