bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a novel type of focal adhesion remodelling via FAK/FRNK replacement, and its contribution to cancer progression
Authors: Tsujioka Masatsune , Miyazawa Keisuke , Ohmuraya Masaki , Nibe Yoichi , Shirokawa Tetsuya , Hayasaka Haruko , Mizushima Tsunekazu , Fukuma Takeshi , Shimizu Shigeomi 
Published: April 2023

AbstractNumerous studies have investigated the various cellular responses against genotoxic stress, including those mediated by focal adhesions. We here identified a novel type of focal adhesion remodelling that occurs under genotoxic stress conditions, which involves the replacement of active focal adhesion kinase (FAK) with FAK-related non-kinase (FRNK). FRNK stabilized focal adhesions, leading to strong cell-matrix adhesion, and FRNK-depleted cells were easily detached from extracellular matrix upon genotoxic stress. This remodelling occurred in a wide variety of cells. In vivo, the stomachs of Frnk-knockout mice were severely damaged by genotoxic stress, highlighting the protective role of FRNK against genotoxic stress. FRNK was also found to play a vital role in cancer progression, because FRNK depletion significantly inhibited cancer dissemination and progression in a mouse cancer model. Furthermore, in human cancers, FRNK was predominantly expressed in metastatic tissues and not in primary tissues. We hence conclude that this novel type of focal adhesion remodelling reinforces cell adhesion and acts against genotoxic stress, which results in the protection of normal tissues, but in turn facilitates cancer progression.
PRPF19 facilitates colorectal cancer liver metastasis through activation of the Src-YAP1 pathway via K63-linked ubiquitination of MYL9
Authors: Zhou Rui , Chen Jie , Xu Yunxiuxiu , Ye Yibiao , Zhong Guoping , Chen Tao , Qiu Lin 
Published: April 2023

AbstractDistant metastasis is one of the leading causes of cancer-related mortality of colorectal cancer (CRC). Dysregulation of E3 ubiquitin ligases has been implicated in acting vital roles in multiple cancers. In this study, we found that the E3 ubiquitin ligase, PRPF19 was positively correlated with liver metastasis, and predicted a worse clinical outcome in CRC. However, the biological effects and the underlying molecular mechanisms of PRPF19 in CRC remain elusive thus far. We illustrated that PRPF19 promoted the migration and invasion capability of CRC cells in both gain- and loss- of function assays. Mechanistically, we uncovered that myosin light chain 9 (MYL9) was the downstream substrate of PRPF19. PRPF19 enhanced the stability of MYL9 via K63-linked ubiquitination, and promoted the migration and invasion capability of CRC cells in an MYL9-mediated manner. Furthermore, the Src–YAP1 cascade was identified as the downstream effector mechanism by which the PRPF19/MYL9 axis promoted metastasis in CRC. Taken together, our findings highlighted that the PRPF19/MYL9 axis served as a novel mechanism in CRC metastasis, which provided an attractive therapeutic strategy for CRC treatment.
Multiple sclerosis plasma IgG aggregates induce complement-dependent neuronal apoptosis
Authors: Zhou Wenbo , Graner Michael , Paucek Petr , Beseler Cheryl , Boisen Matthew , Bubak Andrew , Asturias Francisco , George Woro , Graner Arin , Ormond David , Vollmer Timothy , Alvarez Enrique , Yu Xiaoli 
Published: April 2023

