bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the oxidation chemistry of hydroxy naphthoic acid: An experimental and theoretical study
Authors: Naduvilpurakkal Shibin B. , Menacherry Sunil Paul M. , Nair Sreekanth R. , Nguyen Thao P. , Nair Pramod G. , Aravind Usha K. , Aravindakumar Charuvila T.
Published: July 2022

Elimination of polycyclic aromatic hydrocarbons (PAHs) from aquatic environment is extremely important, as they are identified pollutants. The oxidative degradation of two model PAHs, namely 3‐hydroxy‐2‐naphthoic acid (3HNA) and 6‐hydroxy‐2‐naphthoic acid (6HNA), collectively represented as HNAs in this report, were investigated by utilizing a combined approach of pulse radiolysis, theoretical studies and high‐resolution mass spectrometry (HRMS). Hydroxylated adduct radicals of HNAs (3HNA–λmax; 340 nm; k2 = [1.09 ± 0.07] × 1010 dm3 mol−1 s−1, 6HNA–λmax; 350 nm; k2 = [9.43 ± 0.05] × 109 dm3 mol−1 s−1) were recognized as the immediate intermediates upon their reaction with hydroxyl radical (•OH). While theoretical calculations revealed the contributions from C1 and C4 adducts into the experimentally observed spectrum of 3HNA, the C5 adduct accounted as the major contributor for 6HNA. Investigations using specific oxidants, such as sulfate (SO4•−) and oxide (O•−) radicals, helped to exclude the contributions from other minor pathways (e.g., one‐electron oxidation and hydrogen abstraction). Further, HRMS studies revealed the existence of mono‐ and multi‐hydroxylated derivatives of HNAs as well as many other oxidation products including quinone‐like and ring‐opened structures. The in‐depth mechanistic aspects, including the kinetic and product profile, furnished in this report provide detailed insights in to the oxidation chemistry of highly toxic PAHs, such as the HNAs, in the aquatic environment.
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

Coronavirus 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

Das 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

Bilirubin, 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

This 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

Yi 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

Machine 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

The 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

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

The 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

Cystathionine 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

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

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

Genetic 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.
Ipilimumab and nivolumab in advanced hepatocellular carcinoma after failure of prior immune checkpoint inhibitor-based combination therapies: a multicenter retrospective study
Authors: Roessler Daniel , Öcal Osman , Philipp Alexander B. , Markwardt Daniel , Munker Stefan , Mayerle Julia , Jochheim Leonie S. , Hammer Katharina , Lange Christian M. , Geier Andreas , Seidensticker Max , Reiter Florian P. , De Toni Enrico N. , Ben Khaled Najib
Published: July 2022

Introduction

Immune checkpoint inhibitor (ICI)-based regimens are transforming the landscape of hepatocellular carcinoma (HCC) treatment. We describe the effect of combined ipilimumab and nivolumab in patients with advanced HCC after the failure of prior ICI-based combination treatments.

Methods

The clinical course of patients with advanced HCC who received combined ipilimumab and nivolumab after prior ICI-based combination therapies was assessed. Progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) per RECIST v1.1 and mRECIST, overall survival (OS), and safety were analyzed.

Results

Of 109 patients treated with atezolizumab and bevacizumab or other ICI-based combination treatments, ten patients received subsequent therapy with ipilimumab and nivolumab. The majority of patients had Barcelona Clinic Liver Cancer (BCLC) Stage C (80%) HCC and a preserved liver function as defined by Child–Pugh A (80%). At a median follow-up of 15.3 months, ORR for ipilimumab and nivolumab was 30% with a DCR of 40%. Median PFS was 2.9 months and the median OS was 7.4 months.

Conclusion

This retrospective study demonstrates that combined ipilimumab and nivolumab can be effective and tolerable after prior ICI-based combination therapies and provides a rationale for the prospective clinical evaluation of this treatment sequencing.
Molekularpathologische Diagnostik des Harnblasenkarzinoms – prädiktive und prognostische Marker
Authors: Rüschoff Jan H. , Moch Holger
Published: July 2022

