bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting nerve growth factor-mediated osteosarcoma metastasis: mechanistic insights and therapeutic opportunities using larotrectinib
Authors: Hou Chun-Han , Chen Wei-Li , Lin Chih-Yang 
Published: May 2024

AbstractOsteosarcoma (OS) therapy presents numerous challenges, due largely to a low survival rate following metastasis onset. Nerve growth factor (NGF) has been implicated in the metastasis and progression of various cancers; however, the mechanism by which NGF promotes metastasis in osteosarcoma has yet to be elucidated. This study investigated the influence of NGF on the migration and metastasis of osteosarcoma patients (88 cases) as well as the underlying molecular mechanisms, based on RNA-sequencing and gene expression data from a public database (TARGET-OS). In osteosarcoma patients, the expression of NGF was significantly higher than that of other growth factors. This observation was confirmed in bone tissue arrays from 91 osteosarcoma patients, in which the expression levels of NGF and matrix metallopeptidase-2 (MMP-2) protein were significantly higher than in normal bone, and strongly correlated with tumor stage. In summary, NGF is positively correlated with MMP-2 in human osteosarcoma tissue and NGF promotes osteosarcoma cell metastasis by upregulating MMP-2 expression. In cellular experiments using human osteosarcoma cells (143B and MG63), NGF upregulated MMP-2 expression and promoted wound healing, cell migration, and cell invasion. Pre-treatment with MEK and ERK inhibitors or siRNA attenuated the effects of NGF on cell migration and invasion. Stimulation with NGF was shown to promote phosphorylation along the MEK/ERK signaling pathway and decrease the expression of microRNA-92a-1-5p (miR-92a-1-5p). In in vivo experiments involving an orthotopic mouse model, the overexpression of NGF enhanced the effects of NGF on lung metastasis. Note that larotrectinib (a tropomyosin kinase receptor) strongly inhibited the effect of NGF on lung metastasis. In conclusion, it appears that NGF promotes MMP-2-dependent cell migration by inhibiting the effects of miR-92a-1-5p via the MEK/ERK signaling cascade. Larotrectinib emerged as a potential drug for the treatment of NGF-mediated metastasis in osteosarcoma.
Targeting CK2 eliminates senescent cells and prolongs lifespan in Zmpste24-deficient mice
Authors: Zhang Jie , Sun Pengfei , Wu Zhuping , Wu Jie , Jia Jiali , Zou Haoman , Mo Yanzhen , Zhou Zhongjun , Liu Baohua , Ao Ying , Wang Zimei 
Published: May 2024

AbstractSenescent cell clearance is emerging as a promising strategy for treating age-related diseases. Senolytics are small molecules that promote the clearance of senescent cells; however, senolytics are uncommon and their underlying mechanisms remain largely unknown. Here, we investigated whether genomic instability is a potential target for senolytic. We screened small-molecule kinase inhibitors involved in the DNA damage response (DDR) in Zmpste24−/− mouse embryonic fibroblasts, a progeroid model characterized with impaired DDR and DNA repair. 4,5,6,7-tetrabromo-2-azabenzamidazole (TBB), which specifically inhibits casein kinase 2 (CK2), was selected and discovered to preferentially trigger apoptosis in Zmpste24−/− cells. Mechanistically, inhibition of CK2 abolished the phosphorylation of heterochromatin protein 1α (HP1α), which retarded the dynamic HP1α dissociation from repressive histone mark H3K9me3 and its relocalization with γH2AX to DNA damage sites, suggesting that disrupting heterochromatin remodeling in the initiation of DDR accelerates apoptosis in senescent cells. Furthermore, feeding Zmpste24-deficient mice with TBB alleviated progeroid features and extended their lifespan. Our study identified TBB as a new class senolytic compound that can reduce age-related symptoms and prolong lifespan in progeroid mice.
Ferroptosis: A double-edged sword
Authors: Wang Shengmei , Guo Qiuyan , Zhou Lili , Xia Xinhua 
Published: May 2024

