bluuebunny/crossref_metadata_2025_split huggingface dataset:
The anti-cancer agent APR-246 can activate several programmed cell death processes to kill malignant cells
Authors: Wang Zilu , Hu Huimin , Heitink Luuk , Rogers Kelly , You Yue , Tan Tao , Suen Connie Li Wai , Garnham Alex , Chen Hao , Lieschke Elizabeth , Diepstraten Sarah T. , Chang Catherine , Chen Tianwei , Moujalled Diane , Sutherland Kate , Lessene Guillaume , Sieber Oliver M. , Visvader Jane , Kelly Gemma L. , Strasser Andreas 
Published: February 2023

AbstractMutant TP53 proteins are thought to drive the development and sustained expansion of cancers at least in part through the loss of the wild-type (wt) TP53 tumour suppressive functions. Therefore, compounds that can restore wt TP53 functions in mutant TP53 proteins are expected to inhibit the expansion of tumours expressing mutant TP53. APR-246 has been reported to exert such effects in malignant cells and is currently undergoing clinical trials in several cancer types. However, there is evidence that APR-246 may also kill malignant cells that do not express mutant TP53. To support the clinical development of APR-246 it is important to understand its mechanism(s) of action. By establishing isogenic background tumour cell lines with different TP53/TRP53 states, we found that APR-246 can kill malignant cells irrespective of their TP53/TRP53 status. Accordingly, RNAseq analysis revealed that treatment with APR-246 induces expression of the same gene set in Eμ-Myc mouse lymphoma cells of all four possible TRP53 states, wt, wt alongside mutant, knockout and knockout alongside mutant. We found that depending on the type of cancer cell and the concentration of APR-246 used, this compound can kill malignant cells through induction of various programmed cell death pathways, including apoptosis, necroptosis and ferroptosis. The sensitivity of non-transformed cells to APR-246 also depended on the cell type. These findings reveal that the clinical testing of APR-246 should not be limited to cancers expressing mutant TP53 but expanded to cancers that express wt TP53 or are TP53-deficient.
VHL-HIF-2α axis-induced SEMA6A upregulation stabilized β-catenin to drive clear cell renal cell carcinoma progression
Authors: Ji Jing , Xu Yuxin , Xie Mengru , He Xingbei , Ren Dexu , Qiu Teng , Liu Wenwen , Chen Zefeng , Shi Wen , Zhang Zhen , Wang Xiujun , Wang Weiling , Ma Jinming , Qian Qilan , Jing Aixin , Ma Xinhui , Qin Jingting , Ding Yuanyuan , Geng Ting , Yang Jiayan , Sun Zhichao , Liu Wei , Liu Shunfang , Liu Bin 
Published: February 2023

AbstractSEMA6Ais a multifunctional transmembrane semaphorin protein that participates in various cellular processes, including axon guidance, cell migration, and cancer progression. However, the role ofSEMA6Ain clear cell renal cell carcinoma (ccRCC) is unclear. Based on high-throughput sequencing data, here we report thatSEMA6Ais a novel target gene of theVHL-HIF-2αaxis and overexpressed in ccRCC. Chromatin immunoprecipitation and reporter assays revealed thatHIF-2αdirectly activatedSEMA6Atranscription in hypoxic ccRCC cells.Wnt/β-catenin pathway activation is correlated with the expression ofSEMA6Ain ccRCC; the latter physically interacted withSEC62and promoted ccRCC progression throughSEC62-dependent β-catenin stabilization and activation. Depletion ofSEMA6AimpairedHIF-2α-inducedWnt/β-catenin pathway activation and led to defective ccRCC cell proliferation both in vitro and in vivo.SEMA6Aoverexpression promoted the malignant phenotypes of ccRCC, which was reversed bySEC62depletion. Collectively, this study revealed a potential role forVHL-HIF-2α-SEMA6A-SEC62axis in the activation ofWnt/β-catenin pathway. Thus,SEMA6Amay act as a potential therapeutic target, especially inVHL-deficient ccRCC.
NSUN2 alleviates doxorubicin-induced myocardial injury through Nrf2-mediated antioxidant stress
Authors: Wang Yi , Zan Yuxin , Huang Yingying , Peng Xiaoyun , Ma Shinan , Ren Ji , Li Xiao , Wei Lin , Wang Xiaoli , Yuan Yahong , Tang Junming , Zhan Zhongqun , Wang Zhixiao , Ding Yan 
Published: February 2023

