bluuebunny/crossref_metadata_2025_split huggingface dataset:
Club cells employ regeneration mechanisms during lung tumorigenesis
Authors: Chen Yuanyuan , Toth Reka , Chocarro Sara , Weichenhan Dieter , Hey Joschka , Lutsik Pavlo , Sawall Stefan , Stathopoulos Georgios T. , Plass Christoph , Sotillo Rocio 
Published: August 2022

AbstractThe high plasticity of lung epithelial cells, has for many years, confounded the correct identification of the cell-of-origin of lung adenocarcinoma (LUAD), one of the deadliest malignancies worldwide. Here, we employ lineage-tracing mouse models to investigate the cell of origin of Eml4-Alk LUAD, and show that Club and Alveolar type 2 (AT2) cells give rise to tumours. We focus on Club cell originated tumours and find that Club cells experience an epigenetic switch by which they lose their lineage fidelity and gain an AT2-like phenotype after oncogenic transformation. Single-cell transcriptomic analyses identified two trajectories of Club cell evolution which are similar to the ones used during lung regeneration, suggesting that lung epithelial cells leverage on their plasticity and intrinsic regeneration mechanisms to give rise to a tumour. Together, this study highlights the role of Club cells in LUAD initiation, identifies the mechanism of Club cell lineage infidelity, confirms the presence of these features in human tumours, and unveils key mechanisms conferring LUAD heterogeneity.
Intrinsically fluorescent polyureas toward conformation-assisted metamorphosis, discoloration and intracellular drug delivery
Authors: Zhou Yeqiang , Fan Fan , Zhao Jinling , Wang Zhaoding , Wang Rui , Zheng Yi , Liu Hang , Peng Chuan , Li Jianshu , Tan Hong , Fu Qiang , Ding Mingming 
Published: August 2022

AbstractPeptidomimetic polymers have attracted increasing interest because of the advantages of facile synthesis, high molecular tunability, resistance to degradation, and low immunogenicity. However, the presence of non-native linkages compromises their ability to form higher ordered structures and protein-inspired functions. Here we report a class of amino acid-constructed polyureas with molecular weight- and solvent-dependent helical and sheet-like conformations as well as green fluorescent protein-mimic autofluorescence with aggregation-induced emission characteristics. The copolymers self-assemble into vesicles and nanotubes and exhibit H-bonding-mediated metamorphosis and discoloration behaviors. We show that these polymeric vehicles with ultrahigh stability, superfast responsivity and conformation-assisted cell internalization efficiency could act as an “on-off” switchable nanocarrier for specific intracellular drug delivery and effective cancer theranosis in vitro and in vivo. This work provides insights into the folding and hierarchical assembly of biomacromolecules, and a new generation of bioresponsive polymers and nonconventional luminescent aliphatic materials for diverse applications.
Reactive oxygen species-responsive and Raman-traceable hydrogel combining photodynamic and immune therapy for postsurgical cancer treatment
Authors: Zhang Yiyi , Tian Sidan , Huang Liping , Li Yanan , Lu Yuan , Li Hongyu , Chen Guiping , Meng Fanling , Liu Gang L. , Yang Xiangliang , Tu Jiasheng , Sun Chunmeng , Luo Liang 
Published: August 2022

AbstractCombining immune checkpoint blockade (ICB) therapy with photodynamic therapy (PDT) holds great potential in treating immunologically “cold” tumors, but photo-generated reactive oxygen species (ROS) can inevitably damage co-administered ICB antibodies, hence hampering the therapeutic outcome. Here we create a ROS-responsive hydrogel to realize the sustained co-delivery of photosensitizers and ICB antibodies. During PDT, the hydrogel skeleton poly(deca-4,6-diynedioic acid) (PDDA) protects ICB antibodies by scavenging the harmful ROS, and at the same time, triggers the gradual degradation of the hydrogel to release the drugs in a controlled manner. More interestingly, we can visualize the ROS-responsive hydrogel degradation by Raman imaging, given the ultrastrong and degradation-correlative Raman signal of PDDA in the cellular silent window. A single administration of the hydrogel not only completely inhibits the long-term postoperative recurrence and metastasis of 4T1-tumor-bearing mice, but also effectively restrains the growth of re-challenged tumors. The PDDA-based ROS-responsive hydrogel herein paves a promising way for the durable synergy of PDT and ICB therapy.
Mettl3-mediated mRNA m6A modification controls postnatal liver development by modulating the transcription factor Hnf4a
Authors: Xu Yan , Zhou Zhuowei , Kang Xinmei , Pan Lijie , Liu Chang , Liang Xiaoqi , Chu Jiajie , Dong Shuai , Li Yanli , Liu Qiuli , Sun Yuetong , Yu Shanshan , Zhang Qi 
Published: August 2022