AbstractGrey matter pathology is central to the progression of multiple sclerosis (MS). We discovered that MS plasma immunoglobulin G (IgG) antibodies, mainly IgG1, form large aggregates (>100 nm) which are retained in the flow-through after binding to Protein A. Utilizing an annexin V live-cell apoptosis detection assay, we demonstrated six times higher levels of neuronal apoptosis induced by MS plasma IgG aggregates (n = 190, from two cohorts) compared to other neurological disorders (n = 116) and healthy donors (n = 44). MS IgG aggregate-mediated, complement-dependent neuronal apoptosis was evaluated in multiple model systems including primary human neurons, primary human astrocytes, neuroblastoma SH-SY5Y cells, and newborn mouse brain slices. Immunocytochemistry revealed the co-deposition of IgG, early and late complement activation products (C1q, C3b, and membrane attack complex C5b9), as well as active caspase 3 in treated neuronal cells. Furthermore, we found that MS plasma cytotoxic antibodies are not present in Protein G flow-through, nor in the paired plasma. The neuronal apoptosis can be inhibited by IgG depletion, disruption of IgG aggregates, pan-caspase inhibitor, and is completely abolished by digestion with IgG-cleaving enzyme IdeS. Transmission electron microscopy and nanoparticle tracking analysis revealed the sizes of MS IgG aggregates are greater than 100 nm. Our data support the pathological role of MS IgG antibodies and corroborate their connection to complement activation and axonal damage, suggesting that apoptosis may be a mechanism of neurodegeneration in MS.
Cathepsin B in programmed cell death machinery: mechanisms of execution and regulatory pathways
Authors: Xie Zhen , Zhao Mengyuan , Yan Chengxiang , Kong Wei , Lan Fei , Narengaowa  , Zhao Shuxuan , Yang Qinghu , Bai Zhantao , Qing Hong , Ni Junjun 
Published: April 2023

AbstractCathepsin B (CatB), a cysteine protease, is primarily localized within subcellular endosomal and lysosomal compartments. It is involved in the turnover of intracellular and extracellular proteins. Interest is growing in CatB due to its diverse roles in physiological and pathological processes. In functional defective tissues, programmed cell death (PCD) is one of the regulable fundamental mechanisms mediated by CatB, including apoptosis, pyroptosis, ferroptosis, necroptosis, and autophagic cell death. However, CatB-mediated PCD is responsible for disease progression under pathological conditions. In this review, we provide an overview of the critical roles and regulatory pathways of CatB in different types of PCD, and discuss the possibility of CatB as an attractive target in multiple diseases. We also summarize current gaps in the understanding of the involvement of CatB in PCD to highlight future avenues for research.
Single cell transcriptomic analysis of HPV16-infected epithelium identifies a keratinocyte subpopulation implicated in cancer
Authors: Bedard Mary C. , Chihanga Tafadzwa , Carlile Adrean , Jackson Robert , Brusadelli Marion G. , Lee Denis , VonHandorf Andrew , Rochman Mark , Dexheimer Phillip J. , Chalmers Jeffrey , Nuovo Gerard , Lehn Maria , Williams David E. J. , Kulkarni Aditi , Carey Molly , Jackson Amanda , Billingsley Caroline , Tang Alice , Zender Chad , Patil Yash , Wise-Draper Trisha M. , Herzog Thomas J. , Ferris Robert L. , Kendler Ady , Aronow Bruce J. , Kofron Matthew , Rothenberg Marc E. , Weirauch Matthew T. , Van Doorslaer Koenraad , Wikenheiser-Brokamp Kathryn A. , Lambert Paul F. , Adam Mike , Steven Potter S. , Wells Susanne I. 
Published: April 2023

AbstractPersistent HPV16 infection is a major cause of the global cancer burden. The viral life cycle is dependent on the differentiation program of stratified squamous epithelium, but the landscape of keratinocyte subpopulations which support distinct phases of the viral life cycle has yet to be elucidated. Here, single cell RNA sequencing of HPV16 infected compared to uninfected organoids identifies twelve distinct keratinocyte populations, with a subset mapped to reconstruct their respective 3D geography in stratified squamous epithelium. Instead of conventional terminally differentiated cells, an HPV-reprogrammed keratinocyte subpopulation (HIDDEN cells) forms the surface compartment and requires overexpression of the ELF3/ESE-1 transcription factor. HIDDEN cells are detected throughout stages of human carcinogenesis including primary human cervical intraepithelial neoplasias and HPV positive head and neck cancers, and a possible role in promoting viral carcinogenesis is supported by TCGA analyses. Single cell transcriptome information on HPV-infected versus uninfected epithelium will enable broader studies of the role of individual keratinocyte subpopulations in tumor virus infection and cancer evolution.
Observation of entanglement transition of pseudo-random mixed states
Authors: Liu Tong , Liu Shang , Li Hekang , Li Hao , Huang Kaixuan , Xiang Zhongcheng , Song Xiaohui , Xu Kai , Zheng Dongning , Fan Heng 
Published: April 2023