Abstract
Doxorubicin (DOX) is a commonly used antitumor drug, but its application has been limited because of its strong cardiac damage. This study aims to explore the role of NSUN2 in DOX-induced heart injury. C57BL/6J mice were intraperitoneally injected with 20 mg/Kg DOX to induce heart injury. After 3 days, the cardiac function, cardiac histopathology, myocardial apoptosis, and the expression level of NSUN2 were detected. In vitro, H9C2 cells were transfected with NSUN2 siRNA or overexpressed lentivirus and then treated with 500 ng/ml DOX. After 24 h, the changes in reactive oxygen species (ROS), apoptosis, and NSUN2 expression were detected. After DOX treatment, both in vitro and in vivo experiments showed that the cardiac function decreased, the number of apoptotic cells increased, and the expression level of NSUN2 increased. Interfering the expression of NSUN2 by siRNA promoted DOX-induced heart injury, while overexpression of NSUN2 could inhibit DOX-induced heart injury. Further study showed that NSUN2 promoted antioxidative stress by upregulating the Nrf2 protein level. In addition, NSUN2 overexpression could increase the half-life of Nrf2 mRNA. m5C RNA methylation immunoprecipitation (MeRIP) also showed that the level of Nrf2 m5C mRNA was significantly increased in NSUN2 overexpressed group when compared to the GFP group. NSUN2 enhances the expression of Nrf2 by promoting Nrf2 mRNA m5C modification and enhances its antioxidative stress effect to alleviate DOX-induced myocardial injury.
The GSK3β/Mcl-1 axis is regulated by both FLT3-ITD and Axl and determines the apoptosis induction abilities of FLT3-ITD inhibitors
Authors: Qiu Yang , Li Ying , Chai Meng , Hua Huiming , Wang Rui , Waxman Samuel , Jing Yongkui 
Published: February 2023

AbstractAcute myeloid leukemia (AML) patients with FLT3-ITD mutations are associated with poor prognosis. FLT3-ITD inhibitors are developed and result in transient disease remission, but generally resistance develops. We propose that resistance occurs due to apoptosis evasion. We compared the abilities of five clinically used FLT3-ITD inhibitors, namely, midostaurin, crenolanib, gilteritinib, quizartinib, and sorafenib, to induce apoptosis. These drugs inhibit FLT3-ITD and induce apoptosis. Apoptosis induction is associated with GSK3β activation, Mcl-1 downregulation, and Bim upregulation. Sorafenib-resistant MOLM-13/sor cells have the secondary D835Y mutation and increased Axl signaling pathway with cross-resistance to quizartinib. Gilteritinib and crenolanib inhibit both FLT3-ITD and Axl and induce apoptosis in MOLM-13/sor cells, in which they activate GSK3β and downregulate Mcl-1. Inactivation of GSK3β through phosphorylation and inhibitors blocks apoptosis and Mcl-1 reduction. The Axl/GSK3β/Mcl-1 axis works as a feedback mechanism to attenuate apoptosis of FLT3-ITD inhibition. Homoharringtonine decreases the protein levels of Mcl-1, FLT3-ITD, and Axl. Moreover, it synergistically induces apoptosis with gilteritinib in vitro and prolongs survival of MOLM-13/sor xenografts. The GSK3β/Mcl-1 axis works as the hub of FLT3-ITD inhibitors and plays a critical role in resistance against FLT3-ITD AML-targeted therapy.
MiR-7-5p/KLF4 signaling inhibits stemness and radioresistance in colorectal cancer
Authors: Shang Yuanyuan , Zhu Zhe , Zhang Yuanyuan , Ji Fang , Zhu Lian , Liu Mengcheng , Deng Yewei , Lv Guifen , Li Dan , Zhou Zhuqing , Lu Bing , Fu Chuan-gang 
Published: February 2023

