bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploration of molecular targets and mechanisms of Chinese medicinal formula Acacia Catechu ‐Scutellariae Radix in the treatment of COVID‐19 by a systems pharmacology strategy
Authors: Feng Tian , Zhang Meng , Xu Qiong , Song Fan , Wang Libin , Gai Shouchang , Tang Haifeng , Wang Siwang , Zhou Liying , Li Hua 
Published: July 2022

AbstractCoronavirus disease 2019 (COVID‐19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). In China, the Acacia catechu (AC)‐Scutellariae Radix (SR) formula has been widely used for pulmonary infection in clinical practice for several centuries. However, the potential role and mechanisms of this formula against COVID‐19 remains unclear. The present study was designed to dissect the active ingredients, molecular targets, and the therapeutic mechanisms of AC‐SR formula in the treatment of COVID‐19 based on a systems pharmacology strategy integrated by ADME screening, target prediction, network analysis, GO and KEGG enrichment analysis, molecular docking, and molecular dynamic (MD) simulations. Finally, Quercetin, Fisetin(1‐), kaempferol, Wogonin, Beta‐sitosterol, Baicalein, Skullcapflavone II, Stigmasterol were primarily screened to be the potentially effective active ingredients against COVID‐19. The hub‐proteins were TP53, JUN, ESR1, MAPK1, Akt1, HSP90AA1, TNF, IL‐6, SRC, and RELA. The potential mechanisms of AC‐SR formula in the treatment of COVID‐19 were the TNF signaling pathway, PI3K‐Akt signaling pathway and IL‐17 signaling pathway, etc. Furthermore, virtual docking revealed that baicalein, (+)‐catechin and fisetin(1‐) exhibited high affinity to SARS‐CoV‐2 3CLpro, which has validated by the FRET‐based enzymatic inhibitory assays with the IC50 of 11.3, 23.8, and 44.1 μM, respectively. And also, a concentration‐dependent inhibition of baicalein, quercetin and (+)‐catechin against SARS‐CoV‐2 ACE2 was observed with the IC50 of 138.2, 141.3, and 348.4 μM, respectively. These findings suggested AC‐SR formula exerted therapeutic effects involving “multi‐compounds and multi‐targets.” It might be working through directly inhibiting the virus, improving immune function, and reducing the inflammatory in response to anti‐COVID‐19. Ultimately, this study would provide new perspective for discovering potential drugs and mechanisms against COVID‐19.
Mechanisch‐technologisches Verhalten von ETFE‐Folien und deren Schweißverbindungen
Authors: Surholt Felix , Runge Dominik , Uhlemann Jörg , Stranghöner Natalie 
Published: July 2022

AbstractDas thermoplastische Fluorpolymer Ethylen/Tetrafluorethylen, kurz ETFE, wird seit den 1980er‐Jahren vermehrt in Membranstrukturen des Bauwesens verwendet. Der Kunststoff weist ein nichtlineares viskoelastisches Materialverhalten auf, welches bislang nicht vollumfänglich untersucht ist. Beim Bau von Membranstrukturen mit ETFE‐Folien sind jedoch die Kenntnisse über das nichtlineare viskoelastische Materialverhalten essenziell, um weitspannende, offen wirkende und zugleich sichere und wirtschaftliche Strukturen bauen zu können. Das Materialverhalten kann hierbei in das Kurzzeitzugverhalten und das Langzeitverhalten, sowohl unter monoaxialen als auch biaxialen Beanspruchungen, unterschieden werden. Für die Konfektionierung der Flächentragwerke ist das Verschweißen einzelner Zuschnittsbahnen unabdingbar, da das Grundmaterial nur in begrenzten Warenbreiten erhältlich ist. Über das Tragverhalten geschweißter ETFE‐Folien gibt es bisher nur wenige Untersuchungen. In diesem Aufsatz wird ein Kurzüberblick über das Materialverhalten von ETFE‐Folien in Kurzzeitzug‐ und Langzeitversuchen bereitgestellt. Zudem werden Materialmodelle vorgestellt, die das Materialverhalten in den o. g. Versuchen bzw. Zuständen beschreiben. Weiterhin werden erste Einblicke in das Bruchverhalten geschweißter ETFE‐Folien gegeben.
Benign inheritable disorders of bilirubin metabolism manifested by conjugated hyperbilirubinemia–A narrative review
Authors: Morais Mariana B. , Machado Mariana Verdelho 
Published: July 2022

AbstractBilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice.Hyperbilirubinemia is an important clinical sign that needs to be investigated under a stepwise evaluation. Inherited non‐hemolytic conjugated hyperbilirubinemic conditions include Dubin‐Johnson syndrome (caused by mutations affecting ABCC2 gene) and Rotor syndrome (caused by the simultaneous presence of mutations in SLCO1B1 and SLCO1B3 genes). Although classically viewed as benign conditions requiring no treatment, they lately gained an increased interest since recent studies suggested that mutations in the responsible genes leading to hyperbilirubinemia, as well as minor genetic variants, may result in an increased susceptibility to drug toxicity.This article provides a comprehensive review on the pathophysiology of Dubin‐Johnson and Rotor syndromes, presenting the current knowledge concerning the molecular details and basis of these conditions.
Resentment and Gratitude in Won Buddhism
Authors: Ha Chung Nam 
Published: July 2022

AbstractThis chapter shows how the emotion of resentment was recognized as the cause of the moral illness of the world and how the Won Buddhist ethics provides the way to cure the moral illness by changing the life of resentment to the life of gratitude. The universal beneficence of nature comprises the beneficence of heaven and earth, the beneficence of parents, the beneficence of fellow beings, and the beneficence of laws. The life of gratitude consists in following the general principles of beneficence requital, which are favoring others with no false thought, protecting the helpless, mutual benefit, and doing justice and forsaking injustice. Thus, ‘awareness and requital of beneficence’ is the panacea to cure the emotion of resentment.
Yi Yulgok on the Role of Emotions in Self-cultivation and Ethics: A Korean Confucian and Comparative Interpretation
Authors: Chung Edward Y. J. 
Published: July 2022

AbstractYi I (Yulgok) was a leading Neo-Confucian thinker and one of the greatest statesmen in Joseon Korea. This chapter presents the holistic role of emotions (jeong/qing情) in self-cultivation and statecraft by covering his major philosophical texts, letters, and political essays. We discuss Yulgok’s theory that virtuous emotional harmony and the transformation of one’sgi/qi(vital energy) are important for self-cultivation and why this interpretation is relevant to his political reform measures. The chapter also compares it with Western virtue ethics. It concludes that the modern relevance of Yulgok’s insights emphasizes ethical passions to promote political justice and social wellbeing.
A Review of Medical Federated Learning: Applications in Oncology and Cancer Research
Authors: Chowdhury Alexander , Kassem Hasan , Padoy Nicolas , Umeton Renato , Karargyris Alexandros 
Published: July 2022

AbstractMachine learning has revolutionized every facet of human life, while also becoming more accessible and ubiquitous. Its prevalence has had a powerful impact in healthcare, with numerous applications and intelligent systems achieving clinical level expertise. However, building robust and generalizable systems relies on training algorithms in a centralized fashion using large, heterogeneous datasets. In medicine, these datasets are time consuming to annotate and difficult to collect centrally due to privacy concerns. Recently, Federated Learning has been proposed as a distributed learning technique to alleviate many of these privacy concerns by providing a decentralized training paradigm for models using large, distributed data. This new approach has become the defacto way of building machine learning models in multiple industries (e.g. edge computing, smartphones). Due to its strong potential, Federated Learning is also becoming a popular training method in healthcare, where patient privacy is of paramount concern. In this paper we performed an extensive literature review to identify state-of-the-art Federated Learning applications for cancer research and clinical oncology analysis. Our objective is to provide readers with an overview of the evolving Federated Learning landscape, with a focus on applications and algorithms in oncology space. Moreover, we hope that this review will help readers to identify potential needs and future directions for research and development.
Cosmological relaxation through the dark axion portal
Authors: Domcke Valerie , Schmitz Kai , You Tevong 
Published: July 2022

Abstract
The dark axion portal is a coupling of an axion-like particle to a dark photon kinetically mixed with the visible photon. We show how this portal, when applied to the relaxion, can lead to cosmological relaxation of the weak scale using dark photon production. The key backreaction mechanism involves the Schwinger effect: as long as electroweak symmetry is unbroken, Schwinger production of massless Standard Model fermions, which carry dark millicharges, suppresses the dark photon production. Once the electroweak symmetry is broken, the fermions acquire mass and the suppression is lifted. An enhanced dark photon dissipation then traps the relaxion at a naturally small weak scale. Our model thus provides a novel link between the phenomenological dark axion portal, dark photons, and the hierarchy problem of the Higgs mass.
Virus-induced inhibition of cardiac pacemaker channel HCN4 triggers bradycardia in human-induced stem cell system
Authors: Peischard Stefan , Möller Melina , Disse Paul , Ho Huyen Tran , Verkerk Arie O. , Strutz-Seebohm Nathalie , Budde Thomas , Meuth Sven G. , Schweizer Patrick A. , Morris Silke , Mücher Lena , Eisner Verónica , Thomas Dierk , Klingel Karin , Busch Karin , Seebohm Guiscard 
Published: July 2022