Für Patienten mit einem metastasierten Urothelkarzinom der Harnblase bildete über Jahrzehnte hinweg eine platinhaltige Chemotherapie eine der wenigen verfügbaren Therapieoptionen, die allerdings mit einer schlechten Prognose verbunden war. Erfreulicherweise wurden in den letzten Jahren nicht nur bei den therapeutischen Möglichkeiten deutliche Fortschritte erzielt, sondern auch das Wissen über die molekularen Hintergründe des Harnblasenkarzinoms deutlich erweitert. Um eine personalisierte Anwendung der neuen Therapieansätze zu ermöglichen, werden prädiktive Biomarker benötigt, die meist auf dem Nachweis molekularer Tumorveränderungen basieren. Ziel dieser Arbeit ist ein aktueller Überblick über die molekularen Veränderungen, die daraus entwickelten molekularen Subtypen und die gewebebasierten Biomarkern des Harnblasenkarzinoms. Dazu wurden die aktuelle Literatur und klinische Studiendaten ausgewertet. Für bestimmte molekulare Subtypen des Harnblasenkarzinoms konnte eine prädiktive und prognostische Bedeutung gezeigt werden, jedoch bedarf es für deren Einsatz in der pathologisch-klinischen Routine weiterer (prospektiver) Untersuchungen sowie einer genauen Definition der am besten geeigneten Nachweisverfahren. Eine wichtige neue Therapieoption für das fortgeschrittene Urothelkarzinom ist die Immuntherapie, die allerdings nur bei ca. 25 % der Patienten wirksam ist. Als Biomarker zur Vorhersage eines Therapieansprechens eignen sich neben der immunhistochemisch bestimmten PD-L1(„programmed death ligand 1“)-Expression, auch der MSI(Mikrosatelliteninstabilität)-Status und die Tumormutationslast (TMB). Ferner stellen Veränderungen in den DNA-Reparatur-Genen mögliche Prädiktoren für ein Ansprechen auf Chemotherapie dar.
Endodontic working length measurements of premolars and molars in high-resolution dental MRI: a clinical pilot study for assessment of reliability and accuracy
Authors: Zidan Mousa , Schwindling Franz S. , Juerchott Alexander , Mente Johannes , Gehrig Holger , Nittka Mathias , Hosseini Zahra , Jende Johann M. E. , Heiland Sabine , Bendszus Martin , Hilgenfeld Tim
Published: July 2022

Objectives

To prospectively assess the reliability and accuracy of high-resolution, dental MRI (dMRI) for endodontic working length (WL) measurements of premolars and molars under clinical conditions.

Materials and methods

Three-Tesla dMRI was performed in 9 subjects who also had undergone cone-beam computed tomography (CBCT) (mean age: 47 ± 13.5 years). A total of 34 root canals from 12 molars (4/8, upper/lower jaw; 22 root canals) and 11 premolars (2/9 upper/lower jaw; 12 root canals) were included. CBCT and dMRI datasets were reconstructed to visualize the root canal in one single slice. Subsequently, two radiologists measured the root canal lengths in both modalities twice in blinded fashion. Reliability and accuracy for both modalities were assessed using intraclass correlation coefficients (ICCs) and Bland–Altman analysis, respectively.

Results

Reliability (intra-rater I/II; inter-rater) of dental MRI measurements was excellent and comparable to CBCT for premolars (0.993/0.900; 0.958 vs. 0.993/0.956; 0.951) and for molars (0.978/0.995; 0.986 vs. 0.992/0.996; 0.989). Bland–Altman analysis revealed a mean underestimation/bias (95% confidence interval) of dMRI measurements of 0.8 (− 1.44/3.05) mm for premolars and 0.4 (− 1.55/2.39) mm for molars. In up to 59% of the cases, the accuracy of dMRI for WL measurements was within the underestimation margin of 0 to 2 mm short of the apical foramen AF.

Conclusions

In vivo demonstration and measurement of WL are feasible using dMRI. The reliability of measurements is high and equivalent to CBCT. Nonetheless, due to lower spatial resolution and longer acquisition time, the accuracy of dMRI is inferior to CBCT, impeding its current use for clinical treatment planning.