AbstractResistance to radiotherapy remains a major unmet clinical obstacle in the treatment of locally advanced rectal cancer. Cancer stem cells (CSCs) are considered to mediate tumor development and radioresistance. However, the role of CSCs in regulating resistance to radiotherapy in colorectal cancer (CRC) remains largely unknown. We established two radioresistant CRC cell lines, HCT116-R and RKO-R, using fractionated irradiation. Analysis using miRNA sequencing and quantitative real-time PCR confirmed lower levels of miR-7-5p in both of the radioresistant cells compared to their parental cells. Subsequently, we validated that miR-7-5p expression was decreased in cancerous tissues from radiotherapy-resistant rectal cancer patients. The Cancer Genome Atlas (TCGA) database analyses revealed that low miR-7-5p expression was significantly correlated with poor prognosis in CRC patients. Overexpression of miR-7-5p led to a rescue of radioresistance and an increase in radiation-induced apoptosis, and attenuated the stem cell-like properties in HCT116-R and RKO-R cells. Conversely, knocking down miR-7-5p in parental HCT116 and RKO cells suppressed the sensitivity to radiation treatment and enhance cancer cell stemness. Stemness-associated transcription factor KLF4 was demonstrated as a target of miR-7-5p. Rescue experiments revealed that miR-7-5p/KLF4 axis could induce radiosensitivity by regulating CSCs in colorectal cancer cells. Furthermore, we used CRC tumor tissues which exhibited resistance to neoadjuvant radiotherapy to establish a patient-derived xenograft (PDX) mouse model. Tail vein injection of magnetic nanoparticles carrying miR-7-5p mimics into the PDX mice significantly inhibited tumor growth with or without irradiation treatment in vivo. Our current studies not only demonstrate an anti-cancer function of miR-7-5p in regulating CSC properties and radiosensitivity in colorectal cancer, but also provide a novel potential strategy for delaying or reverse radiation resistance in preoperative radiotherapy of CRC patients.
Chiral excitonic order from twofold van Hove singularities in kagome metals
Authors: Scammell Harley D. , Ingham Julian , Li Tommy , Sushkov Oleg P. 
Published: February 2023

AbstractRecent experiments on kagome metals AV3Sb5 (A=K,Rb,Cs) identify twofold van Hove singularities (TvHS) with opposite concavity near the Fermi energy, generating two approximately hexagonal Fermi surfaces – one electron-like and the other hole-like. Here we propose that a TvHS generates a novel time-reversal symmetry breaking excitonic order – arising due to bound pairs of electrons and holes located at opposite concavity van Hove singularities. We introduce a minimal model for the TvHS and investigate interaction induced many-body instabilities via the perturbative renormalisation group technique and a free energy analysis. Specialising to parameters appropriate for the kagome metals AV3Sb5, we construct a phase diagram comprising chiral excitons, charge density wave and a region of coexistence. We propose this as an explanation of a diverse range of experimental observations in AV3Sb5. Notably, the chiral excitonic state gives rise to a quantum anomalous Hall conductance, providing an appealing interpretation of the observed anomalous Hall effect in kagome metals. Possible alternative realisations of the TvHS mechanism in bilayer materials are also discussed. We suggest that TvHS open up interesting possibilities for correlated phases, enriching the set of competing ground states to include excitonic order.
Direct observation of accelerating hydrogen spillover via surface-lattice-confinement effect
Authors: Liu Yijing , Zhang Rankun , Lin Le , Wang Yichao , Liu Changping , Mu Rentao , Fu Qiang 
Published: February 2023

AbstractUncovering how hydrogen transfers and what factors control hydrogen conductivity on solid surface is essential for enhancing catalytic performance of H-involving reactions, which is however hampered due to the structural complexity of powder catalysts, in particular, for oxide catalysts. Here, we construct stripe-like MnO(001) and grid-like Mn3O4(001) monolayers on Pt(111) substrate and investigate hydrogen spillover atop. Atomic-scale visualization demonstrates that hydrogen species from Pt diffuse unidirectionally along the stripes on MnO(001), whereas it exhibits an isotropic pathway on Mn3O4(001). Dynamic surface imaging in H2 atmosphere reveals that hydrogen diffuses 4 times more rapidly on MnO than the case on Mn3O4, which is promoted by one-dimension surface-lattice-confinement effect. Theoretical calculations indicate that a uniform and medium O-O distance favors hydrogen diffusion while low-coordinate surface O atom inhibits it. Our work illustrates the surface-lattice-confinement effect of oxide catalysts on hydrogen spillover and provides a promising route to improve the hydrogen spillover efficiency.
Ambient temperature CO2 fixation to pyruvate and subsequently to citramalate over iron and nickel nanoparticles
Authors: Beyazay Tuğçe , Belthle Kendra S. , Farès Christophe , Preiner Martina , Moran Joseph , Martin William F. , Tüysüz Harun 
Published: February 2023