AbstractFerroptosis represents a form of programmed cell death that is propelled by iron-dependent lipid peroxidation, thereby being distinguished by the prominent features of iron accumulation and lipid peroxidation. Ferroptosis has been implicated in numerous physiological and pathological phenomena, with mounting indications that it holds significant implications for cancer and other medical conditions. On one side, it demonstrates anti-cancer properties by triggering ferroptosis within malignant cells, and on the other hand, it damages normal cells causing other diseases. Therefore, in this paper, we propose to review the paradoxical regulation of ferroptosis in tumors and other diseases. First, we introduce the development history, concept and mechanism of ferroptosis. The second part focuses on the methods of inducing ferroptosis in tumors. The third section emphasizes the utilization of ferroptosis in different medical conditions and strategies to inhibit ferroptosis. The fourth part elucidates the key contradictions in the control of ferroptosis. Finally, potential research avenues in associated domains are suggested.
Rapid P-TEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy
Authors: Walker Faye M. , Sobral Lays Martin , Danis Etienne , Sanford Bridget , Donthula Sahiti , Balakrishnan Ilango , Wang Dong , Pierce Angela , Karam Sana D. , Kargar Soudabeh , Serkova Natalie J. , Foreman Nicholas K. , Venkataraman Sujatha , Dowell Robin , Vibhakar Rajeev , Dahl Nathan A. 
Published: May 2024

AbstractDynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. P-TEFb-mediated pause-release of RNA polymerase II (Pol II) is a conserved regulatory mechanism for synchronous transcriptional induction in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. Using model systems of pediatric high-grade glioma, we show that rapid genome-wide reorganization of active chromatin facilitates P-TEFb-mediated nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of P-TEFb disrupts this chromatin reorganization and blunts transcriptional induction, abrogating key adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival. These studies reveal a central role for P-TEFb underpinning the early adaptive response to radiotherapy, opening avenues for combinatorial treatment in these lethal malignancies.
The observation of π-shifts in the Little-Parks effect in 4Hb-TaS2
Authors: Almoalem Avior , Feldman Irena , Mangel Ilay , Shlafman Michael , Yaish Yuval E. , Fischer Mark H. , Moshe Michael , Ruhman Jonathan , Kanigel Amit 
Published: May 2024

AbstractFinding evidence of non-trivial pairing states is one of the greatest experimental challenges in the field of unconventional superconductivity. Such evidence requires phase-sensitive probes susceptible to the internal structure of the order parameter. We report the measurement of the Little-Parks effect in the unconventional superconductor candidate 4Hb-TaS2. In half of our rings, which are fabricated from single-crystals, we find a π-shift in the transition-temperature oscillations. According to theory, such a π-shift is only possible if the order parameter is non-s-wave. In the absence of crystallographic defects, the shift provides evidence of a multi-component order parameter. Thus, this observation increases the likelihood of the two-component order parameter scenario in 4Hb-TaS2. Furthermore, we show that Tc is enhanced as a function of the out-of-plane field when a constant in-plane field is applied, which we explain using a two-component order-parameter.
Heatwave attribution based on reliable operational weather forecasts
Authors: Leach Nicholas J. , Roberts Christopher D. , Aengenheyster Matthias , Heathcote Daniel , Mitchell Dann M. , Thompson Vikki , Palmer Tim , Weisheimer Antje , Allen Myles R. 
Published: May 2024

AbstractThe 2021 Pacific Northwest heatwave was so extreme as to challenge conventional statistical and climate-model-based approaches to extreme weather attribution. However, state-of-the-art operational weather prediction systems are demonstrably able to simulate the detailed physics of the heatwave. Here, we leverage these systems to show that human influence on the climate made this event at least 8 [2–50] times more likely. At the current rate of global warming, the likelihood of such an event is doubling every 20 [10–50] years. Given the multi-decade lower-bound return-time implied by the length of the historical record, this rate of change in likelihood is highly relevant for decision makers. Further, forecast-based attribution can synthesise the conditional event-specific storyline and unconditional event-class probabilistic approaches to attribution. If developed as a routine service in forecasting centres, it could provide reliable estimates of human influence on extreme weather risk, which is critical to supporting effective adaptation planning.
FLI1 promotes IFN-γ-induced kynurenine production to impair anti-tumor immunity
Authors: Chen Enni , Wu Jiawei , Huang Jiajia , Zhu Wancui , Sun Haohui , Wang Xiaonan , Lin Dagui , Li Xiaodi , Shi Dingbo , Liu Zhiqiao , Huang Jinsheng , Chen Miao , Xie Fangyun , Deng Wuguo 
Published: May 2024

