bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptomic profiling analysis of human endometrial stromal cells treated with autologous platelet‐rich plasma
Authors: Kuroda Keiji , Matsumoto Akemi , Horikawa Takashi , Takamizawa Satoru , Ochiai Asako , Kawamura Kazuhiro , Nakagawa Koji , Sugiyama Rikikazu
Published: January 2023

Purpose

To clarify the mechanisms of intrauterine platelet‐rich plasma (PRP) infusion that support embryo implantation in in vitro fertilization treatment.

Methods

Blood and endometrial samples were collected from four infertile women. Human endometrial stromal cells (HESCs) were cultured and passaged equally into four cell culture dishes in each patient. Two were treated with PRP twice, and the other two were treated with vehicle. Subsequently, two cultures with and without PRP were decidualized with 8‐bromoadenosine 3′,5′‐cyclic AMP and progesterone for 5 days.

Results

The gene expression in undifferentiated or decidualized HESCs with and without PRP was compared. In the microarray analysis, 381 and 63 differentially expressed genes were detected in undifferentiated and decidualized HESCs, respectively. In the undifferentiated HESCs, PRP was found to promote the gene expression associated with cell growth, tissue regeneration, proinflammatory response, and antibiotic effects. In decidualized HESCs, PRP was found to attenuate the gene expression involved in cell proliferation and inflammation by inhibiting the expression of phosphoinositide 3‐kinase signaling.

Conclusions

Platelet‐rich plasma regulates the reprogramming of cell proliferation and inflammation depending on menstrual cycle phases in an appropriate manner, suggesting that PRP has the potential to increase endometrial thickness in the proliferative phase and improve immune tolerance in the secretory phase.
Dengue determinants: Necessities and challenges for universal dengue vaccine development
Authors: Hussain Zahid , Rani Saima , Ma Fanshu , Li Wenjing , Shen Wenqi , Gao Tian , Wang Jine , Pei Renjun
Published: January 2023

Dengue illness can range from mild illness to life‐threatening haemorrhage. It is an Aedes‐borne infectious disease caused by the dengue virus, which has four serotypes. Each serotype acts as an independent infectious agent. The antibodies against one serotype confer homotypic immunity but temporary protection against heterotypic infection. Dengue has become a growing health concern for up to one third of the world's population. Currently, there is no potent anti‐dengue medicine, and treatment for severe dengue relies on intravenous fluid management and pain medications. The burden of dengue dramatically increases despite advances in vector control measures. These factors underscore the need for a vaccine. Various dengue vaccine strategies have been demonstrated, that is, live attenuated vaccine, inactivated vaccine, DNA vaccine, subunit vaccine, and viral‐vector vaccines, some of which are at the stage of clinical testing. Unfortunately, the forefront candidate vaccine is less than satisfactory, and its performance depends on serostatus and age factors. The lessons from clinical studies depicted ambiguity concerning the efficacy of dengue vaccine. Our study highlighted that viral structural heterogeneity, epitope accessibility, autoimmune complications, genetic variants, genetic diversities, antigen competition, virulence variation, host‐pathogen specific interaction, antibody‐dependent enhancement, cross‐reactive immunity among Flaviviruses, and host‐susceptibility determinants not only influence infection outcomes but also hampered successful vaccine development. This review integrates dengue determinants allocated necessities and challenges, which would provide insight for universal dengue vaccine development.
Trapped Pore Waters in the Open Proton Channel HV1
Authors: Boytsov Danila , Brescia Stefania , Chaves Gustavo , Koefler Sabina , Hannesschlaeger Christof , Siligan Christine , Goessweiner‐Mohr Nikolaus , Musset Boris , Pohl Peter
Published: January 2023

The voltage‐gated proton channel, HV1, is crucial for innate immune responses. According to alternative hypotheses, protons either hop on top of an uninterrupted water wire or bypass titratable amino acids, interrupting the water wire halfway across the membrane. To distinguish between both hypotheses, the water mobility for the putative case of an uninterrupted wire is estimated. The predicted single‐channel water permeability 2.3 × 10−12 cm3 s−1 reflects the permeability‐governing number of hydrogen bonds between water molecules in single‐file configuration and pore residues. However, the measured unitary water permeability does not confirm the predicted value. Osmotic deflation of reconstituted lipid vesicles reveals negligible water permeability of the HV1 wild‐type channel and the D174A mutant open at 0 mV. The conductance of 1400 H+ s−1 per wild‐type channel agrees with the calculated diffusion limit for a ≈2 Å capture radius for protons. Removal of a charged amino acid (D174) at the pore mouth decreases H+ conductance by reducing the capture radius. At least one intervening amino acid contributes to H+ conductance while interrupting the water wire across the membrane.
An In Situ Assembled Trapping Gel Repairs Spinal Cord Injury by Capturing Glutamate and Free Calcium Ions
Authors: Huang Ying , Wang Jialun , Yue Chunyan , Wang Ran , Guo Qiyuan , Wang Tingyu , Wang Daojuan , Dong Hong , Hu Yiqiao , Tao Gaojian , Li Xihan
Published: January 2023