AbstractHepatic specification and functional maturation are tightly controlled throughout development. N6-methyladenosine (m6A) is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. However, the function of m6A in liver development remains elusive. Here we dissect the role of Mettl3-mediated m6A modification in postnatal liver development and homeostasis. Knocking out Mettl3 perinatally withAlb-Cre(Mettl3cKO) induces apoptosis and steatosis of hepatocytes, results in severe liver injury, and finally leads to postnatal lethality within 7 weeks. m6A-RIP sequencing and RNA-sequencing reveal that mRNAs of a series of crucial liver-enriched transcription factors are modified by m6A, includingHnf4a, a master regulator for hepatic parenchymal formation. Deleting Mettl3 reduces m6A modification onHnf4a, decreases its transcript stability in an Igf2bp1-dependent manner, and down-regulatesHnf4aexpression, while overexpressing Hnf4a with AAV8 alleviates the liver injury and prolongs the lifespan ofMettl3cKO mice. However, knocking out Mettl3 in adults usingAlb-CreERT2does not affect liver homeostasis. Our study identifies a dynamic role of Mettl3-mediated RNA m6A modification in liver development.
Tuning crystal-phase of bimetallic single-nanoparticle for catalytic hydrogenation
Authors: Liu Shuang , Li Yong , Yu Xiaojuan , Han Shaobo , Zhou Yan , Yang Yuqi , Zhang Hao , Jiang Zheng , Zhu Chuwei , Li Wei-Xue , Wöll Christof , Wang Yuemin , Shen Wenjie 
Published: August 2022

AbstractBimetallic nanoparticles afford geometric variation and electron redistribution via strong metal-metal interactions that substantially promote the activity and selectivity in catalysis. Quantitatively describing the atomic configuration of the catalytically active sites, however, is experimentally challenged by the averaging ensemble effect that is caused by the interplay between particle size and crystal-phase at elevated temperatures and under reactive gases. Here, we report that the intrinsic activity of the body-centered cubic PdCu nanoparticle, for acetylene hydrogenation, is one order of magnitude greater than that of the face-centered cubic one. This finding is based on precisely identifying the atomic structures of the active sites over the same-sized but crystal-phase-varied single-particles. The densely-populated Pd-Cu bond on the chemically ordered nanoparticle possesses isolated Pd site with a lower coordination number and a high-lying valenced-band center, and thus greatly expedites the dissociation of H2over Pd atom and efficiently accommodates the activated H atoms on the particle top/subsurfaces.
Detection of companion galaxies around hot dust-obscured hyper-luminous galaxy W0410-0913
Authors: Ginolfi M. , Piconcelli E. , Zappacosta L. , Jones G. C. , Pentericci L. , Maiolino R. , Travascio A. , Menci N. , Carniani S. , Rizzo F. , Arrigoni Battaia F. , Cantalupo S. , De Breuck C. , Graziani L. , Knudsen K. , Laursen P. , Mainieri V. , Schneider R. , Stanley F. , Valiante R. , Verhamme A. 
Published: August 2022

AbstractThe phase transition between galaxies and quasars is often identified with the rare population of hyper-luminous, hot dust-obscured galaxies. Galaxy formation models predict these systems to grow via mergers, that can deliver large amounts of gas toward their centers, induce intense bursts of star formation and feed their supermassive black holes. Here we report the detection of 24 galaxies emitting Lyman-α emission on projected physical scales of about 400 kpc around the hyper-luminous hot dust-obscured galaxy W0410-0913, at redshift z = 3.631, using Very Large Telescope observations. While this indicates that W0410-0913 evolves in a very dense environment, we do not find clear signs of mergers that could sustain its growth. Data suggest that if mergers occurred, as models expect, these would involve less massive satellites, with only a moderate impact on the internal interstellar medium of W0410-0913, which is sustained by a rotationally-supported fast-rotating molecular disk, as Atacama Large Millimeter Array observations suggest.
Disease-associated mutations within the yeast DNAJB6 homolog Sis1 slow conformer-specific substrate processing and can be corrected by the modulation of nucleotide exchange factors
Authors: Bhadra Ankan K. , Rau Michael J. , Daw Jil A. , Fitzpatrick James A. J. , Weihl Conrad C. , True Heather L. 
Published: August 2022