AbstractNasopharyngeal carcinoma (NPC)-mediated immunosuppression within the tumor microenvironment (TME) frequently culminates in the failure of otherwise promising immunotherapies. In this study, we identify tumor-intrinsic FLI1 as a critical mediator in impairing T cell anti-tumor immunity. A mechanistic inquiry reveals that FLI1 orchestrates the expression of CBP and STAT1, facilitating chromatin accessibility and transcriptional activation of IDO1 in response to T cell-released IFN-γ. This regulatory cascade ultimately leads to augmented IDO1 expression, resulting in heightened synthesis of kynurenine (Kyn) in tumor cells. This, in turn, fosters CD8+ T cell exhaustion and regulatory T cell (Treg) differentiation. Intriguingly, we find that pharmacological inhibition of FLI1 effectively obstructs the CBP/STAT1-IDO1-Kyn axis, thereby invigorating both spontaneous and checkpoint therapy-induced immune responses, culminating in enhanced tumor eradication. In conclusion, our findings delineate FLI1-mediated Kyn metabolism as an immune evasion mechanism in NPC, furnishing valuable insights into potential therapeutic interventions.
Elastic strain-induced amorphization in high-entropy alloys
Authors: Bu Yeqiang , Wu Yuan , Lei Zhifeng , Yuan Xiaoyuan , Liu Leqing , Wang Peng , Liu Xiongjun , Wu Honghui , Liu Jiabin , Wang Hongtao , Ritchie R. O. , Lu Zhaoping , Yang Wei 
Published: May 2024

AbstractElastic stability is the basis for understanding structural responses to external stimuli in crystalline solids, including melting, incipient plasticity and fracture. In this work, elastic stability is investigated in a series of high-entropy alloys (HEAs) using in situ mechanical tests and atomic-resolution characterization in transmission electron microscopy. Under tensile loading, the HEA lattices are observed to undergo a sudden loss of ordering as the elastic strain reached ∽ 10%. Such elastic strain-induced amorphization stands in intrinsic contrast to previously reported dislocation-mediated elastic instability and defect accumulation-mediated amorphization, introducing a form of elastic instability. Together with the first principle calculations and atomic-resolution chemical mapping, we identify that the elastic strain-induced amorphization is closely related to the depressed dislocation nucleation due to the local atomic environment inhomogeneity of HEAs. Our findings provide insights for the understanding of the fundamental nature of physical mechanical phenomena like elastic instability and incipient plasticity.
The debranching enzyme Dbr1 regulates lariat turnover and intron splicing
Authors: Buerer Luke , Clark Nathaniel E. , Welch Anastasia , Duan Chaorui , Taggart Allison J. , Townley Brittany A. , Wang Jing , Soemedi Rachel , Rong Stephen , Lin Chien-Ling , Zeng Yi , Katolik Adam , Staley Jonathan P. , Damha Masad J. , Mosammaparast Nima , Fairbrother William G. 
Published: May 2024