AbstractThe chemical reactions that formed the building blocks of life at origins required catalysts, whereby the nature of those catalysts influenced the type of products that accumulated. Recent investigations have shown that at 100 °C awaruite, a Ni3Fe alloy that naturally occurs in serpentinizing systems, is an efficient catalyst for CO2 conversion to formate, acetate, and pyruvate. These products are identical with the intermediates and products of the acetyl-CoA pathway, the most ancient CO2 fixation pathway and the backbone of carbon metabolism in H2-dependent autotrophic microbes. Here, we show that Ni3Fe nanoparticles prepared via the hard-templating method catalyze the conversion of H2 and CO2 to formate, acetate and pyruvate at 25 °C under 25 bar. Furthermore, the 13C-labeled pyruvate can be further converted to acetate, parapyruvate, and citramalate over Ni, Fe, and Ni3Fe nanoparticles at room temperature within one hour. These findings strongly suggest that awaruite can catalyze both the formation of citramalate, the C5 product of pyruvate condensation with acetyl-CoA in microbial carbon metabolism, from pyruvate and the formation of pyruvate from CO2 at very moderate reaction conditions without organic catalysts. These results align well with theories for an autotrophic origin of microbial metabolism under hydrothermal vent conditions.
ESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling
Authors: Gentili Matteo , Liu Bingxu , Papanastasiou Malvina , Dele-Oni Deborah , Schwartz Marc A. , Carlson Rebecca J. , Al’Khafaji Aziz M. , Krug Karsten , Brown Adam , Doench John G. , Carr Steven A. , Hacohen Nir 
Published: February 2023

AbstractStimulator of interferon genes (STING) is an intracellular sensor of cyclic di-nucleotides involved in the innate immune response against pathogen- or self-derived DNA. STING trafficking is tightly linked to its function, and its dysregulation can lead to disease. Here, we systematically characterize genes regulating STING trafficking and examine their impact on STING-mediated responses. Using proximity-ligation proteomics and genetic screens, we demonstrate that an endosomal sorting complex required for transport (ESCRT) complex containing HGS, VPS37A and UBAP1 promotes STING degradation, thereby terminating STING-mediated signaling. Mechanistically, STING oligomerization increases its ubiquitination by UBE2N, forming a platform for ESCRT recruitment at the endosome that terminates STING signaling via sorting in the lysosome. Finally, we show that expression of a UBAP1 mutant identified in patients with hereditary spastic paraplegia and associated with disrupted ESCRT function, increases steady-state STING-dependent type I IFN responses in healthy primary monocyte-derived dendritic cells and fibroblasts. Based on these findings, we propose that STING is subject to a tonic degradative flux and that the ESCRT complex acts as a homeostatic regulator of STING signaling.
Insights into azalomycin F assembly-line contribute to evolution-guided polyketide synthase engineering and identification of intermodular recognition
Authors: Zhai Guifa , Zhu Yan , Sun Guo , Zhou Fan , Sun Yangning , Hong Zhou , Dong Chuan , Leadlay Peter F. , Hong Kui , Deng Zixin , Zhou Fuling , Sun Yuhui 
Published: February 2023

AbstractModular polyketide synthase (PKS) is an ingenious core machine that catalyzes abundant polyketides in nature. Exploring interactions among modules in PKS is very important for understanding the overall biosynthetic process and for engineering PKS assembly-lines. Here, we show that intermodular recognition between the enoylreductase domain ER1/2 inside module 1/2 and the ketosynthase domain KS3 inside module 3 is required for the cross-module enoylreduction in azalomycin F (AZL) biosynthesis. We also show that KS4 of module 4 acts as a gatekeeper facilitating cross-module enoylreduction. Additionally, evidence is provided that module 3 and module 6 in the AZL PKS are evolutionarily homologous, which makes evolution-oriented PKS engineering possible. These results reveal intermodular recognition, furthering understanding of the mechanism of the PKS assembly-line, thus providing different insights into PKS engineering. This also reveals that gene duplication/conversion and subsequent combinations may be a neofunctionalization process in modular PKS assembly-lines, hence providing a different case for supporting the investigation of modular PKS evolution.
Conductive and elastic bottlebrush elastomers for ultrasoft electronics
Authors: Xu Pengfei , Wang Shaojia , Lin Angela , Min Hyun-Kee , Zhou Zhanfeng , Dou Wenkun , Sun Yu , Huang Xi , Tran Helen , Liu Xinyu 
Published: February 2023