AbstractThe enterovirus Coxsackievirus B3 (CVB3) is known to be a major source for the development of cardiac dysfunctions like viral myocarditis (VMC) and dilatative cardiomyopathy (DCM), but also results in bradycardia and fatal cardiac arrest. Besides clinical reports on bradycardia and sudden cardiac death, very little is known about the influence of CVB3 on the activity of human cardiac pacemaker cells. Here, we address this issue using the first human induced pluripotent stem cell (hiPSC)-derived pacemaker-like cells, in which the expression of a transgenic non-infectious variant of CVB3 can be controlled dose- and time-dependently. We found that CVB3 drastically changed hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) distribution and function in hiPSC-derived pacemaker-like tissue. In addition, using HCN4 cell expression systems, we found that HCN4 currents were decreased with altered voltage dependency of activation when CVB3 was expressed. Increased autophagosome formation and autophagosomal HCN4 insertion was observed in hiPSC-derived pacemaker-like cells under CVB3 expression as well. Individual effects of single, non-structural CVB3 proteins were analyzed and demonstrated that CVB3 proteins 2C and 3A had the most robust effect on HCN4 activity. Treatment of cells with the Rab7 inhibitor CID 106770 or the CVB3-3A inhibitor GW5074 led to the recovery of the cytoplasmatic HCN4 accumulation into a healthy appearing phenotype, indicating that malfunctioning Rab7-directed autophagosome transport is involved in the disturbed, cytoplasmatic HCN4 accumulation in CVB3-expressing human pacemaker-like cells. Summarizing, the enterovirus CVB3 inhibits human cardiac pacemaker function by reducing the pacemaker channel plasma membrane density, an effect that can be corrected by pharmacological intervention of endocytic vesicle trafficking.
ISG15 as a prognostic biomarker in solitary fibrous tumour
Authors: Mondaza-Hernandez Jose L. , Moura David S. , Lopez-Alvarez María , Sanchez-Bustos Paloma , Blanco-Alcaina Elena , Castilla-Ramirez Carolina , Collini Paola , Merino-Garcia Jose , Zamora Jorge , Carrillo-Garcia Jaime , Maestro Roberta , Hindi Nadia , Garcia-Foncillas Jesus , Martin-Broto Javier 
Published: July 2022

Abstract
Background
Solitary fibrous tumour (SFT) is a rare mesenchymal malignancy that lacks robust prognostic and predictive biomarkers. Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like modifier, associated with tumour progression, and with poor survival of SFT patients, as previous published by our group. Here, we describe the role of ISG15 in the biology of this rare tumour.

Methods
ISG15 expression was assessed by immunohistochemistry in tissue microarrays from SFT patients and tested for correlation with progression-free survival and overall survival (OS). The effects of ISG15 knockdown or induction were investigated for cancer stem cell (CSC) characteristics and for drug sensitivity in unique in vitro models of SFT.

Results
The prognostic value of ISG15 for OS was validated at protein level in malignant SFT patients, prospectively treated with pazopanib and enrolled in GEIS-32 trial. In SFT in vitro models, ISG15 knockdown lead to a decrease in the expression of CSC-related genes, including SOX2, NANOG, ALDH1A1, ABCB1 and ABCC1. Likewise, ISG15 downregulation decreased the clonogenic/ tumoursphere-forming ability of SFT cells, while enhancing apoptotic cell death after doxorubicin, pazopanib or trabectedin treatment in 3D cell cultures. The regulation of CSC-related genes by ISG15 was confirmed after inducing its expression with interferon-β1; ISG15 induction upregulated 1.28- to 451-fold the expression of CSC-associated genes.