Spinal cord injury (SCI) can lead to devastating autonomic dysfunction. One of the most challenging issues for functional repair in SCI is the secondary damage caused by the increased release of glutamate and free Ca2+ from injured cells. Here, an in situ assembled trapping gel (PF‐SA‐GAD) is developed to sweep glutamate and Ca2+, promoting SCI repair. The hydrogel solution is a mixture of recombinant glutamate decarboxylase 67 (rGAD67) protein, sodium alginate (SA), and pluronic F‐127 (PF‐127). After intrathecal administration, temperature‐sensitive PF‐127 promoted in situ gelation. Glutamate (Glu) is captured and decarboxylated by rGAD67 into γ‐aminobutyric acid (GABA). SA reacted with the free Ca2+ to generate gellable calcium alginate. Thereby, this in situ trapping gel retarded secondary neuron injury caused by Glu and free Ca2+ during SCI. In rat models of SCI, PF‐SA‐GAD reduces the lesion volume and inflammatory response after SCI, restores the motor function of rats with SCI. Together, the in situ assembled trapping gel is a long‐term effective and minimally invasive sweeper for the direct elimination of glutamate and Ca2+ from injury lesions and can be a novel strategy for SCI repair by preventing secondary injury.
Ultrahigh Detectivity Broad Spectrum UV Photodetector with Rapid Response Speed Based on p‐β Ga2O3/n‐GaN Heterojunction Fabricated by a Reversed Substitution Doping Method
Authors: Han Yurui , Wang Yuefei , Fu Shihao , Ma Jiangang , Xu Haiyang , Li Bingsheng , Liu Yichun
Published: January 2023

An excellent broad‐spectrum (220–380 nm) UV photodetector, covering the UVA‐UVC wavelength range, with an ultrahigh detectivity of ≈1015 cm Hz1/2 W−1, is reported. It is based on a p‐β Ga2O3/n‐GaN heterojunction, in which p‐β Ga2O3 is synthesized by thermal oxidation of GaN and a heterostructure is constructed with the bottom n‐GaN. XRD shows the oxide layer is (−201) preferred oriented β‐phase Ga2O3 films. SIMS and XPS indicate that the residual N atoms as dopants remain in β Ga2O3. XPS also demonstrates that the Fermi level is 0.2 eV lower than the central level of the band gap, indicating that the dominant carriers are holes and the β Ga2O3 is p‐type conductive. Under a bias of −5 V, the photoresponsivity is 56 and 22 A W−1 for 255 and 360 nm, respectively. Correspondingly, the detectivities reach an ultrahigh value of 2.7 × 1015 cm Hz1/2 W−1 (255 nm) and 1.1 × 1015 cm Hz1/2 W−1 (360 nm). The high performance of this UV photodetector is attributed mainly to the continuous conduction band of the p‐β Ga2O3/n‐GaN heterojunction without a potential energy barrier, which is more helpful for photogenerated electron transport from the space charge region to the n‐type GaN layer.
Active BiVO4 Swimmers Propelled by Depletion Gradients Caused by Photodeposition
Authors: Wittmann Martin , Voigtmann Maximilian , Simmchen Juliane
Published: January 2023

Artificial active matter often self‐propels by creating gradients of one or more species or quantities. For chemical swimmers, most frequently either O2 or H+ that are created in certain catalytic reactions are causing the interfacial flows which drive the self‐propulsion. While the palette of reactions is extending constantly, especially toward more bio‐compatible fuels, the depletion of species is often overlooked. Here, the photodeposition of metal species on BiVO4 micro swimmers is considered. During the photodeposition reaction, metal ions are removed from the solution creating a depleted region around the particle. The ability of this depletion to drive active motion of artificial micro swimmers, as well as the influences of different metal ions and counter ions on the motion are investigated and cross compared.
The coral‐inspired steam evaporator for efficient solar desalination via porous and thermal insulation bionic design
Authors: Zhang He , Li Xiaoke , Zheng Size , Wen Jin , Zhou Jiaying , Yang Rui , Luo Wenmei , Yang Liu , Wu Xiaohu
Published: January 2023

The solar‐driven interfacial evaporation (SIE) technology shows great prospects in seawater desalination and sewage treatment, but it is unable to obtain highly efficient and high‐quality clean nontoxic water at low cost. Here, a novel biodegradable hydrogel‐based solar evaporator (BBH‐L) with a bionic coral structure taking Chinese ink as the solar absorber was developed. This evaporator consists of chitosan/polyvinyl alcohol hydrogel and a loofah substrate. The average evaporation rate and efficiency of BBH‐L reach 4.37 kg/(m2·h) and 98.2%, respectively, under one sun illumination (1 kW/m2), which are attributed to its excellent thermal localization and water transporting abilities. Meanwhile, high salt resistance enables BBH‐L to achieve efficient desalination and purification of other unconventional water. Heavy metal ions in seawater can be effectively removed by chelation and forming hydrogen bonds in hydrogels. This study is anticipated to provide new possibilities to enhance evaporation performance and reduce the costs of water treatment systems.
Highly Sensitive Detection of Complicated Mutations of Drug Resistance in Mycobacterium tuberculosis Using a Simple, Accurate, Rapid, and Low‐Cost Tailored‐Design Competitive Wild‐Type Blocking Assay
Authors: Yan Mengqiu , Zhao Zhenzhen , Wu Tao , Liu Tangyuheng , Xu Gaolian , Xu Hong , Ying Binwu
Published: January 2023