AbstractRandom quantum states serve as a powerful tool in various scientific fields, including quantum supremacy and black hole physics. It has been theoretically predicted that entanglement transitions may happen for different partitions of multipartite random quantum states; however, the experimental observation of these transitions is still absent. Here, we experimentally demonstrate the entanglement transitions witnessed by negativity on a fully connected superconducting processor. We apply parallel entangling operations, that significantly decrease the depth of the pseudo-random circuits, to generate pseudo-random pure states of up to 15 qubits. By quantum state tomography of the reduced density matrix of six qubits, we measure the negativity spectra. Then, by changing the sizes of the environment and subsystems, we observe the entanglement transitions that are directly identified by logarithmic entanglement negativities based on the negativity spectra. In addition, we characterize the randomness of our circuits by measuring the distance between the distribution of output bit-string probabilities and the Porter-Thomas distribution. Our results show that superconducting processors with all-to-all connectivity constitute a promising platform for generating random states and understanding the entanglement structure of multipartite quantum systems.
Circulating blood eNAMPT drives the circadian rhythms in locomotor activity and energy expenditure
Authors: Park Jae Woo , Roh Eun , Kang Gil Myoung , Gil So Young , Kim Hyun Kyong , Lee Chan Hee , Jang Won Hee , Park Se Eun , Moon Sang Yun , Kim Seong Jun , Jeong So Yeon , Park Chae Beom , Lim Hyo Sun , Oh Yu Rim , Jung Han Na , Kwon Obin , Youn Byung Soo , Son Gi Hoon , Min Se Hee , Kim Min-Seon 
Published: April 2023

AbstractNicotinamide adenine dinucleotide (NAD+) is an essential cofactor of critical enzymes including protein deacetylase sirtuins/SIRTs and its levels in mammalian cells rely on the nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathway. Intracellular NAMPT (iNAMPT) is secreted and found in the blood as extracellular NAMPT (eNAMPT). In the liver, the iNAMPT−NAD+ axis oscillates in a circadian manner and regulates the cellular clockwork. Here we show that the hypothalamic NAD+ levels show a distinct circadian fluctuation with a nocturnal rise in lean mice. This rhythm is in phase with that of plasma eNAMPT levels but not with that of hypothalamic iNAMPT levels. Chemical and genetic blockade of eNAMPT profoundly inhibit the nighttime elevations in hypothalamic NAD+ levels as well as those in locomotor activity (LMA) and energy expenditure (EE). Conversely, elevation of plasma eNAMPT by NAMPT administration increases hypothalamic NAD+ levels and stimulates LMA and EE via the hypothalamic NAD+−SIRT−FOXO1−melanocortin pathway. Notably, obese animals display a markedly blunted circadian oscillation in blood eNAMPT−hypothalamic NAD+−FOXO1 axis as well as LMA and EE. Our findings indicate that the eNAMPT regulation of hypothalamic NAD+ biosynthesis underlies circadian physiology and that this system can be significantly disrupted by obesity.
A supramolecular gel-elastomer system for soft iontronic adhesives
Authors: Gao Dace , Thangavel Gurunathan , Lee Junwoo , Lv Jian , Li Yi , Ciou Jing-Hao , Xiong Jiaqing , Park Taiho , Lee Pooi See 
Published: April 2023

