bluuebunny/crossref_metadata_2025_split huggingface dataset:
From virtual patients to digital twins in immuno-oncology: lessons learned from mechanistic quantitative systems pharmacology modeling
Authors: Wang Hanwen , Arulraj Theinmozhi , Ippolito Alberto , Popel Aleksander S. 
Published: July 2024

AbstractVirtual patients and digital patients/twins are two similar concepts gaining increasing attention in health care with goals to accelerate drug development and improve patients’ survival, but with their own limitations. Although methods have been proposed to generate virtual patient populations using mechanistic models, there are limited number of applications in immuno-oncology research. Furthermore, due to the stricter requirements of digital twins, they are often generated in a study-specific manner with models customized to particular clinical settings (e.g., treatment, cancer, and data types). Here, we discuss the challenges for virtual patient generation in immuno-oncology with our most recent experiences, initiatives to develop digital twins, and how research on these two concepts can inform each other.
Expression, purification and application of a recombinant, membrane permeating version of the light chain of botulinum toxin B
Authors: Buzzatto Micaela Vanina , Benegas Guerrero Fabiana Cristina , Álvarez Pablo Ariel , Zizzias María Paz , Polo Luis Mariano , Tomes Claudia Nora 
Published: July 2024

Abstract
Botulinum neurotoxins (BoNTs) are valuable tools to unveil molecular mechanisms of exocytosis in neuronal and non-neuronal cells due to their peptidase activity on exocytic isoforms of SNARE proteins. They are produced by Clostridia as single-chain polypeptides that are proteolytically cleaved into light, catalytic domains covalently linked via disulfide bonds to heavy, targeting domains. This format of two subunits linked by disulfide bonds is required for the full neurotoxicity of BoNTs. We have generated a recombinant version of BoNT/B that consists of the light chain of the toxin fused to the protein transduction domain of the human immunodeficiency virus-1 (TAT peptide) and a hexahistidine tag. His6-TAT-BoNT/B-LC, expressed in Escherichia coli and purified by affinity chromatography, penetrated membranes and exhibited strong enzymatic activity, as evidenced by cleavage of the SNARE synaptobrevin from rat brain synaptosomes and human sperm cells. Proteolytic attack of synaptobrevin hindered exocytosis triggered by a calcium ionophore in the latter. The novel tool reported herein disrupts the function of a SNARE protein within minutes in cells that may or may not express the receptors for the BoNT/B heavy chain, and without the need for transient transfection or permeabilization.
Entwicklung der Ärzt*innenzahlen und Beschäftigungsverhältnisse in
Bayern – Trends in den Ärzt*innenstatistiken der Bayerischen Landesärztekammer
und der Kassenärztlichen Vereinigung Bayerns
Authors: Gigou Sophie , Corazza Laura , Fett Sandra , Tauscher Martin , Gerlach Roman , Donnachie Ewan , Schneider Antonius 
Published: July 2024