Establishing simple, rapid, and highly sensitive molecular assays is crucial for timely diagnosis and effective treatment of drug‐resistant tuberculosis. However, current genotypic drug susceptibility testing (DST) still encounters enormous challenges including lower sensitivity than phenotypic DST and insufficient accuracy. Herein, a simple, low‐cost, multiplex real‐time polymerase chain reaction‐based assay is established to achieve highly sensitive detection of low‐abundant mutants through competitive wild‐type blocking (COWTB). Analytical performance of the COWTB assay can achieve 1% or even 0.1% mutants under background of 10 000 wild‐type genomes/test. Furthermore, clinical practice feasibility is evaluated to identify resistance to rifampicin (RIF), isoniazid (INH), and streptomycin (SM) on 92 actual clinical samples, its sensitivity is 93.8% for RIF and 100% for INH and SM, and specificity is 100% each for RIF, INH, and SM when using DNA sequencing as the reference standard. In comparison, the sensitivity of reverse dot blotting assay commonly used in clinics is 93.8%, 90.0%, and 84.6%, and the specificity is 96.1%, 98.6%, and 100% for RIF, INH, and SM, respectively. Importantly, the COWTB assay can also be applicable for other drug‐resistant mutations and pave a promising detection strategy to fill the gap between phenotypic and genotypic DST for detecting low‐abundant drug‐resistant M. tuberculosis.
Engineering a Synthetic RNA Segregation System
Authors: Hürtgen Daniel , Mascarenhas Judita , Vibhute Mahesh A. , Weise Laura I. , Mayr Viktoria S. , Sourjik Victor , Mutschler Hannes
Published: January 2023

Cells possess a number of active segregation machineries for both chromosomal and large extrachromosomal DNA elements to avoid stochastic loss during cell division. In contrast, system that can be exploited for active, general segregation of RNA molecules including mRNAs or self‐replicating RNA constructs are currently lacking. Here, we present an artificial RNA segregation system derived from the bacterial type II ParMRC plasmid segregation system and the RNA coliphage MS2. We show that fusing the partition protein ParR with the MS2 RNA coat protein enables specific binding to microbeads decorated with RNA‐repeats of the archetypical MS2 RNA operator hairpin. Addition of the actin homologue ParM protein triggers efficient and rapid microbeads segregation via ATP‐dependent ParM polymerization. Our new RNA partitioning system could be used for specific localization of mRNAs and/or the stable maintenance of self‐replicating RNA vectors in various contexts such as living and artificial cells.
Computational Social Science for Public Policy
Authors: Margetts Helen , Dorobantu Cosmina
Published: January 2023

Computational Social Science (CSS), which brings together the power of computational methods and the analytical rigour of the social sciences, has the potential to revolutionise policymaking. This growing field of research can help governments take advantage of large-scale data on human behaviour and provide policymakers with insights into where policy interventions are needed, which interventions are most likely to be effective, and how to avoid unintended consequences. In this chapter, we show how Computational Social Science can improve policymaking by detecting, measuring, predicting, explaining, and simulating human behaviour. We argue that the improvements that CSS can bring to government are conditional on making ethical considerations an integral part of the process of scientific discovery. CSS has an opportunity to reveal bias and inequalities in public administration and a responsibility to tackle them by taking advantage of research advancements in ethics and responsible innovation. Finally, we identify the primary factors that prevented Computational Social Science from realising its full potential during the Covid-19 pandemic and posit that overcoming challenges linked to limited data flows, siloed models, and rigid organisational structures within government can usher in a new era of policymaking.
Computational Climate Change: How Data Science and Numerical Models Can Help Build Good Climate Policies and Practices
Authors: Tavoni Massimo
Published: January 2023

Computational social science can help advance climate policy and help solve the climate crises. To do so, several steps need to be overcome to make the best use of the wealth of data and variety of models available to evaluate climate change policies. Here, we review the state of the art of numerical modelling and data science methods applied to policy evaluation. We emphasize that significant progress has been made but that critical social and economic phenomena—especially related to climate justice—are not yet fully captured and thus limit the predictivity and usefulness of computational approaches. We posit that the integration of statistical and numerical approaches is key to developing a new impact evaluation science that overcomes the traditional divide between ex ante and ex post approaches.
Digital Epidemiology
Authors: Mejova Yelena
Published: January 2023

Computational social science has had a profound impact on the study of health and disease, mainly by providing new data sources for all of the primary Ws—what, who, when, and where—in order to understand the final “why” of disease. Anonymized digital trace data bring a new level of detail to contact networks, search engine and social media logs allow for the now-casting of symptoms and behaviours, and media sharing informs the formation of attitudes pivotal in health decision-making. Advances in computational methods in network analysis, agent-based modelling, as well as natural language processing, data mining, and time series analysis allow both the extraction of fine-grained insights and the construction of abstractions over the new data sources. Meanwhile, numerous challenges around bias, privacy, and ethics are being negotiated between data providers, academia, the public, and policymakers in order to ensure the legitimacy of the resulting insights and their responsible incorporation into the public health decision-making. This chapter outlines the latest research on the application of computational social science to epidemiology and the data sources and computational methods involved and spotlights ongoing efforts to address the challenges in its integration into policymaking.
Improving CBCT image quality to the CT level using RegGAN in esophageal cancer adaptive radiotherapy
Authors: Wang Hao , Liu Xiao , Kong Lingke , Huang Ying , Chen Hua , Ma Xiurui , Duan Yanhua , Shao Yan , Feng Aihui , Shen Zhenjiong , Gu Hengle , Kong Qing , Xu Zhiyong , Zhou Yongkang
Published: January 2023

Objective

This study aimed to improve the image quality and CT Hounsfield unit accuracy of daily cone-beam computed tomography (CBCT) using registration generative adversarial networks (RegGAN) and apply synthetic CT (sCT) images to dose calculations in radiotherapy.