AbstractMolecular chaperones, or heat shock proteins (HSPs), protect against the toxic misfolding and aggregation of proteins. As such, mutations or deficiencies within the chaperone network can lead to disease. Dominant mutations within DNAJB6 (Hsp40)—an Hsp70 co-chaperone—lead to a protein aggregation-linked myopathy termed Limb-Girdle Muscular Dystrophy Type D1 (LGMDD1). Here, we used the yeast prion model client in conjunction with in vitro chaperone activity assays to gain mechanistic insights into the molecular basis of LGMDD1. Here, we show how mutations analogous to those found in LGMDD1 affect Sis1 (a functional homolog of human DNAJB6) function by altering the structure of client protein aggregates, interfering with the Hsp70 ATPase cycle, dimerization and substrate processing; poisoning the function of wild-type protein. These results uncover the mechanisms through which LGMDD1-associated mutations alter chaperone activity, and provide insights relevant to potential therapeutic interventions.
Enantioselective construction of ortho-sulfur- or nitrogen-substituted axially chiral biaryls and asymmetric synthesis of isoplagiochin D
Authors: Yang He , Tang Wenjun 
Published: August 2022

AbstractAxially chiral biaryl motifs possessing ortho-heteroatom-substituted functionalities exist widely in the structures of natural products and have served as foundation for constructing prominent chiral organocatalysts, ligands, functional materials, and even bioactive molecules. However, a general and enantioselective synthesis of such chiral structures with high synthetic value is rare. Taking advantage of the BaryPhos-facilitated asymmetric Suzuki-Miyaura cross-coupling, we have established a general, efficient and enantioselective construction of the ortho sulfur- or nitrogen-substituted axially chiral biaryls. The protocol shows excellent compatibility to various functional groups and structural features, delivering chiral biaryl structures with ortho-sulfonyl groups or with ortho-nitro groups at a broad range of molecular diversity and complexity. The immobilization of BaryPhos on polyethylene glycol (PEG) support has enabled homogeneous enantioselective cross-coupling in aqueous media and the palladium catalyst recycling for multiple times. The method has enabled a concise 10-step asymmetric synthesis of isoplagiochin D as well as the construction of chiroptical molecules with circularly polarized luminescence (CPL) properties.
Single-cell transcriptome and cell type-specific molecular pathways of human non-alcoholic steatohepatitis
Authors: Fred Rikard G. , Steen Pedersen Julie , Thompson Jonatan J. , Lee Julie , Timshel Pascal N. , Stender Stefan , Opseth Rygg Marte , Gluud Lise Lotte , Bjerregaard Kristiansen Viggo , Bendtsen Flemming , Hansen Torben , Pers Tune H. 
Published: August 2022

AbstractThe aim of this study is to characterize cell type-specific transcriptional signatures in non-alcoholic steatohepatitis (NASH) to improve our understanding of the disease. We performed single-cell RNA sequencing on liver biopsies from 10 patients with NASH. We applied weighted gene co-expression network analysis and validated our findings using a publicly available RNA sequencing data set derived from 160 patients with non-alcoholic fatty liver disease (NAFLD) and 24 controls with normal liver histology. Our study provides a comprehensive single-cell analysis of NASH pathology in humans, describing 19,627 single-cell transcriptomes from biopsy-proven NASH patients. Our data suggest that the previous notion of ”NASH-associated macrophages” can be explained by an up-regulation of normally existing subpopulations of liver macrophages. Similarly, we describe two distinct populations of activated hepatic stellate cells, associated with the level of fibrosis. Finally, we find that the expression of several circulating markers of NAFLD are co-regulated in hepatocytes together with predicted effector genes from NAFLD genome-wide association studies (GWAS), coupled to abnormalities in the complement system. In sum, our single-cell transcriptomic data set provides insights into novel cell type-specific and general biological processes associated with inflammation and fibrosis, emphasizing the importance of studying cell type-specific biological processes in human NASH.
The association of APOE genotype with COVID-19 disease severity
Authors: Safdari Lord Javad , Soltani Rezaiezadeh Javad , Yekaninejad Mir Saeed , Izadi Pantea 
Published: August 2022