Zusammenfassung
Hintergrund Obwohl die Zahl der Medizinstudienplätze und Ärzt*innen in
Deutschland in den letzten 25 Jahren zugenommen hat, droht ein Ärzt*innenmangel.
Anhand der Ärztestatistiken der Bayerischen Landesärztekammer (BLÄK) sowie der
Kassenärztlichen Vereinigung Bayerns (KVB) soll eine fachgebietsübergreifende
Analyse der bayerischen Arztzahlen über einen längeren Zeitraum vorgenommen
werden, um aktuelle Entwicklungen im zeitlichen Verlauf einordnen zu können
sowie Ansatzpunkte für die Gestaltung der medizinischen Versorgung zu gewinnen.
Die Kennzahlen wurden hinsichtlich der Verteilung der Ärzt*innen nach ambulantem
und stationärem Sektor sowie hinsichtlich der Entwicklung der
Angestelltenzahlen, des Beschäftigungsumfangs und der Geschlechterverteilung im
ambulanten Sektor analysiert.
Methoden Als Datengrundlage dienten die jährlich veröffentlichten und
zusammengeführten Ärztestatistiken der BLÄK von 2000 bis 2022 sowie die
ambulanten GKV-Abrechnungsdaten der niedergelassenen und angestellten Ärzt*innen
in Bayern von 2010 bis 2022, aufbereitet durch die KVB. Es wurden deskriptive
Analysen durchgeführt.
Ergebnisse Seit 2000 ist die Zahl der Ärzt*innen in Bayern im stationären
Setting um 83%, im ambulanten Setting um 35% angestiegen. In der Konsequenz sind
seit 2010 mehr Ärzt*innen im Krankenhaus als in der ambulanten Versorgung tätig
(2022: 28976 ambulant und 34243 stationär tätige Ärzt*innen). In der ambulanten
Versorgung geht der Trend in allen Fachgebieten weg von der Niederlassung und
Vollzeittätigkeit hin zur Anstellung und Teilzeittätigkeit. Angestellte
Ärzt*innen weisen einen durchschnittlich geringeren Beschäftigungsumfang auf als
selbstständige Ärzt*innen. Der Frauenanteil in der Ärzt*innenschaft ist
kontinuierlich gestiegen, wobei Ärztinnen im Vergleich zu Ärzten eher angestellt
und in Teilzeit tätig sind. Dennoch ist auch bei Ärzten heute in einigen
Fachgebieten eine Teilzeittätigkeit prominent vertreten.
Schlussfolgerungen Der fachgebietsübergreifende Trend hin zur Ausübung der
ärztlichen Tätigkeit in Anstellung und Teilzeit ist ungebrochen, sodass mehr
Personen nötig sind, um die Anzahl der aktuell verfügbaren Arztstunden über die
Zeit aufrechtzuerhalten. Neben Niederlassungsanreizen muss diesem Trend bei der
Planung der Versorgung Rechnung getragen werden. Gleichzeitig ist fraglich, ob
eine Steigerung von Medizinstudienplätzen ohne bedarfsgerechte Steuerung eine
geeignete Maßnahme gegen den Ärzt*innenmangel ist, wenn ein immer größerer
Anteil der Ärzt*innen langfristig in Kliniken tätig wird.
Comparison between extraperitoneal and transperitoneal cesarean
section: Retrospective case-control study
Authors: Bačić Boris , Hrgović Zlatko , Cerovac Anis , Barčot Ognjen , Sabljić Jelena , Markoski Blagoja , Leskur Mateo 
Published: July 2024

Abstract
Introduction  The main advantage of extraperitoneal cesarean section
(EXPCS) is not only less pain, faster recovery, and less potential for infection
but also a possible lack of intraperitoneal adhesions.
Methods  In a 3-year period from 2019 to 2022, 88 EXPCSs were performed. A
comparison was made with 90 patients who underwent a standard transperitoneal
cesarean section (TPCS). For both groups, the inclusion criterion was uterine
inertia and prolonged labor as an indication for cesarean section. Only pregnant
women from 37 to 42 weeks were included. After this, 51 patients remained in the
EXPCS arm, and 49 remained in the TPCS arm.
Results  No statistical difference was found in gestational weeks, newborn
weight, Apgar score, erythrocyte (Er), hemoglobin (Hgb), and hematocrit (Htc)
values and duration of operative time between the EXPCS and TPCS groups.
Leukocytes, C-reactive protein (CRP) with fever higher than >38°C on the
third postoperative day were found statistically significantly (p=0.005) higher
in the TPCS group. The usage of tramadol + metamizole at 3, 6, and 9 hours after
delivery and diclofenac at 6, 12, and 18 hours after surgery was statistically
significantly (p<0.05) higher in the TPCS group. On the visual analog scale
(VAS) 24 hours after surgery, a statistically significant difference was found
(p = 0.001) between the two groups. In the small group of patients who underwent
a TPCS section after an EXPCS, intraperitoneal adhesions were not found; in
another group of patients who underwent a TPCS twice, adhesions were found in 12
patients; Fisher's exact test (p=0.04).
Conclusion  The protective effect of EXPCS for infection could be proven
in prolonged delivery. EXPCS could be a good solution in the fight against
adhesions and infection in women who undergo second, third, or even fourth
cesarean sections.
Design and Efficient Synthesis of New 4-Amino-Substituted 2-(4-Bromobenzyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines of Anticancer Interest and Their In Silico Study
Authors: Kumar Raj , Arora Sahil , Thakur Shikha , Kaki Venkata Rao 
Published: July 2024