Clinical relevance

dMRI is a promising radiation-free imaging technique. Its reliability for endodontic working length measurements is high, but its accuracy is not satisfactory enough yet.
Exploring the future building: representational effects on projecting oneself into the future office space
Authors: Weerasinghe Maheshya , Čopič Pucihar Klen , Ducasse Julie , Quigley Aaron , Toniolo Alice , Miguel Angela , Caluya Nicko , Kljun Matjaž
Published: July 2022

While virtual reality (VR) has been explored in the field of architecture, its implications on people who experience their future office space in such a way has not been extensively studied. In this explorative study, we are interested in how VR and other representation methods support users in projecting themselves into their future office space and how this might influence their willingness to relocate. In order to compare VR with other representations, we used (i) standard paper based floor plans and renders of the future building (as used by architects to present their creations to stakeholders), (ii) a highly-detailed virtual environment of the same building experienced on a computer monitor (desktop condition), and (iii) the same environment experienced on a head mounted display (VR condition). Participants were randomly assigned to conditions and were instructed to freely explore their representation method for up to 15 min without any restrictions or tasks given. The results show, that compared to other representation methods, VR significantly differed for the sense of presence, user experience and engagement, and that these measures are correlated for this condition only. In virtual environments, users were observed looking at the views through the windows, spent time on terraces between trees, explored the surroundings, and even “took a walk” to work. Nevertheless, the results show that representation method influences the exploration of the future building as users in VR spent significantly more time exploring the environment, and provided more positive comments about the building compared to users in either desktop or paper conditions. We show that VR representation used in our explorative study increased users’ capability to imagine future scenarios involving their future office spaces, better supported them in projecting themselves into these spaces, and positively affected their attitude towards relocating.
Proton TOCSY NMR relaxation rates quantitate protein side chain mobility in the Pin1 WW domain
Authors: Danmaliki Gaddafi I. , Hwang Peter M.
Published: July 2022

Protein side chain dynamics play a vital role in many biological processes, but differentiating mobile from rigid side chains remains a technical challenge in structural biology. Solution NMR spectroscopy is ideally suited for this but suffers from limited signal-to-noise, signal overlap, and a need for fractional 13C or 2H labeling. Here we introduce a simple strategy measuring initial 1H relaxation rates during a 1H TOCSY sequence like DIPSI-2, which can be appended to the beginning of any multi-dimensional NMR sequence that begins on 1H. The TOCSY RF field compels all 1H atoms to behave similarly under the influence of strong coupling and rotating frame cross-relaxation, so that differences in relaxation rates are due primarily to side chain mobility. We apply the scheme to a thermostable mutant Pin1 WW domain and demonstrate that the observed 1H relaxation rates correlate well with two independent NMR measures of side-chain dynamics, cross-correlated 13C relaxation rates in 13CβH2 methylene groups and maximum observable 3J couplings sensitive to the χ1 side chain dihedral angle (3JHα,Hβ, 3JN,Hβ, and 3JCO,Hβ). The most restricted side chains belong to Trp26 and Asn40, which are closely packed to constitute the folding center of the WW domain. None of the other conserved aromatic residues is as immobile as the first tryptophan side chain of the WW domain. The proposed 1H relaxation methodology should make it relatively easy to measure side chain dynamics on uniformly 15N- or 13C-labeled proteins, so long as chemical shift assignments are obtainable.
Wasserstein-based fairness interpretability framework for machine learning models
Authors: Miroshnikov Alexey , Kotsiopoulos Konstandinos , Franks Ryan , Ravi Kannan Arjun
Published: July 2022

The objective of this article is to introduce a fairness interpretability framework for measuring and explaining the bias in classification and regression models at the level of a distribution. In our work, we measure the model bias across sub-population distributions in the model output using the Wasserstein metric. To properly quantify the contributions of predictors, we take into account favorability of both the model and predictors with respect to the non-protected class. The quantification is accomplished by the use of transport theory, which gives rise to the decomposition of the model bias and bias explanations to positive and negative contributions. To gain more insight into the role of favorability and allow for additivity of bias explanations, we adapt techniques from cooperative game theory.
Re-fluidising the aged gel for high-density alumina green body
Authors: Wu Xiaolang , Zhao Jin , Shimai Shunzo , Mao Xiaojian , Zhang Jian , Wang Shiwei
Published: July 2022

A green body with a density as high as possible is critical to diminish the crisis of deformation or cracking when large-size parts are sintered. Here, a new method, i.e., re-fluidising the aged ceramic gel is developed to prepare the high-density green body. Alumina slurry with 56 vol% solid loading and copolymers of isobutylene and maleic anhydride were aged without vaporisation and re-fluidised by non-intrusive shearing after removing the exuded water. The re-fluidised slurry was re-casted. The resultant wet gel was dried and deboned at a low temperature. The relative density of the obtained green body was 64.6%, 1.5% higher than that without aging and re-fluidising. The linear sintering shrinkage of the body decreased by 0.7%. The enhanced green density is explained from the viewpoint of the solid loading and the structure of the slurry.
JUST VENMO ME: Does form of payment affect risk taking and intertemporal choice?
Authors: Hoel Jessica B. , Jain Prachi , Galaty Bridget
Published: July 2022