AbstractCOVID-19 has caused the recent pandemic of respiratory infection, which threatened global health. The severity of the symptoms varies among affected individuals, from asymptotic or mild signs to severe or critical illness. Genetic predisposition explains the variation in disease severity among patients who suffer from severe symptoms without any known background risk factors. The present study was performed to show the association between APOE genotype and the severity of COVID-19 disease. The APOE genotype of 201 COVID-19 patients (101 patients with asymptomatic to mild form of the disease as the control group and 100 patients with severe to critical illness without any known background risk factors as the case group) were detected via multiplex tetra-primer ARMS-PCR method. Results showed that the e4 allele increased the risk of the COVID-19 infection severity more than five times and the e4/e4 genotype showed a 17-fold increase in the risk of severe disease. In conclusion, since our study design was based on the exclusion of patients with underlying diseases predisposing to severe form of COVID-19 and diseases related to the APOE gene in the study population, our results showed that the e4 genotype is independently associated with the severity of COVID-19 disease. However, further studies are needed to confirm these findings in other nations and to demonstrate the mechanisms behind the role of these alleles in disease severity.
Canal-Net for automatic and robust 3D segmentation of mandibular canals in CBCT images using a continuity-aware contextual network
Authors: Jeoun Bo-Soung , Yang Su , Lee Sang-Jeong , Kim Tae-Il , Kim Jun-Min , Kim Jo-Eun , Huh Kyung-Hoe , Lee Sam-Sun , Heo Min-Suk , Yi Won-Jin 
Published: August 2022

AbstractThe purpose of this study was to propose a continuity-aware contextual network (Canal-Net) for the automatic and robust 3D segmentation of the mandibular canal (MC) with high consistent accuracy throughout the entire MC volume in cone-beam CT (CBCT) images. The Canal-Net was designed based on a 3D U-Net with bidirectional convolutional long short-term memory (ConvLSTM) under a multi-task learning framework. Specifically, the Canal-Net learned the 3D anatomical context information of the MC by incorporating spatio-temporal features from ConvLSTM, and also the structural continuity of the overall MC volume under a multi-task learning framework using multi-planar projection losses complementally. The Canal-Net showed higher segmentation accuracies in 2D and 3D performance metrics (p < 0.05), and especially, a significant improvement in Dice similarity coefficient scores and mean curve distance (p < 0.05) throughout the entire MC volume compared to other popular deep learning networks. As a result, the Canal-Net achieved high consistent accuracy in 3D segmentations of the entire MC in spite of the areas of low visibility by the unclear and ambiguous cortical bone layer. Therefore, the Canal-Net demonstrated the automatic and robust 3D segmentation of the entire MC volume by improving structural continuity and boundary details of the MC in CBCT images.
Deep learning-based noise filtering toward millisecond order imaging by using scanning transmission electron microscopy
Authors: Ihara Shiro , Saito Hikaru , Yoshinaga Mizumo , Avala Lavakumar , Murayama Mitsuhiro 
Published: August 2022

AbstractApplication of scanning transmission electron microscopy (STEM) to in situ observation will be essential in the current and emerging data-driven materials science by taking STEM’s high affinity with various analytical options into account. As is well known, STEM’s image acquisition time needs to be further shortened to capture a targeted phenomenon in real-time as STEM’s current temporal resolution is far below the conventional TEM’s. However, rapid image acquisition in the millisecond per frame or faster generally causes image distortion, poor electron signals, and unidirectional blurring, which are obstacles for realizing video-rate STEM observation. Here we show an image correction framework integrating deep learning (DL)-based denoising and image distortion correction schemes optimized for STEM rapid image acquisition. By comparing a series of distortion corrected rapid scan images with corresponding regular scan speed images, the trained DL network is shown to remove not only the statistical noise but also the unidirectional blurring. This result demonstrates that rapid as well as high-quality image acquisition by STEM without hardware modification can be established by the DL. The DL-based noise filter could be applied to in-situ observation, such as dislocation activities under external stimuli, with high spatio-temporal resolution.
Assessment of potential exposure to As, Cd, Pb and Zn in vegetable garden soils and vegetables in a mining region
Authors: Vejvodová Kateřina , Ash Christopher , Dajčl Julie , Tejnecký Václav , Johanis Hana , Spasić Marko , Polák Filip , Praus Lukáš , Borůvka Luboš , Drábek Ondřej 
Published: August 2022