Methods

The CBCT/planning CT images of 150 esophageal cancer patients undergoing radiotherapy were used for training (120 patients) and testing (30 patients). An unsupervised deep-learning method, the 2.5D RegGAN model with an adaptively trained registration network, was proposed, through which sCT images were generated. The quality of deep-learning-generated sCT images was quantitatively compared to the reference deformed CT (dCT) image using mean absolute error (MAE), root mean square error (RMSE) of Hounsfield units (HU), and peak signal-to-noise ratio (PSNR). The dose calculation accuracy was further evaluated for esophageal cancer radiotherapy plans, and the same plans were calculated on dCT, CBCT, and sCT images.

Results

The quality of sCT images produced by RegGAN was significantly improved compared to the original CBCT images. ReGAN achieved image quality in the testing patients with MAE sCT vs. CBCT: 43.7 ± 4.8 vs. 80.1 ± 9.1; RMSE sCT vs. CBCT: 67.2 ± 12.4 vs. 124.2 ± 21.8; and PSNR sCT vs. CBCT: 27.9 ± 5.6 vs. 21.3 ± 4.2. The sCT images generated by the RegGAN model showed superior accuracy on dose calculation, with higher gamma passing rates (93.3 ± 4.4, 90.4 ± 5.2, and 84.3 ± 6.6) compared to original CBCT images (89.6 ± 5.7, 85.7 ± 6.9, and 72.5 ± 12.5) under the criteria of 3 mm/3%, 2 mm/2%, and 1 mm/1%, respectively.

Conclusion

The proposed deep-learning RegGAN model seems promising for generation of high-quality sCT images from stand-alone thoracic CBCT images in an efficient way and thus has the potential to support CBCT-based esophageal cancer adaptive radiotherapy.
Kinder- und Jugendgesundheit in der Klimakrise
Authors: Eichinger Michael , Andreas Marike , Hoeppe Alice , Nisius Katja , Rink Katharina
Published: January 2023

Kinder und Jugendliche sind aufgrund ihrer Physiologie und längerer Expositionszeiten besonders von den gesundheitlichen Folgen der Klimakrise betroffen. Darüber hinaus wird die Klimakrise ohne Gegenmaßnahmen vorbestehende gesundheitliche Ungleichheiten verschärfen, da Kinder und Jugendliche aus Familien mit niedrigem sozioökonomischen Status und schlechterem Gesundheitszustand besonders stark von den gesundheitlichen Folgen der Klimakrise betroffen sind.

Die Klimakrise wirkt sich über zahlreiche Mechanismen auf die Gesundheit von Kindern und Jugendlichen aus, wobei jedes Organsystem betroffen sein kann. Extremwetterereignisse gehen u. a. mit einem erhöhten Risiko für Hitzschläge, Elektrolytstörungen, Verletzungen und psychische Erkrankungen einher. Der Temperaturanstieg führt zu veränderten Ausbreitungsgebieten von Krankheitsvektoren, die u. a. die Erreger der Borreliose oder des West-Nil-Fiebers übertragen. Im Bereich der psychischen Gesundheit stehen Klimaangst und die psychischen Auswirkungen von Extremwetterereignissen im Vordergrund.

Zahlreiche Maßnahmen in den Bereichen Klimaschutz und Klimafolgenanpassung haben zugleich positive Effekte auf die Gesundheit und werden daher als Win-Win-Lösungen bezeichnet (z. B. aktiver Transport, Ausweitung urbaner Grünflächen). Kinder- und Jugendärzt:innen können einen wichtigen Beitrag zu Prävention und adäquater Behandlung von klimawandelassoziierten Erkrankungen leisten, indem sie u. a. in U‑Untersuchungen Win-Win-Lösungen adressieren und klimawandelbedingte Belastungsfaktoren in der Anamnese berücksichtigen. Darüber hinaus können sie durch ihr Engagement in Organen der ärztlichen Selbstverwaltung (z. B. Etablierung nachhaltiger Anlagestrategien in ärztlichen Versorgungswerken) oder durch die Umsetzung von Maßnahmen in Gesundheitseinrichtungen aktiv zum Klimaschutz beitragen.
Identification of major quantitative trait loci and candidate genes for seed weight in soybean
Authors: Xu Mengge , Kong Keke , Miao Long , He Jianbo , Liu Tengfei , Zhang Kai , Yue Xiuli , Jin Ting , Gai Junyi , Li Yan
Published: January 2023

Key message

Four major quantitative trait loci for 100-seed weight were identified in a soybean RIL population under five environments, and the most likely candidate genes underlying these loci were identified.

Seed weight is an important target of soybean breeding. However, the genes underlying the major quantitative trait loci (QTL) controlling seed weight remain largely unknown. In this study, a soybean population of 300 recombinant inbred lines (RILs) derived from a cross between PI595843 (PI) and WH was used to map the QTL and identify candidate genes for seed weight. The RIL population was genotyped through whole genome resequencing, and phenotyped for 100-seed weight under five environments. A total of 38 QTL were detected, and four major QTL, each explained at least 10% of the variation in 100-seed weight, were identified. Six candidate genes within these four major QTL regions were identified by analyses of their tissue expression patterns, gene annotations, and differential gene expression levels in soybean seeds during four developmental stages between two parental lines. Further sequence variation analyses revealed a C to T substitution in the first exon of the Glyma.19G143300, resulting in an amino acid change between PI and WH, and thus leading to a different predicted kinase domain, which might affect its protein function. Glyma.19G143300 is highly expressed in soybean seeds and encodes a leucine-rich repeat receptor-like protein kinase (LRR-RLK). Its predicted protein has typical domains of LRR-RLK family, and phylogenetic analyses reveled its similarity with the known LRR-RLK protein XIAO (LOC_Os04g48760), which is involved in controlling seed size. The major QTL and candidate genes identified in this study provide useful information for molecular breeding of new soybean cultivars with desirable seed weight.
Mechanical characterization of high volume fraction Al7075-Al2O3 composite fabricated by semisolid powder processing
Authors: Aghajani Saeed , Pouyafar Vahid , Meshkabadi Ramin , Volinsky Alex A. , Bolouri Amir
Published: January 2023