We use an experiment to examine whether form of payment (cash or mobile money) affects estimates of intertemporal choice and risk taking. We find that form of payment does not affect temporal discounting and risk taking. Given that participants prefer payment via mobile money, the results suggest that there are minimal concerns with using mobile money to pay participants in experimental studies.
Effect of sap-feeding insects, plant characteristics, and weather parameters on sooty moulds in the temperate zone
Authors: Flessa Fabienne , Babel Wolfgang , Kehl Alexandra , Rambold Gerhard , Kohl Matthias
Published: July 2022

In this study, relevant variables were determined to predict the probability of sooty mould biofilm (SMB) occurrence on willow leaves in a multivariate model. Despite a large temporal gap between the main sap-feeding insect (SFI) season in spring (May to June) and the main season of SMBs in late summer and fall (August to September), trees infested with SFIs on four or more observation dates had significantly more SMBs (3.7-fold) toward the end of the growing season. In addition, a horizontal leaf position and recessed leaf veins, traits that may increase the wettability of the leaves, positively influenced SMB occurrence (27.8-fold). Among the weather parameters, those that lead to higher moisture on leaf surfaces, namely high morning and evening relative humidity, higher precipitation sums, and lower vapour pressure deficit values, also had the strongest positive effect. In addition to these parameters, higher wind speeds also had a strong positive effect on SMB occurrence.
Digitalization and Uncertainty in the University: Coherence and Collegiality Through a Metacurriculum
Authors: Johnson Mark William , Suvorova Elena A. , Karelina Alina A.
Published: July 2022

Recent initiatives to promote ‘digitalization’ in education exhorting increased digital literacy and ‘computational thinking’ have invited implementation research methods to transform curricula, teaching, and learning. While conceived as a movement from the present of education to an imagined future where envisaged curricula embrace data-oriented and computational practices across subjects, we ask: whose present? Whose future? We revisit the concept of a metacurriculum (first conceived in the 1990s) as a way of addressing this question, while not avoiding the challenges inherent in the adaptation of education to an increasingly complex postdigital environment. We argue that the principal challenge facing institutional and individual adaptation is increasing environmental uncertainty produced by technology, not deficiency in individual skills. Using the uncertainty concept, we present a practical co-designed and dialogical approach supporting the student and teacher journeys towards the transdisciplinary opportunities opened out by technology, based on a cybernetic model of intersubjectivity. We discuss the explanatory power of uncertainty in this context, focusing on the ways it can encourage dialogue, collegiality, and experimentation. Evidence for this is presented in a case study from a Russian University Business School where a large group of teachers co-designed and delivered a dialogical module on digitalization and interdisciplinarity over a period of 4 years—a collaboration ended by recent geopolitical events. In analyzing data from one of the central activities of this course, we focus on the teacher collegiality and the students’ mechanisms of selection in navigating the transdisciplinary space, and how these mechanisms may provide deeper insight into the dialogical underpinnings of education.
Liquid Crystals and Their Computer Simulations
Authors: Zannoni Claudio
Published: July 2022

Standing as the first unified textbook on the subject, Liquid Crystals and Their Computer Simulations provides a comprehensive and up-to-date treatment of liquid crystals and of their Monte Carlo and molecular dynamics computer simulations. Liquid crystals have a complex physical nature, and, therefore, computer simulations are a key element of research in this field. This modern text develops a uniform formalism for addressing various spectroscopic techniques and other experimental methods for studying phase transitions of liquid crystals, and emphasises the links between their molecular organisation and observable static and dynamic properties. Aided by the inclusion of a set of Appendices containing detailed mathematical background and derivations, this book is accessible to a broad and multidisciplinary audience. Primarily intended for graduate students and academic researchers, it is also an invaluable reference for industrial researchers working on the development of liquid crystal display technology.
Pulsar Astronomy
Authors: Lyne Andrew , Graham-Smith Francis , Stappers Benjamin
Published: July 2022