AbstractMining and smelting activities can contaminate soils and affect farming due to high emissions and input of potentially toxic elements (PTE) into the environment. Soils (sampled from two depths) and market vegetables from vegetable gardens located within the vicinity of unconfined slag deposits from decades of mining and smelting activities in Kutná Hora, Czechia were assessed to determine to what extent they pose a health hazard to communities that use these gardens. Pseudo-total As concentrations in the soils exceeded background levels (4.5 mg kg−1) 1.9–93 times, with higher concentrations in the deeper layer. The pseudo-total concentrations of PTE in soils ranked in the order As > Zn > Cd > Pb. Phyto-available concentrations of PTE in soils were relatively low, compared to pseudo-total concentrations. Concentration of As, Cd, Pb and Zn in the vegetables exceeded guideline values, with the highest concentrations found in the fruits of cucumber, peppers, and zucchini. Despite low phyto-available PTE concentrations in soils, all the PTE concentrations in the vegetables surpassed the guidelines set by the Czech Ministry of Health and EU directive, indicating a health hazard to consumers.
TGFβ-induced changes in membrane curvature influence Ras oncoprotein membrane localization
Authors: Damalas Alexandros , Vonkova Ivana , Tutkus Marijonas , Stamou Dimitrios 
Published: August 2022

AbstractIn the course of cancer progression tumor cells undergo morphological changes that lead to increased motility and invasiveness thus promoting formation of metastases. This process called epithelial to mesenchymal transition (EMT) is triggered by transforming growth factor (TGFβ) but for gaining the full invasive potential an interplay between signaling of TGFβ and Ras GTPases is required. Ras proteins possess a lipidated domain that mediates Ras association with the plasma membrane, which is essential for Ras biological functions. Type and number of the lipid anchors are the main difference among three Ras variants—H-ras, N-ras and K-ras. The lipid anchors determine membrane partitioning of lipidated proteins into membrane areas of specific physico-chemical properties and curvature. In this study, we investigated the effect of TGFβ treatment on the subcellular localization of H-ras and K-ras. We show that TGFβ increases positive plasma membrane curvature, which is subsequently sensed by H-ras, leading to its elevated plasma membrane localization and activation. This observation suggests the existence of a novel positive feedback loop whereby the increased level of plasma membrane curvature during TGFβ induced EMT attracts more Ras molecules to the plasma membrane resulting in increased Ras activity which in turn promotes further EMT and thus ultimately enables the acquisition of full invasive potential.
Functional human cell-based vascularised cardiac tissue model for biomedical research and testing
Authors: Koivisto Maria , Tolvanen Tuomas A. , Toimela Tarja , Miinalainen Ilkka , Kiviaho Antti , Kesseli Juha , Nykter Matti , Eklund Lauri , Heinonen Tuula 
Published: August 2022

AbstractCardiomyocytes derived from human induced pluripotent stem cells (hiPSC) are widely used in in vitro biomedical research and testing. However, fully matured, adult cardiomyocyte characteristics have not been achieved. To improve the maturity and physiological relevance of hiPSC-derived cardiomyocytes, we co-cultured them with preconstructed vascular-like networks to form a functional, human cell-based cardiac tissue model. The morphology and gene expression profiles indicated advanced maturation in the cardiac tissue model compared to those of a cardiomyocyte monoculture. The cardiac tissue model’s functionality was confirmed by measuring the effects of 32 compounds with multielectrode array and comparing results to human data. Our model predicted the cardiac effects with a predictive accuracy of 91%, sensitivity of 90% and specificity of 100%. The correlation between the effective concentration (EC50) and the reported clinical plasma concentrations was 0.952 (R2 = 0.905). The developed advanced human cell-based cardiac tissue model showed characteristics and functionality of human cardiac tissue enabling accurate transferability of gained in vitro data to human settings. The model is standardized and thus, it would be highly useful in biomedical research and cardiotoxicity testing.