AbstractElectroadhesion provides a promising route to augment robotic functionalities with continuous, astrictive, and reversible adhesion force. However, the lack of suitable conductive/dielectric materials and processing capabilities have impeded the integration of electroadhesive modules into soft robots requiring both mechanical compliance and robustness. We present herein an iontronic adhesive based on a dynamically crosslinked gel-elastomer system, including an ionic organohydrogel as adhesive electrodes and a resilient polyurethane with high electrostatic energy density as dielectric layers. Through supramolecular design and synthesis, the dual-material system exhibits cohesive heterolayer bonding and autonomous self-healing from damages. Iontronic soft grippers that seamlessly integrate actuation, adhesive prehension, and exteroceptive sensation are devised via additive manufacturing. The grippers can capture soft and deformable items, bear high payload under reduced voltage input, and rapidly release foreign objects in contrast to electroadhesives. Our materials and iontronic mechanisms pave the way for future advancement in adhesive-enhanced multifunctional soft devices.
Predicting compound activity from phenotypic profiles and chemical structures
Authors: Moshkov Nikita , Becker Tim , Yang Kevin , Horvath Peter , Dancik Vlado , Wagner Bridget K. , Clemons Paul A. , Singh Shantanu , Carpenter Anne E. , Caicedo Juan C. 
Published: April 2023

AbstractPredicting assay results for compounds virtually using chemical structures and phenotypic profiles has the potential to reduce the time and resources of screens for drug discovery. Here, we evaluate the relative strength of three high-throughput data sources—chemical structures, imaging (Cell Painting), and gene-expression profiles (L1000)—to predict compound bioactivity using a historical collection of 16,170 compounds tested in 270 assays for a total of 585,439 readouts. All three data modalities can predict compound activity for 6–10% of assays, and in combination they predict 21% of assays with high accuracy, which is a 2 to 3 times higher success rate than using a single modality alone. In practice, the accuracy of predictors could be lower and still be useful, increasing the assays that can be predicted from 37% with chemical structures alone up to 64% when combined with phenotypic data. Our study shows that unbiased phenotypic profiling can be leveraged to enhance compound bioactivity prediction to accelerate the early stages of the drug-discovery process.
Improving the generalizability of protein-ligand binding predictions with AI-Bind
Authors: Chatterjee Ayan , Walters Robin , Shafi Zohair , Ahmed Omair Shafi , Sebek Michael , Gysi Deisy , Yu Rose , Eliassi-Rad Tina , Barabási Albert-László , Menichetti Giulia 
Published: April 2023

AbstractIdentifying novel drug-target interactions is a critical and rate-limiting step in drug discovery. While deep learning models have been proposed to accelerate the identification process, here we show that state-of-the-art models fail to generalize to novel (i.e., never-before-seen) structures. We unveil the mechanisms responsible for this shortcoming, demonstrating how models rely on shortcuts that leverage the topology of the protein-ligand bipartite network, rather than learning the node features. Here we introduce AI-Bind, a pipeline that combines network-based sampling strategies with unsupervised pre-training to improve binding predictions for novel proteins and ligands. We validate AI-Bind predictions via docking simulations and comparison with recent experimental evidence, and step up the process of interpreting machine learning prediction of protein-ligand binding by identifying potential active binding sites on the amino acid sequence. AI-Bind is a high-throughput approach to identify drug-target combinations with the potential of becoming a powerful tool in drug discovery.
A neutrophil mimicking metal-porphyrin-based nanodevice loaded with porcine pancreatic elastase for cancer therapy
Authors: Cui Tingting , Zhang Yu , Qin Geng , Wei Yue , Yang Jie , Huang Ying , Ren Jinsong , Qu Xiaogang 
Published: April 2023