The mechanical properties and physical characteristics of aluminum alloy composites can be significantly improved by adding reinforcing phases. However, the high loading of the reinforcement phase in Al7075-Al2O3 composites has not been thoroughly studied. In this work, a combination of semisolid metal powder processing and powder metallurgy is used to process and manufacture Al7075-Al2O3 composites with a high reinforcement fraction of > 40 vol.%. The effects of processing parameters on the microstructures and mechanical properties of the composite material are discussed in detail. The loading limits of the high volume Al2O3 reinforcement in Al7075 composites are identified and linked to the processing parameters. A methodology is introduced to estimate the consolidation temperature of Al7075 alloy using compaction testing. Al2O3 particles (the average particle size of 120 µm) were mechanically milled with Al7075 powder (the average particle size of 20 µm) for 10 min and 5 h using a high-energy planetary ball mill. The mixture was then compacted in the semisolid state at 615 °C under the compaction pressures of 50 MPa and 100 MPa. By increasing the milling time from 10 min to 5 h, the deformation of aluminum powders and the fracture of Al2O3 reinforcement particles occur, restricting the loading limit of reinforcement. The milling time also shows a dominant effect on the powder morphology, microstructure, and mechanical properties of Al7075-Al2O3 composites. Increasing compaction pressure from 50 to 100 MPa significantly improved the compressive strength of the composite from 218 to 652 MPa. Al7075-Al2O3 composite with 40 vol.% of reinforcing phase exhibits the highest hardness of 198.2 HV and 96.9% relative density when it is milled for 5 h and compacted at 100 MPa. However, this composite shows the highest strength of 652 MPa when it is milled for 10 min. By increasing the reinforcing phase to 50 vol.% and 60 vol.%, the hardness, density, and compressive strength of composites decreased. The composites with 60 vol.% of reinforcing phase appeared overloaded. Results show that semisolid metal powder processing has huge potential for the fabrication of high loading Al2O3 in Al7075 matrix with near theoretical density.
Measurement and identification of translational static stiffness in workspace of a machine tool
Authors: Jastrzębska Joanna , Parus Arkadiusz , Jastrzębski Daniel , Pawełko Piotr
Published: January 2023

This work presents a measurement for the identification of translational quasi-static stiffness of machine tool using Stiffness Workspace System (SWS). The novelty of this work is a significant modification of the SWS. The changes in measurement procedure and data analysis as well as new technical solutions are described in detail. A methodology for generalised translational static stiffness determination is presented. The major purpose of this paper is to provide the information about quasi-static stiffness values that characterise a typical machine tool. The measurement procedure is implemented in a case study on a 5-axis machining centre. Measurement results were used to determine the generalised translational stiffness indicators of points in the workspace. Then, the static stiffness distribution on the XY plane over machining space was estimated. The obtained results confirm the importance of analyses of static stiffness distribution as they point out areas where some possible changes occur. In the conclusion of the paper the utility value of the information of translational static stiffness is emphasised.
Transcriptional profiling of the developing rat ovary following intrauterine exposure to the endocrine disruptors diethylstilbestrol and ketoconazole
Authors: Kugathas Indusha , Johansson Hanna K. L. , Chan Sock Peng Edith , Toupin Maryne , Evrard Bertrand , Darde Thomas A. , Boberg Julie , Draskau Monica K. , Rolland Antoine D. , Mazaud-Guittot Séverine , Chalmel Frédéric , Svingen Terje
Published: January 2023

Exposure to endocrine-disrupting chemicals (EDCs) during development may cause reproductive disorders in women. Although female reproductive endpoints are assessed in rodent toxicity studies, a concern is that typical endpoints are not sensitive enough to detect chemicals of concern to human health. If so, measured endpoints must be improved or new biomarkers of effects included. Herein, we have characterized the dynamic transcriptional landscape of developing rat ovaries exposed to two well-known EDCs, diethylstilbestrol (DES) and ketoconazole (KTZ), by 3’ RNA sequencing. Rats were orally exposed from day 7 of gestation until birth, and from postnatal day 1 until days 6, 14 or 22. Three exposure doses for each chemical were used: 3, 6 and 12 µg/kg bw/day of DES; 3, 6, 12 mg/kg bw/day of KTZ. The transcriptome changed dynamically during perinatal development in control ovaries, with 1137 differentially expressed genes (DEGs) partitioned into 3 broad expression patterns. A cross-species deconvolution strategy based on a mouse ovary developmental cell atlas was used to map any changes to ovarian cellularity across the perinatal period to allow for characterization of actual changes to gene transcript levels. A total of 184 DEGs were observed across dose groups and developmental stages in DES-exposed ovaries, and 111 DEGs in KTZ-exposed ovaries across dose groups and developmental stages. Based on our analyses, we have identified new candidate biomarkers for female reproductive toxicity induced by EDC, including Kcne2, Calb2 and Insl3.
Development of a quantitative proteomics approach for cyclooxygenases and lipoxygenases in parallel to quantitative oxylipin analysis allowing the comprehensive investigation of the arachidonic acid cascade
Authors: Hartung Nicole M. , Mainka Malwina , Pfaff Rebecca , Kuhn Michael , Biernacki Sebastian , Zinnert Lilli , Schebb Nils Helge
Published: January 2023