Conclusions
ISG15 is a prognostic factor in malignant SFT, regulating the expression of CSC-related genes and CSCs maintenance. Our results suggest that ISG15 could be a novel therapeutic target in SFT, which could improve the efficacy of the currently available treatments.
Polymerogenic neuroserpin causes mitochondrial alterations and activates NFκB but not the UPR in a neuronal model of neurodegeneration FENIB
Authors: D’Acunto E. , Gianfrancesco L. , Serangeli I. , D’Orsi M. , Sabato V. , Guadagno N. A. , Bhosale G. , Caristi S. , Failla A. V. , De Jaco A. , Cacci E. , Duchen M. R. , Lupo G. , Galliciotti G. , Miranda E. 
Published: July 2022

AbstractThe neurodegenerative condition FENIB (familiar encephalopathy with neuroserpin inclusion bodies) is caused by heterozygous expression of polymerogenic mutant neuroserpin (NS), with polymer deposition within the endoplasmic reticulum (ER) of neurons. We generated transgenic neural progenitor cells (NPCs) from mouse fetal cerebral cortex stably expressing either the control protein GFP or human wild type, polymerogenic G392E or truncated (delta) NS. This cellular model makes it possible to study the toxicity of polymerogenic NS in the appropriated cell type by in vitro differentiation to neurons. Our previous work showed that expression of G392E NS in differentiated NPCs induced an adaptive response through the upregulation of several genes involved in the defence against oxidative stress, and that pharmacological reduction of the antioxidant defences by drug treatments rendered G392E NS neurons more susceptible to apoptosis than control neurons. In this study, we assessed mitochondrial distribution and found a higher percentage of perinuclear localisation in G392E NS neurons, particularly in those containing polymers, a phenotype that was enhanced by glutathione chelation and rescued by antioxidant molecules. Mitochondrial membrane potential and contact sites between mitochondria and the ER were reduced in neurons expressing the G392E mutation. These alterations were associated with a pattern of ER stress that involved the ER overload response but not the unfolded protein response. Our results suggest that intracellular accumulation of NS polymers affects the interaction between the ER and mitochondria, causing mitochondrial alterations that contribute to the neuronal degeneration seen in FENIB patients.
H2S biogenesis by cystathionine beta-synthase: mechanism of inhibition by aminooxyacetic acid and unexpected role of serine
Authors: Petrosino Maria , Zuhra Karim , Kopec Jola , Hutchin Andrew , Szabo Csaba , Majtan Tomas 
Published: July 2022

AbstractCystathionine beta-synthase (CBS) is a pivotal enzyme of the transsulfuration pathway responsible for diverting homocysteine to the biosynthesis of cysteine and production of hydrogen sulfide (H2S). Aberrant upregulation of CBS and overproduction of H2S contribute to pathophysiology of several diseases including cancer and Down syndrome. Therefore, pharmacological CBS inhibition has emerged as a prospective therapeutic approach. Here, we characterized binding and inhibitory mechanism of aminooxyacetic acid (AOAA), the most commonly used CBS inhibitor. We found that AOAA binds CBS tighter than its respective substrates and forms a dead-end PLP-bound intermediate featuring an oxime bond. Surprisingly, serine, but not cysteine, replaced AOAA from CBS and formed an aminoacrylate reaction intermediate, which allowed for the continuation of the catalytic cycle. Indeed, serine rescued and essentially normalized the enzymatic activity of AOAA-inhibited CBS. Cellular studies confirmed that AOAA decreased H2S production and bioenergetics, while additional serine rescued CBS activity, H2S production and mitochondrial function. The crystal structure of AOAA-bound human CBS showed a lack of hydrogen bonding with residues G305 and Y308, found in the serine-bound model. Thus, AOAA-inhibited CBS could be reactivated by serine. This difference may be important in a cellular environment in multiple pathophysiological conditions and may modulate the CBS-inhibitory activity of AOAA. In addition, our results demonstrate additional complexities of using AOAA as a CBS-specific inhibitor of H2S biogenesis and point to the urgent need to develop a potent, selective and specific pharmacological CBS inhibitor.
Cellular localization of nucleolin determines the prognosis in cancers: a meta-analysis
Authors: Yangngam Supaporn , Prasopsiri Jaturawitt , Hatthakarnkul Phimmada , Thongchot Suyanee , Thuwajit Peti , Yenchitsomanus Pa-thai , Edwards Joanne , Thuwajit Chanitra 
Published: July 2022