AbstractPrecise discrimination and eradication of cancer cells by immune cells independent of antigen recognition is promising for solid tumor therapeutics, yet remains a tremendous challenge. Inspired by neutrophils, here we design and construct a tumor discrimination nanodevice based on the differential histone H1 isoform expression. In this nanodevice, neutrophil membrane camouflage and glutathione (GSH)-unlocking effect on Fe-porphyrin metal−organic framework structure ensures selectivity to cancer cells. The released porcine pancreatic elastase (PPE) simulates neutrophils’ action to induce histone H1 release-dependent selective cancer cell killing. Meanwhile, nuclear localization signal (NLS) peptide-tagged porphyrin (porphyrin-NLS) acts as in-situ singlet oxygen (1O2) generator to amplify histone H1 nucleo-cytoplasmic translocation by inducing DNA double-strand breaks (DSBs) under laser irradiation, further promoting elimination of cancer cells. The overexpressed histone H1 isoform in cancer cells improves selectivity of our nanodevice to cancer cells. In vivo studies demonstrate that our design can not only inhibit primary tumor growth, but also induce adaptive T-cell response-mediated abscopal effect to against distal tumors.
A neuromorphic bionic eye with filter-free color vision using hemispherical perovskite nanowire array retina
Authors: Long Zhenghao , Qiu Xiao , Chan Chak Lam Jonathan , Sun Zhibo , Yuan Zhengnan , Poddar Swapnadeep , Zhang Yuting , Ding Yucheng , Gu Leilei , Zhou Yu , Tang Wenying , Srivastava Abhishek Kumar , Yu Cunjiang , Zou Xuming , Shen Guozhen , Fan Zhiyong 
Published: April 2023

AbstractSpherical geometry, adaptive optics, and highly dense network of neurons bridging the eye with the visual cortex, are the primary features of human eyes which enable wide field-of-view (FoV), low aberration, excellent adaptivity, and preprocessing of perceived visual information. Therefore, fabricating spherical artificial eyes has garnered enormous scientific interest. However, fusing color vision, in-device preprocessing and optical adaptivity into spherical artificial eyes has always been a tremendous challenge. Herein, we demonstrate a bionic eye comprising tunable liquid crystal optics, and a hemispherical neuromorphic retina with filter-free color vision, enabled by wavelength dependent bidirectional synaptic photo-response in a metal-oxide nanotube/perovskite nanowire hybrid structure. Moreover, by tuning the color selectivity with bias, the device can reconstruct full color images. This work demonstrates a unique approach to address the color vision and optical adaptivity issues associated with artificial eyes that can bring them to a new level approaching their biological counterparts.
The IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer
Authors: Li Nan , Quan Alex , Li Dan , Pan Jiajia , Ren Hua , Hoeltzel Gerard , de Val Natalia , Ashworth Dana , Ni Weiming , Zhou Jing , Mackay Sean , Hewitt Stephen M. , Cachau Raul , Ho Mitchell 
Published: April 2023

AbstractHeterogeneous antigen expression is a key barrier influencing the activity of chimeric antigen receptor (CAR) T cells in solid tumors. Here, we develop CAR T cells targeting glypican-1 (GPC1), an oncofetal antigen expressed in pancreatic cancer. We report the generation of dromedary camel VHH nanobody (D4)-based CAR T cells targeting GPC1 and the optimization of the hinge (H) and transmembrane domain (TM) to improve activity. We find that a structurally rigid IgG4H and CD28TM domain brings the two D4 fragments in proximity, driving CAR dimerization and leading to enhanced T-cell signaling and tumor regression in pancreatic cancer models with low antigen density in female mice. Furthermore, single-cell-based proteomic and transcriptomic analysis of D4-IgG4H-CD28TM CAR T cells reveals specific genes (e.g., HMGB1) associated with high T-cell polyfunctionality. This study demonstrates the potential of VHH-based CAR T for pancreatic cancer therapy and provides an engineering strategy for developing potent CAR T cells targeting membrane-distal epitopes.
Collateral sensitivity profiling in drug-resistant Escherichia coli identifies natural products suppressing cephalosporin resistance
Authors: Liu Dennis Y. , Phillips Laura , Wilson Darryl M. , Fulton Kelly M. , Twine Susan M. , Wong Alex , Linington Roger G. 
Published: April 2023