AbstractThienopyrimidines are an emerging class of fused pyrimidines due to their broad spectrum of pharmacological properties, including antimicrobial, anti-inflammatory, antimalarial, anticancer, etc. The anticancer activity of these compounds has been mechanistically proven via the inhibition of validated drug targets, such as EGFR, VEGFR-2, PI3K, and c-kit. In this research article, we designed and synthesized new 4-amino-substituted 2-(4-bromobenzyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines to explore their anticancer potential. These heterocycles were designed based on pharmacophoric features of the core heterocycle, varying its C4 substitution with a variety of amines and considering cancer protein-ligand interactions with the aim to obtain potent lead molecules. The target compound-protein interaction complexes were analyzed, and lead compounds were identified based on their better binding affinity in molecular docking studies.
Ring-Closing Metathesis as Methodology for the Synthesis of 2- and 3-Arylbenzo[b]furans
Authors: Bezuidenhoudt Barend C. B. , Visser Melanie , Twigge Linette , Marais Charlene 
Published: July 2024

AbstractOlefin metathesis, which is well established in the petrochemical industry, is also emerging as a green technology in the manufacture of pharmaceutical and specialty chemicals. Arylbenzofurans are of interest for potential medicinal applications. In this paper we report on the synthesis of various 2-aryl- and 3-arylbenzo[b]furans with natural substitution patterns from readily available starting materials in a strategy that applies ring-closing metathesis with the Grubbs second generation catalyst as key step.
Ni–H-Catalyzed Chemo- and Regioselective Hydroarylation of Vinylsilanes
Authors: Oestreich Martin , Brösamlen Daniel 
Published: July 2024

AbstractA chemo- and regioselective hydroarylation of vinylsilanes with (hetero)aryl iodides under Ni–H catalysis is reported. This mild and straightforward protocol furnishes the anti-Markovnikov products in good yields as single regioisomers. This study demonstrates excellent control over the chemoselectivity and complements existing methods for the construction of homobenzylic silanes.
Hydrazide–Hydrazones as Potential Antitubercular Agents: An Overview of the Literature (1999–2023)
Authors: Mali Suraj N. , Pandey Anima , Shah Umang , Jawarkar Rahul D , Somani Rakesh 
Published: July 2024

AbstractHydrazide–hydrazone derivatives are prevalent in numerous bioactive compounds, showcasing a diverse array of biological effects including antibacterial, antitubercular, antifungal, anticancer, anti-inflammatory, anticonvulsant, antiviral, and antiprotozoal properties. Consequently, numerous medicinal chemists have undertaken the synthesis of various hydrazide–hydrazones, subjecting them to evaluation for their biological activities. Among these, antituberculosis activity stands out as a recurring focus in the scientific literature. This paper provides a comprehensive overview of research spanning the last 24 years (1999–2023), concentrating on the antituberculosis properties of hydrazide–hydrazone derivatives. The insights presented herein could serve as a valuable roadmap for the development of novel hydrazide–hydrazones with potential antimicrobial efficacy.
Simple Access to 3-(Hetero)arylated Derivatives of 2-Furoic Acid via Ru(II)-Catalyzed C3-H Arylation of 2-Furoylimidazole
Authors: Chernyshev Victor M. , Ananikov Valentine P. , Shepelenko Konstantin E. , Gnatiuk Irina G. , Lavrentev Igor V. , Minyaev Mikhail E. 
Published: July 2024

AbstractA new approach for the preparation of a variety of 3-arylated 2-furoic acid derivatives has been developed. The approach involves selective Ru-catalyzed C3-H arylation of the furan moiety of readily available 2-furoyl-1-methylimidazole (using imidazole as a removable N-donor directing group), subsequent N-methylation, and nucleophilic substitution of the imidazole moiety with N, O, S, and C nucleophiles.
Evaluation of Physical Properties in Carboxymethyl Chitosan Modified Glass Ionomer Cements and the Effect for Dentin Remineralization: SEM/EDX, Compressive Strength, and Ca/P Ratio
Authors: Putranto Aditya Wisnu , Meidyawati Ratna , Dwiseptyoga Senyan , Zikrullah Dicky Yudha Andhika 
Published: July 2024