Abstract
Nucleolin (NCL) is a multifunctional protein expressed in the nucleus, cytoplasm, and cell membrane. Overexpression of NCL has a controversial role as a poor prognostic marker in cancers. In this study, a meta-analysis was performed to evaluate the prognostic value of NCL in different subcellular localizations (cytoplasmic (CyNCL) and nuclear (NuNCL)) across a range of cancers. PubMed was searched for relevant publications. Data were extracted and analyzed from 12 studies involving 1221 patients with eight cancer types. The results revealed high total NCL was significantly associated with poor overall survival (OS) (HR = 2.85 (1.94, 4.91), p < 0.00001, I2 = 59%) and short disease-free survival (DFS) (HR = 3.57 (2.76, 4.62), p < 0.00001, I2 = 2%). High CyNCL was significantly associated with poor OS (HR = 4.32 (3.01, 6.19), p < 0.00001, I2 = 0%) and short DFS (HR = 3.00 (2.17, 4.15), p < 0.00001, I2 = 0%). In contrast, high NuNCL correlated with increased patient OS (HR = 0.42 (0.20, 0.86), p = 0.02, I2 = 66%), with no significant correlation to DFS observed (HR = 0.46 (0.19, 1.14), p = 0.09, I2 = 57%). This study supports the role of subcellular NCL as a poor prognostic cancer biomarker.
The learning curve in robotic assisted knee arthroplasty is flattened by the presence of a surgeon experienced with robotic assisted surgery
Authors: Schopper Clemens , Proier Philipp , Luger Matthias , Gotterbarm Tobias , Klasan Antonio 
Published: July 2022

Abstract
Purpose
The purpose of this study was to investigate the learning curve associated with robotic assisted knee arthroplasty (RAS KA). Therefore, the evaluation of the influence of an experienced surgeon on the overall team performance of three surgeons regarding the learning curve in RAS KA was investigated. It was hypothesized that the presence of an experienced surgeon flattens the learning curve and that there was no inflection point for the learning curve of the surgical team.

Methods
Fifty-five cases consisting of 31 total knee arthroplasties (TKA) and 24 unicompartmental arthroplasties (UKA) performed by three surgeons during 2021 were prospectively investigated. Single surgeon and team performance for operation time learning curve and inflection points were investigated using cumulative sum analysis (CUSUM).

Results
A downward trend line for individual surgeons and the team performance regarding the operation time learning curve was observed. No inflexion point was observed for the overall team performance regarding TKA and UKA. The surgeon that performed all cases with the assistance of the experienced surgeon had significantly shorter surgical times than the surgeon that only occasionally received assistance from the experienced surgeon (p = 0.004 TKA; p = 0.002 UKA).

Conclusion
The presence of an experienced surgeon in robotically assisted knee arthroplasty can flatten the learning curve of the surgical team formerly unexperienced in robotic assisted systems. Manufacturers should provide expanded support during initial cases in centres without previous experience to robotic assisted knee arthroplasty.

Level of evidence
III.
The high-K calc-alkaline to shoshonitic volcanism of Limnos, Greece: implications for the geodynamic evolution of the northern Aegean
Authors: Gläser Leon , Grosche Anna , Voudouris Panagiotis C. , Haase Karsten M. 
Published: July 2022

AbstractGenetic models for the formation of K-rich magmas in subduction-related settings range from partial melting of subduction-affected mantle sources to melting of crustal rocks depending on the local tectonic framework. The Miocene high-K calc-alkaline to shoshonitic rocks of Limnos Island reflect the magmatic activity in the northern Aegean, which migrated southwards in response to trench retreat and the collision of continental terranes in the Hellenic subduction system. New whole rock and mineral data of basaltic andesites, dacites and monzonites from Limnos indicate that the magmas underwent fractional crystallization of olivine, clinopyroxene, amphibole, apatite, and Fe-Ti oxides at 1100 to 700 °C and 0.5 to 0.1 GPa without significant assimilation of crustal rocks during the magma evolution. The strong enrichment of large ion lithophile elements and light rare-earth elements relative to depleted heavy rare earth and high-field strength elements points towards a mantle source that has been extensively hybridized by subducted sedimentary material. New Sr–Nd-Pb isotope data reveal a distinct isotopic composition of the Limnos rocks with high 207Pb/204Pb at low 206Pb/204Pb and 143Nd/144Nd ratios that is likely related to the subduction of the continental crustal succession of the Apulian block which was subducted prior to the onset of magmatism on Limnos. Partial melting models assuming a hybridized mantle source suggest that the primary melts of Limnos formed by melting of a phlogopite pyroxenite at melting degrees of 5 to 10%. Compositional differences between high-K calc-alkaline and shoshonitic magmas are explained by variable melting degrees and varying amounts of sediment supply to the mantle. The magmatic and tectonic evolution of Limnos island is typical for the Oligocene and Miocene volcanic centres of the migrating western Aegean arc front.