Oxylipins derived from the cyclooxygenase (COX) and lipoxygenase (LOX) pathways of the arachidonic acid (ARA) cascade are essential for the regulation of the inflammatory response and many other physiological functions. Comprehensive analytical methods comprised of oxylipin and protein abundance analysis are required to fully understand mechanisms leading to changes within these pathways. Here, we describe the development of a quantitative multi-omics approach combining liquid chromatography tandem mass spectrometry–based targeted oxylipin metabolomics and proteomics. As the first targeted proteomics method to cover these pathways, it enables the quantitative analysis of all human COX (COX-1 and COX-2) and relevant LOX pathway enzymes (5-LOX, 12-LOX, 15-LOX, 15-LOX-2, and FLAP) in parallel to the analysis of 239 oxylipins with our targeted oxylipin metabolomics method from a single sample. The detailed comparison between MRM3 and classical MRM-based detection in proteomics showed increased selectivity for MRM3, while MRM performed better in terms of sensitivity (LLOQ, 16–122 pM vs. 75–840 pM for the same peptides), linear range (up to 1.5–7.4 μM vs. 4–368 nM), and multiplexing capacities. Thus, the MRM mode was more favorable for this pathway analysis. With this sensitive multi-omics approach, we comprehensively characterized oxylipin and protein patterns in the human monocytic cell line THP-1 and differently polarized primary macrophages. Finally, the quantification of changes in protein and oxylipin levels induced by lipopolysaccharide stimulation and pharmaceutical treatment demonstrates its usefulness to study molecular modes of action involved in the modulation of the ARA cascade.

Graphical Abstract
Evolution of TOP1 and TOP1MT Topoisomerases in Chordata
Authors: Moreira Filipa , Arenas Miguel , Videira Arnaldo , Pereira Filipe
Published: January 2023

Type IB topoisomerases relax the torsional stress associated with DNA metabolism in the nucleus and mitochondria and constitute important molecular targets of anticancer drugs. Vertebrates stand out among eukaryotes by having two Type IB topoisomerases acting specifically in the nucleus (TOP1) and mitochondria (TOP1MT). Despite their major importance, the origin and evolution of these paralogues remain unknown. Here, we examine the molecular evolutionary processes acting on both TOP1 and TOP1MT in Chordata, taking advantage of the increasing number of available genome sequences. We found that both TOP1 and TOP1MT evolved under strong purifying selection, as expected considering their essential biological functions. Critical active sites, including those associated with resistance to anticancer agents, were found particularly conserved. However, TOP1MT presented a higher rate of molecular evolution than TOP1, possibly related with its specialized activity on the mitochondrial genome and a less critical role in cells. We could place the duplication event that originated the TOP1 and TOP1MT paralogues early in the radiation of vertebrates, most likely associated with the first round of vertebrate tetraploidization (1R). Moreover, our data suggest that cyclostomes present a specialized mitochondrial Type IB topoisomerase. Interestingly, we identified two missense mutations replacing amino acids in the Linker region of TOP1MT in Neanderthals, which appears as a rare event when comparing the genome of both species. In conclusion, TOP1 and TOP1MT differ in their rates of evolution, and their evolutionary histories allowed us to better understand the evolution of chordates.
Multivalent adaptor proteins specifically target NK cells carrying a universal chimeric antigen receptor to ErbB2 (HER2)-expressing cancers
Authors: Pfeifer Serrahima Jordi , Zhang Congcong , Oberoi Pranav , Bodden Malena , Röder Jasmin , Arndt Claudia , Feldmann Anja , Kiefer Anne , Prüfer Maren , Kühnel Ines , Tonn Torsten , Bachmann Michael , Wels Winfried S.
Published: January 2023

Chimeric antigen receptor (CAR)-engineered immune effector cells constitute a promising approach for adoptive cancer immunotherapy. Nevertheless, on-target/off-tumor toxicity and immune escape due to antigen loss represent considerable challenges. These may be overcome by adaptor CARs that are selectively triggered by bispecific molecules that crosslink the CAR with a tumor-associated surface antigen. Here, we generated NK cells carrying a first- or second-generation universal CAR (UniCAR) and redirected them to tumor cells with so-called target modules (TMs) which harbor an ErbB2 (HER2)-specific antibody domain for target cell binding and the E5B9 peptide recognized by the UniCAR. To investigate differential effects of the protein design on activity, we developed homodimeric TMs with one, two or three E5B9 peptides per monomer, and binding domains either directly linked or separated by an IgG4 Fc domain. The adaptor molecules were expressed as secreted proteins in Expi293F cells, purified from culture supernatants and their bispecific binding to UniCAR and ErbB2 was confirmed by flow cytometry. In cell killing experiments, all tested TMs redirected NK cell cytotoxicity selectively to ErbB2-positive tumor cells. Nevertheless, we found considerable differences in the extent of specific cell killing depending on TM design and CAR composition, with adaptor proteins carrying two or three E5B9 epitopes being more effective when combined with NK cells expressing the first-generation UniCAR, while the second-generation UniCAR was more active in the presence of TMs with one E5B9 sequence. These results may have important implications for the further development of optimized UniCAR and target module combinations for cancer immunotherapy.
Low on-treatment levels of serum soluble CD8 (sCD8) predict better outcomes in advanced non-small cell lung cancer patients treated with atezolizumab
Authors: Siemiątkowska Anna , Bryl Maciej , Kosicka-Noworzyń Katarzyna , Tvrdoň Jakub , Gołda-Gocka Iwona , Główka Franciszek K.
Published: January 2023