Abstract
Objective The aim of this article was to evaluate the effects of modifying glass ionomer cement (GIC) with carboxymethyl chitosan (CMC) on surface morphology and remineralization outcomes by examining dentin morphology and calcium ion composition changes.
Materials and Methods Thirty holes in a cylindrical acrylic mold were filled with three groups of restorative materials: GIC, GIC modified with CMC (GIC-CMC) 5%, and GIC-CMC10%. The surface morphology of each group's materials was observed using scanning electron microscopy (SEM). The compressive strength measurement was performed using a universal testing machine. The dentin remineralization process was performed by applying GIC, GIC-CMC5%, and GIC-CMC10% materials for 14 days on demineralized dentin cavities treated with 17% ethylenediamine tetraacetic acid (EDTA) for 7 days. A morphological evaluation was conducted using SEM. The calcium ion composition and calcium-to-phosphorous (Ca/P) ratio were examined using an energy-dispersive X-ray (EDX).
Statistical Analysis The one-way ANOVA and post-hoc Bonferroni test were used to evaluate the compressive strength within the three groups (p < 0.05). The Kruskal–Wallis and subsequent Mann–Whitney U tests were conducted to compare the four groups of calcium ions (p < 0.05).
Results The modification of GIC with CMC affected the morphological changes in the materials in the form of reduced porosity and increased fractures. A significant difference was found in compressive strength between the GIC-CMC modification materials of GIC-CMC5% and GIC-CMC10% and the GIC control group. The dentin tubule morphology and surface changes were observed after applying GIC, GIC-CMC5%, and GIC-CMC10% materials for 14 days, as evaluated by SEM. The EDX examination showed an increase in calcium ion content and hydroxyapatite formation (Ca/P ratio) after applying the GIC-CMC10% material.
Conclusion The surface porosity of the GIC modification material with the addition of CMC tended to decrease. However, an increase in cracked surfaces that widened, along with the rise in CMC percentage, was found. This modification also reduced the compressive strength of the materials, with the lowest average yield at 10% CMC addition. Therefore, the modification of GIC with CMC affects changes in morphology, calcium ion composition, and Ca/P ratio in demineralized dentin.
From MilkingBots to RoboDolphins: How AI changes human-animal relations and enables alienation towards animals
Authors: Bossert Leonie N. , Coeckelbergh Mark 
Published: July 2024

AbstractTechnologies, especially disruptive technologies, have a great potential to change and reshape human-human as well as human-technology relations. This creates various ethical challenges that need to be addressed. However, technologies also have great potential to change human-animal relations. Since this aspect is underexplored in the academic debate on technologies’ impact on relations, we believe that it is important to (1), descriptively, study how new and emerging technologies impact human-animal relations, and (2), normatively, to enrich the debate with a non-anthropocentric perspective that recognizes that human-animal relations also have moral significance. Therefore, in this paper we investigate how artificial intelligence (AI) technologies and robotics impact human-animal relations, and we discuss the moral significance of these changes. AI technologies change human-animal relations due to, first, automation, and second, replacement processes. Automation processes mainly take place in the animal agriculture sector, and the replacement of biological animals with artificial AI-driven animals mainly in the context of zoos, companion animals and laboratories. We address both processes (automation and replacement), thereby providing an overview of how the use of AI technologies will—or can—change human-animal relations, at both the individual and societal levels. While doing so, we highlight the morally significant aspects that come along with such changes and provide first thoughts on which uses of AI are welcomed from a perspective of human-animal relations.
Wavelength modulation laser-induced fluorescence for plasma characterization
Authors: Romadanov I. , Raitses Y. , Smolyakov A. 
Published: July 2024

Laser-Induced Fluorescence (LIF) spectroscopy is an essential tool for probing ion and atom velocity distribution functions (VDFs) in complex plasmas. VDFs carry information about the kinetic properties of species that is critical for plasma characterization. Accurate interpretation of these functions is challenging due to factors such as multicomponent distributions, broadening effects, and background emissions. Our research investigates the use of Wavelength Modulation (WM) LIF to enhance the sensitivity of VDF measurements. Unlike standard Amplitude Modulation (AM) methods, WM–LIF measures the derivative of the LIF signal. This approach makes variations in VDF shape more pronounced. VDF measurements with WM–LIF were investigated with both numerical modeling and experimental measurements. The developed model enables the generation of both WM and AM signals, facilitating comparative analysis of fitting outcomes. Experiments were conducted in a weakly collisional argon plasma with magnetized electrons and non-magnetized ions. Measurements of the argon ion VDFs employed a narrow-band tunable diode laser, which scanned the 4p4D7/2–3d4F9/2 transition centered at 664.553 nm in vacuum. A lock-in amplifier detected the second harmonic WM signal, which was generated by modulating the laser wavelength with an externally controlled piezo-driven mirror of the diode laser. Our findings indicate that the WM–LIF signal is more sensitive to fitting parameters, allowing for better identification of VDF parameters such as the number of distribution components, their temperatures, and velocities. In addition, WM–LIF can serve as an independent method to verify AM measurements and is particularly beneficial in environments with substantial light noise or background emissions, such as those involving thermionic cathodes and reflective surfaces.
The acquisition of generic null subjects under the Borer-Chomsky conjecture
Authors: Bertolino Karina 
Published: July 2024