After more than half a century since their unexpected discovery and identification as neutron stars, the observation and understanding of pulsars touches upon many areas of astronomy and astrophysics. The literature on pulsars is vast and the observational techniques used now cover the whole of the electromagnetic spectrum from radio to gamma-rays. Now in its fifth edition, this volume has been reorganised and features new material throughout. It provides an introduction in historical and physical terms to the many aspects of neutron stars, including condensed matter, physics of the magnetosphere, supernovae and the development of the pulsar population, propagation in the interstellar medium, binary stars, gravitation and general relativity. The current development of a new generation of powerful radio telescopes, designed with pulsar research in mind, makes this survey and guide essential reading for a growing body of students and astronomers.
The “General Close of Military Operations” as the Benchmark for the Declassification of Armed Conflicts and the End of the Applicability of International Humanitarian Law
Authors: GRIGNON JULIA
Published: July 2022

When does an armed conflict end? When does the specific body of law applicable to such a situation — namely, international humanitarian law (IHL) — cease to apply? There is, to date, no clear-cut answer to these questions in treaty law but, rather, a functional approach to the matter. Anchored in wider research related to the temporal scope of applicability of IHL, this contribution demonstrates how the notion of the “general close of military operations,” which appears in Article 6, paragraph 2, of Geneva Convention IV and in Article 3(b) of Additional Protocol I, fulfills the function of determining that any armed conflict has ended.
Calabi–Yau properties of Postnikov diagrams
Authors: Pressland Matthew
Published: July 2022

We show that the dimer algebra of a connected Postnikov diagram in the disc is bimodule internally

$3$

-Calabi–Yau in the sense of the author’s earlier work [43]. As a consequence, we obtain an additive categorification of the cluster algebra associated to the diagram, which (after inverting frozen variables) is isomorphic to the homogeneous coordinate ring of a positroid variety in the Grassmannian by a recent result of Galashin and Lam [18]. We show that our categorification can be realised as a full extension closed subcategory of Jensen–King–Su’s Grassmannian cluster category [28], in a way compatible with their bijection between rank

$1$

modules and Plücker coordinates.
A spatially accelerating turbulent flow with longitudinally contracting walls
Authors: Falcone M. , He S.
Published: July 2022

This paper describes a study of spatially accelerating turbulent flow based on the direct numerical simulation of a flow with longitudinally accelerating moving walls to create a relative acceleration between the fluid and the wall without inducing streamline curvature. The results show a broad similarity to those of previous investigations of spatial acceleration, albeit with some differences. A new interpretation has been proposed considering this spatially accelerating flow to be characterised by the formation of a new boundary layer superimposed on the pre-existing turbulent flow. This is followed by the transition of the flow in response to the development of this new boundary layer. This can be seen as an extension of the transition theory for temporally accelerating turbulent flows (He & Seddighi, J. Fluid Mech., vol. 715, 2013, pp. 60–102). The existing turbulent structures act as disturbances for the new boundary layer similar to the role of free-stream turbulence in bypass transition. This boundary layer modulates the pre-existing near-wall structures, amplifying and elongating the streaks. Some streaks eventually become unstable in a sinuous mechanism reminiscent of streak breakdown in near-wall turbulence, resulting in the formation localised turbulent spots which spread until the entire wall is covered in new turbulence. This interpretation naturally splits the flow into a new boundary layer region and a core (or free-stream) flow with interactions between the two dominating a significant length of the flow development and potentially offers a new explanation for the slow evolution of the turbulent stresses observed previously.
Does high-performance work system bring job satisfaction? Exploring the non-linear effect of high-performance work system using the ‘too much of a good thing’ theory
Authors: Yan Liang , Zhao Jing , Zhang Qian , Sass Mary D.
Published: July 2022

We examine the relationship between high-performance work system (HPWS) and job satisfaction, drawing on the ‘too much of a good thing’ theory, to establish whether a non-linear relationship can explain conflicts in previous findings. Moreover, we extend the study by exploring the mediating role of work overload and the moderating role of person–organization fit (P–O fit). Based on a cross-sectional data set of 220 employees and a longitudinal data set of 373 employees from organizations in China, the empirical findings show an invertedU-shaped relationship between HPWS and job satisfaction. Results also indicate that the relationship between HPWS and job satisfaction is fully mediated by work overload, and that P–O fit negatively moderates HPWS-work overload and HPWS-job satisfaction relationships. These results shed new light on how HPWS impacts employee outcomes and practical implications for managers are discussed.