Background

Immunotherapy has changed the paradigm of treating non-small cell lung cancer (NSCLC). But, selecting patients who will achieve long-term benefits from treatment remains unsatisfactory. Here, we investigated the possible use of the soluble form of CD8 antigen (sCD8) in predicting durable disease control after PD-1/PD-L1 blockade. CD8 is a marker of the cytotoxic T lymphocytes. Its soluble form (sCD8) is secreted under activation of the immune system but also has immunosuppressive properties. The data about serum sCD8 in patients dosed with anti-PD-1/PD-L1 drugs are lacking.

Methods and results

We included 42 NSCLC patients and collected samples at baseline and for the first 3 months of atezolizumab immunotherapy. The serum sCD8 concentrations were measured with the ELISA kit and correlated with treatment outcomes. Patients with durable (≥ 12 months) disease control presented lower serum sCD8 than those without long-term benefits. The sCD8 levels measured at the end of cycle 2 (sCD8.2) were the earliest time point that successfully differentiated patients (3.76 vs. 9.68 ng/mL, respectively, p < 0.001). Individuals with low sCD8.2 (≤ 4.09 ng/mL) presented longer progression-free survival (HR = 0.061, p < 0.001) and overall survival (HR = 0.104, p < 0.05) compared to individuals with high sCD8.2 (median values unreached vs. 4.4 months and 14.4 months for PFS and OS, respectively).

Conclusions

Serum sCD8 could be an early biomarker of durable disease control after anti-PD-L1 treatment. Higher sCD8 in patients with worse outcomes could suggest the inhibitory effect of sCD8 on cytotoxic T-cells activation.
Cribriform morular thyroid carcinoma: a case report with pathological, immunohistochemical, and molecular findings suggesting an origin from follicular cells (or their endodermal precursors)
Authors: Echegoyen-Silanes Ana , Pineda-Arribas José Javier , Sánchez-Ares María , Cameselle-García Soledad , Sobrino Beatriz , Ruíz-Ponte Clara , Piso-Neira Magalí , Anda Emma , Cameselle-Teijeiro José Manuel
Published: January 2023

Cribriform morular thyroid carcinoma (CMTC) is a rare malignant thyroid tumor with a peculiar growth pattern secondary to permanent activation of the WNT/β-catenin pathway. CMTC may be associated with familial adenomatous polyposis or sporadic; it shares morphological features with papillary thyroid carcinoma (PTC) and was considered a variant of PTC in the 2017 WHO classification of tumors of endocrine organs. The new 5th edition of the WHO classification of endocrine and neuroendocrine tumors considered CMTC an independent thyroid neoplasm of uncertain histogenesis. A thymic/ultimobranchial pouch-related differentiation in CMTC has been recently postulated. We, however, have used the pathological and immunohistochemical features of this case of CMTC with 2 novel oncogenic somatic variants (c.3428_3429insA, p.(Tyr1143Ter) and c.3565del, p. (Ser1189Hisfs*76) of the APC gene to propose an origin from follicular cells (or their endodermal precursors). As usual in CMTC, the morular component of this tumor was positive for CDX2. Given the fact that WNT/β-catenin signaling, through CDX2, activates large intestine and small intestine gene expression, we postulate that in CMTC, the tumor cells have their terminal differentiation blocked, thus showing a peculiar primitive endodermal (intestinal-like) phenotype negative for sodium-iodide symporter, thyroperoxidase, and thyroglobulin. Establishing the histogenesis of CMTC is very relevant for the development of appropriate therapies of redifferentiation, particularly in patients where the tumor cannot be controlled by surgery.
MTA1 as negative prognostic marker in vulvar carcinoma
Authors: Wanka Giulia , Jueckstock Julia , Wild Carl Mathis , Vattai Aurelia , Fürst Sophie , Heidegger Helene H. , Kuhn Christina , Schmoeckel Elisa , Jeschke Udo , Dannecker Christian
Published: January 2023

Purpose

Vulvar cancer is the fourth most common malignancy of the female genital tract after endometrial, ovarian, and cervical carcinoma and affects mainly elderly women. In 2020 there were registered more than 17,000 deaths worldwide related to vulvar carcinoma. Data about target-based therapies and predictive biomarkers for vulva carcinomas are rare so far. The metastasis-associated gene MTA1 is a transcriptional repressor with a potential effect on cancer. Expression of MTA1 was found to be significantly enhanced in gynecological malignancies as breast or ovarian cancer tissues with advanced cancer stages and higher FIGO grading, indicating an important role of MTA1 in the progression of those tumor entities. Due to the lack of information around MTA1 and its significance regarding vulvar carcinoma, this study focuses on the expression of MTA1 in vulvar carcinoma and its correlation to clinicopathological characteristics and prognosis.

Methods

A total of 157 paraffin-embedded vulvar cancer tissues were immunohistochemically stained and examined for MTA1 expression by using the immunoreactive score. Subsequently, the values were correlated with clinicopathological parameters.