AbstractUnderstanding biological systems and mimicking their functions require electronic tools that can interact with biological tissues with matched softness. These tools involve biointerfacing materials that should concurrently match the softness of biological tissue and exhibit suitable electrical conductivities for recording and reading bioelectronic signals. However, commonly employed intrinsically soft and stretchable materials usually contain solvents that limit stability for long-term use or possess low electronic conductivity. To date, an ultrasoft (i.e., Young’s modulus <30 kPa), conductive, and solvent-free elastomer does not exist. Additionally, integrating such ultrasoft and conductive materials into electronic devices is poorly explored. This article reports a solvent-free, ultrasoft and conductive PDMS bottlebrush elastomer (BBE) composite with single-wall carbon nanotubes (SWCNTs) as conductive fillers. The conductive SWCNT/BBE with a filler concentration of 0.4 − 0.6 wt% reveals an ultralow Young’s modulus (<11 kPa) and satisfactory conductivity (>2 S/m) as well as adhesion property. Furthermore, we fabricate ultrasoft electronics based on laser cutting and 3D printing of conductive and non-conductive BBEs and demonstrate their potential applications in wearable sensing, soft robotics, and electrophysiological recording.
Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis
Authors: Okuda Kosaku , Nakahara Kengo , Ito Akihiro , Iijima Yuta , Nomura Ryosuke , Kumar Ashutosh , Fujikawa Kana , Adachi Kazuya , Shimada Yuki , Fujio Satoshi , Yamamoto Reina , Takasugi Nobumasa , Onuma Kunishige , Osaki Mitsuhiko , Okada Futoshi , Ukegawa Taichi , Takeuchi Yasuo , Yasui Norihisa , Yamashita Atsuko , Marusawa Hiroyuki , Matsushita Yosuke , Katagiri Toyomasa , Shibata Takahiro , Uchida Koji , Niu Sheng-Yong , Lang Nhi B. , Nakamura Tomohiro , Zhang Kam Y. J. , Lipton Stuart A. , Uehara Takashi 
Published: February 2023

AbstractDNA methyltransferases (DNMTs) catalyze methylation at the C5 position of cytosine withS-adenosyl-l-methionine. Methylation regulates gene expression, serving a variety of physiological and pathophysiological roles. The chemical mechanisms regulating DNMT enzymatic activity, however, are not fully elucidated. Here, we show that protein S-nitrosylation of a cysteine residue in DNMT3B attenuates DNMT3B enzymatic activity and consequent aberrant upregulation of gene expression. These genes include Cyclin D2 (Ccnd2), which is required for neoplastic cell proliferation in some tumor types. In cell-based and in vivo cancer models, only DNMT3B enzymatic activity, and not DNMT1 or DNMT3A, affectsCcnd2expression. Using structure-based virtual screening, we discovered chemical compounds that specifically inhibitS-nitrosylation without directly affecting DNMT3B enzymatic activity. The lead compound, designated DBIC, inhibitsS-nitrosylation of DNMT3B at low concentrations (IC50 ≤ 100 nM). Treatment with DBIC prevents nitric oxide (NO)-induced conversion of human colonic adenoma to adenocarcinoma in vitro. Additionally, in vivo treatment with DBIC strongly attenuates tumor development in a mouse model of carcinogenesis triggered by inflammation-induced generation of NO. Our results demonstrate that de novo DNA methylation mediated by DNMT3B is regulated by NO, and DBIC protects against tumor formation by preventing aberrantS-nitrosylation of DNMT3B.
Universal exploration dynamics of random walks
Authors: Régnier Léo , Dolgushev Maxim , Redner S. , Bénichou Olivier 
Published: February 2023

AbstractThe territory explored by a random walk is a key property that may be quantified by the number of distinct sites that the random walk visits up to a given time. We introduce a more fundamental quantity, the timeτnrequired by a random walk to find a site that it never visited previously when the walk has already visitedndistinct sites, which encompasses the full dynamics about the visitation statistics. To study it, we develop a theoretical approach that relies on a mapping with a trapping problem, in which the spatial distribution of traps is continuously updated by the random walk itself. Despite the geometrical complexity of the territory explored by a random walk, the distribution of theτncan be accounted for by simple analytical expressions. Processes as varied as regular diffusion, anomalous diffusion, and diffusion in disordered media and fractals, fall into the same universality classes.
Self-spinning filaments for autonomously linked microfibers
Authors: Barber Dylan M. , Emrick Todd , Grason Gregory M. , Crosby Alfred J. 
Published: February 2023

AbstractFilamentous bundles are ubiquitous in Nature, achieving highly adaptive functions and structural integrity from assembly of diverse mesoscale supramolecular elements. Engineering routes to synthetic, topologically integrated analogs demands precisely coordinated control of multiple filaments’ shapes and positions, a major challenge when performed without complex machinery or labor-intensive processing. Here, we demonstrate a photocreasing design that encodes local curvature and twist into mesoscale polymer filaments, enabling their programmed transformation into target 3-dimensional geometries. Importantly, patterned photocreasing of filament arrays drives autonomous spinning to form linked filament bundles that are highly entangled and structurally robust. In individual filaments, photocreases unlock paths to arbitrary, 3-dimensional curves in space. Collectively, photocrease-mediated bundling establishes a transformative paradigm enabling smart, self-assembled mesostructures that mimic performance-differentiating structures in Nature (e.g., tendon and muscle fiber) and the macro-engineered world (e.g., rope).