AbstractThe rapid emergence of antimicrobial resistance presents serious health challenges to the management of infectious diseases, a problem that is further exacerbated by slowing rates of antimicrobial drug discovery in recent years. The phenomenon of collateral sensitivity (CS), whereby resistance to one drug is accompanied by increased sensitivity to another, provides new opportunities to address both these challenges. Here, we present a high-throughput screening platform termed Collateral Sensitivity Profiling (CSP) to map the difference in bioactivity of large chemical libraries across 29 drug-resistant strains of E. coli. CSP screening of 80 commercial antimicrobials demonstrated multiple CS interactions. Further screening of a 6195-member natural product library revealed extensive CS relationships in nature. In particular, we report the isolation of known and new analogues of borrelidin A with potent CS activities against cephalosporin-resistant strains. Co-dosing ceftazidime with borrelidin A slows broader cephalosporin resistance with no recognizable resistance to borrelidin A itself.
Engineering tumor-specific gene nanomedicine to recruit and activate T cells for enhanced immunotherapy
Authors: Wang Yue , Zhou Shi-Kun , Wang Yan , Lu Zi-Dong , Zhang Yue , Xu Cong-Fei , Wang Jun 
Published: April 2023

AbstractPD-1/PD-L1 blockade therapy that eliminates T-cell inhibition signals is successful, but poor benefits are often observed. Increasing T-cell infiltration and quantity of PD-1/PD-L1 inhibitors in tumor can improve efficacy but remains challenging. Here, we devise tumor-specific gene nanomedicines to mobilize tumor cells to secrete CXCL9 (T-cell chemokine) and anti-PD-L1 scFv (αPD-L1, PD-L1 blocking agent) for enhanced immunotherapy. The tyrosinase promoter-driven NPTyr-C9AP can specifically co-express CXCL9 and αPD-L1 in melanoma cells, thereby forming a CXCL9 gradient for T-cell recruitment and high intratumoral αPD-L1 concentration for enhancing T-cell activation. As a result, NPTyr-C9AP shows strong antimelanoma effects. Moreover, specific co-expression of CXCL9 and αPD-L1 in various tumor cells is achieved by replacing the tyrosinase promoter of NPTyr-C9AP with a survivin promoter, which increases T-cell infiltration and activation and therapeutic efficacy in multiple tumors in female mice. This study provides a strategy to maximize the immunotherapeutic outcome regardless of the heterogeneous tumor microenvironment.
A direct observation of up-converted room-temperature phosphorescence in an anti-Kasha dopant-matrix system
Authors: Li Jiuyang , Li Xun , Wang Guangming , Wang Xuepu , Wu Minjian , Liu Jiahui , Zhang Kaka 
Published: April 2023

AbstractIt is common sense that emission maxima of phosphorescence spectra (λP) are longer than those of fluorescence spectra (λF). Here we report a serendipitous finding of up-converted room-temperature phosphorescence (RTP) withλP < λFand phosphorescence lifetime > 0.1 s upon doping benzophenone-containing difluoroboron β-diketonate (BPBF2) into phenyl benzoate matrices. The up-converted RTP is originated from BPBF2’s Tn(n ≥ 2) states which show typical3n-π* characters from benzophenone moieties. Detailed studies reveal that, upon intersystem crossing from BPBF2’s S1states of charge transfer characters, the resultant T1and Tnstates build T1-to-Tnequilibrium. Because of their3n-π* characters, the Tnstates possess large phosphorescence rates that can strongly compete RTP(T1) to directly emit RTP(Tn) which violates Kasha’s rule. The direct observation of up-converted RTP provides deep understanding of triplet excited state dynamics and opens an intriguing pathway to devise visible-light-excitable deep-blue afterglow emitters, as well as stimuli-responsive afterglow materials.