Results

MTA1 was found to be expressed in 94% of the patients in the cytoplasm and 91% in the nucleus. Cytoplasmatic expression of MTA1 was significantly increased in non-keratinizing squamous cell carcinoma and in vulvar carcinoma of the condylomatous type, compared to keratinizing squamous cell carcinoma and vulvar carcinoma of the verrucous type. High MTA1 expression in the nucleus was associated with advanced tumor size as well as higher FIGO grading. In addition, p16 negative vulvar carcinomas showed a higher nuclear expression of MTA1 compared to p16 positive vulvar carcinomas. Suprisingly, Kaplan–Meier analysis showed a significantly lower disease-free survival in tumor samples without a nuclear expression of MTA1.

Conclusions

MTA1 was identified as a negative prognostic marker for vulvar carcinoma associated with advanced tumor stage and FIGO grading. A possible explanation could be that the antibody used for this study does not bind to a possible mutation in the C terminal region of MTA leading to negative immunohistochemical staining and this can be correlated with early recurrence in patients with vulvar carcinoma.
Anisotropic Poroelastic Modelling of Depletion-Induced Pore Pressure Changes in Valhall Overburden
Authors: Duda Marcin Ireneusz , Bakk Audun , Holt Rune Martin , Stenebråten Jørn Fredrik
Published: January 2023

Stress and pore pressure changes due to depletion of or injection into a reservoir are key elements in stability analysis of overburden shales. However, the undrained pore pressure response in shales is often neglected but needs to be considered because of their low permeability. Due to the anisotropic nature of shales, the orientation of both rock and stresses should be considered. To account for misalignment of the medium and the stress tensor, we used anisotropic poroelasticity theory to derive an angle-dependent expression for the pore pressure changes in transversely isotropic media under true-triaxial stress conditions. We experimentally estimated poroelastic pore pressure parameters of a shale from the Lista formation at the Valhall field. We combined the experimental results with finite element modelling to estimate the pore pressure development in the Valhall overburden over a period of nearly 40 years. The results indicate non-negligible pore pressure changes several hundred meters above the reservoir, as well as significant differences between pore pressure and effective stress estimates obtained using isotropic and anisotropic pore pressure parameters. We formulate a simple model approximating the undrained pore pressure response in low permeable overburden. Our results suggest that in the proximity of the reservoir the amplitude of the undrained pore pressure changes may be comparable to effective stresses. Combined with the findings of joint analysis of locations of casing deformation and total and effective stresses, the results suggest that pore pressure modelling may become an important element of casing collapse and caprock failure risk analysis and mitigation.
Synchro-Sub, an adaptive multi-algorithm framework for real-time subtitling synchronisation of multi-type TV programmes
Authors: Masiello-Ruiz Jose Manuel , Ruiz-Mezcua Belen , Martinez Paloma , Gonzalez-Carrasco Israel
Published: January 2023

Subtitles are critical elements in making TV as accessible as possible for people with hearing impairment, elderly people and other end-users that could need this kind of service. Moreover, delay in live-originated TV captions or subtitles is a significant factor in the audience’s perception of the absence of quality for the deaf and hard of hearing. This lack of synchronisation leads to poor quality broadcasts because of the inconsistency between images and subtitles presented to the viewer. In some cases, this situation leads to a misunderstanding of the message. Subtitling is a reactive process that starts once a minimum of audio information has been generated and ends when an insertion time, deletion time and text are allocated. Therefore, there will always be a delay associated with this process, related to the audio duration being subtitled and the subtitle production time. Moreover, in live TV programmes, unsynchronised audio and subtitles are inherent to the subtitling process because the broadcasting is performed in real-time. In this paper, the authors present the Synchro-Sub framework for synchronising subtitles with the audio-visual contents for live-captioned TV programs. For doing this, and considering the knowledge obtained in previous approaches defined by the authors, several improvements have been included in the transcription and chronization phases of the framework that increase the percentage of correctly timed subtitles.
A minimally invasive tubular retractor–assisted retropleural approach for thoracic disc herniations — case series and technical note
Authors: Hubertus Vanessa , Selhausen Peter , Meinert Franziska , Meyer Frerk , Onken Julia S. , Schneider Ulf C. , Hecht Nils , Czabanka Marcus , Vajkoczy Peter , Woitzik Johannes
Published: January 2023

Purpose

Thoracic disc herniations are uncommon and carry a high risk for neurological deterioration. Traditional surgical approaches include thoracotomy, costotransversectomy or posterior approaches with considerable morbidity. In this technical note with case series, we describe a minimally invasive tubular retractor–assisted retropleural approach for simple and less invasive microsurgical exploration of thoracic disc herniations from a lateral angle.

Methods

Surgical technique consisted of partial rib resection and retropleural dissection followed by the placement of a tubular retractor (METRx Tubes, Medtronic) for an anterior-lateral exposure of the disc and neuroforamen. Epidemiological, clinical and surgical patient data were acquired.

Results

Between 2017 and 2020, six patients were surgically treated using the minimally invasive tubular retractor–assisted retropleural approach. Microsurgical exposure of the disc and neural structures was achieved from a lateral direction without requiring thoracotomy or lung deflation. Control imaging confirmed resection in all cases without relevant residuum. As postoperative complications, one dural injury and one postoperative pneumothorax occured. No neurologic deterioration or recurrence occurred during a median follow-up of 3 months.

Conclusion

The described tubular retractor–assisted retropleural exposure serves as a feasible minimally invasive microsurgical approach to the anterior-lateral thoracic spine.