Abstract
This chapter examines how Brazilian Portuguese (BP)-speaking children acquire a critical property
associated with partial null-subject languages, generic null subjects. The purpose is to investigate whether the data
about the acquisition of generic null subjects are compatible with the idea that parametric variation is caused by the
cross-linguistic distribution of features in functional heads (known as the Borer-Chomsky conjecture). To acquire the
distribution of (null) subjects, the child should pay close attention to ϕ-features on T and D.
Studies have shown that children become sensitive to the presence of verbal inflections and determiners before their
first words (Dye et al., 2019), which leads to the prediction that children
should not show evidence of parameter misssetting. We found that generic null subjects emerge as early as 1;9 in BP,
which is consistent with the prediction of early parameter setting. However, generic null subjects did not appear
frequently in spontaneous production and they increase as the child grows older. As generic null subjects are used to
talk about rules, patterns and generalizations, not about specific individuals, the production of generic null
subjects increases as children’s conversational topics become less egocentric.
Quantifier comprehension in Brazilian Portuguese and the extra-object visual effect
Authors: Rodrigues Erica , Forster Renê , Sicuro Corrêa Letícia 
Published: July 2024

Abstract
Universal quantifiers are complex for children to comprehend, and over-exhaustive errors can occur
even with adults in sentence-picture verification tasks. This paper addresses visual design factors that may explain
these difficulties. We examine what we call the “single extra object attraction hypothesis” (SEOH), according to which
the visual prominence of a uniquely unpaired extra object compromises attentional resources during these tasks. We
manipulated the type of extra-object – single or double – in an eye-tracking experiment with adult speakers of
Brazilian Portuguese. Contrary to the SEOH prediction, double objects gave rise to earlier and longer fixations than
single objects. There was no difference in accuracy. We discuss the implications of these results for developmental
research.
Between source language constructions and target language expectations
Authors: Oster Ulrike , Tello Isabel 
Published: July 2024

Abstract
This paper is situated within Cognitive Translation Studies (CTS). It follows Halverson’s Gravitational Pull
Hypothesis (2003, 2010, 2017, 2024), a framework that explains the
translation process and its outcome by invoking the cognitive mechanisms of the bilingual mind. The paper adopts the cognitive,
multi-method approach of the GPH to describe and compare the use of Spanish passive constructions in a multilingual comparable
corpus of translated and non-translated texts. In doing so, it pushes the boundaries of the model by: (a) following an
onomasiological rather than a semasiological approach; (b) focusing on constructions rather than lexical items; and (c) explicitly
incorporating the aspect of translator socialisation into the hypothesis formulation, thereby taking into account the situatedness
of translation. The results provide evidence in support of the GPH, as salience of a construction in the source or target language
leads to its overrepresentation in the translated texts, and non-salience leads to its underrepresentation.
Equivalent electrical circuits for electroacoustic MEMS design: a review
Authors: Liechti Romain 
Published: July 2024

AbstractAt the era of powerful computers, it is tempting to employ finite element models early in the design phase of a device. However, especially for MEMS devices, the dimensional ratios and short wavelengths compared to the device’s dimensions, along with the involvement of multiple physics, can necessitate complex and computationally intensive models, making them impractical for optimization processes. Hence, reduced order models, like the lumped element model, are often preferred as they accurately represent complex system behaviour within a defined frequency range. This review explores the use of lumped element models and their corresponding electrical equivalent circuits for simulating MEMS electro-acoustic devices, offering insights into their diverse applications within this specific domain.
Morphology of films deposited on the sidewall during the Bosch process using C4F8 plasmas
Authors: Nonaka Tomoyuki , Takahashi Kazuo , Uchida Akimi , Tsuji Osamu 
Published: July 2024

Abstract
In the Bosch process, C4F8 plasmas are used to deposit passivation films. In this study, the passivation films were deposited in micro-scale trenches by changing the C4F8 flow rate, ICP power, and pressure, and their cross sections were observed by scanning electron microscopy. The results showed that the morphology of the passivation film and its relative deposition rate at each depth varied depending on the plasma discharge conditions. There is a correlation between the C–CF
x
bond content and the morphology of passivation films, with high C–CF
x
bond content resulting in smooth morphology and low C–CF
x
bond content resulting in a rough morphology. Furthermore, it was found that ion bombardment reduced the roughness of the passivation film. Through these experiments, we also found the possibility of controlling the deposition rate of the passivation film at each trench depth by adjusting the plasma discharge conditions.