AbstractThe majority of genic transcription is intronic. Introns are removed by splicing as branched lariat RNAs which require rapid recycling. The branch site is recognized during splicing catalysis and later debranched by Dbr1 in the rate-limiting step of lariat turnover. Through generation of a viable DBR1 knockout cell line, we find the predominantly nuclear Dbr1 enzyme to encode the sole debranching activity in human cells. Dbr1 preferentially debranches substrates that contain canonical U2 binding motifs, suggesting that branchsites discovered through sequencing do not necessarily represent those favored by the spliceosome. We find that Dbr1 also exhibits specificity for particular 5’ splice site sequences. We identify Dbr1 interactors through co-immunoprecipitation mass spectrometry. We present a mechanistic model for Dbr1 recruitment to the branchpoint through the intron-binding protein AQR. In addition to a 20-fold increase in lariats, Dbr1 depletion increases exon skipping. Using ADAR fusions to timestamp lariats, we demonstrate a defect in spliceosome recycling. In the absence of Dbr1, spliceosomal components remain associated with the lariat for a longer period of time. As splicing is co-transcriptional, slower recycling increases the likelihood that downstream exons will be available for exon skipping.
Discovering two general characteristic times of transient responses in solid oxide cells
Authors: Liang Zhaojian , Wang Jingyi , Ren Keda , Jiao Zhenjun , Ni Meng , An Liang , Wang Yang , Yang Jinbin , Li Mengying 
Published: May 2024

AbstractA comprehensive understanding of the transient characteristics in solid oxide cells (SOCs) is crucial for advancing SOC technology in renewable energy storage and conversion. However, general formulas describing the relationship between SOC transients and multiple parameters remain elusive. Through comprehensive numerical analysis, we find that the thermal and gaseous response times of SOCs upon rapid electrical variations are on the order of two characteristic times (τh and τm), respectively. The gaseous response time is approximately 1τm, and the thermal response time aligns with roughly 2τh. These characteristic times represent the overall heat and mass transfer rates within the cell, and their mathematical relationships with various SOC design and operating parameters are revealed. Validation of τh and τm is achieved through comparison with an in-house experiment and existing literature data, achieving the same order of magnitude for a wide range of electrochemical cells, showcasing their potential use for characterizing transient behaviors in a wide range of electrochemical cells. Moreover, two examples are presented to demonstrate how these characteristic times can streamline SOC design and control without the need for complex numerical simulations, thus offering valuable insights and tools for enhancing the efficiency and durability of electrochemical cells.
Hydrogen peroxide serves as pivotal fountainhead for aerosol aqueous sulfate formation from a global perspective
Authors: Gao Jie , Wang Haoqi , Liu Wenqi , Xu Han , Wei Yuting , Tian Xiao , Feng Yinchang , Song Shaojie , Shi Guoliang 
Published: May 2024

AbstractTraditional atmospheric chemistry posits that sulfur dioxide (SO2) can be oxidized to sulfate (SO42–) through aqueous-phase reactions in clouds and gas-phase oxidation. Despite adequate knowledge of traditional mechanisms, several studies have highlighted the potential for SO2 oxidation within aerosol water. Given the widespread presence of tropospheric aerosols, SO42− production through aqueous-phase oxidation in aerosol water could have a pervasive global impact. Here, we quantify the potential contributions of aerosol aqueous pathways to global sulfate formation based on the GEOS-Chem simulations and subsequent theoretical calculations. Hydrogen peroxide (H2O2) oxidation significantly influences continental regions both horizontally and vertically. Over the past two decades, shifts in the formation pathways within typical cities reveal an intriguing trend: despite reductions in SO2 emissions, the increased atmospheric oxidation capacities, like rising H2O2 levels, prevent a steady decline in SO42− concentrations. Abating oxidants would facilitate the benefit of SO2 reduction and the positive feedback in sulfate mitigation.
The quantum geometric origin of capacitance in insulators
Authors: Komissarov Ilia , Holder Tobias , Queiroz Raquel 
Published: May 2024

AbstractIn band insulators, without a Fermi surface, adiabatic transport can exist due to the geometry of the ground state wavefunction. Here we show that for systems driven at a small but finite frequency ω, transport likewise depends sensitively on quantum geometry. We make this statement precise by expressing the Kubo formula for conductivity as the variation of the time-dependent polarization with respect to the applied field. We find that at linear order in frequency, the longitudinal conductivity results from an intrinsic capacitance determined by the ratio of the quantum metric and the spectral gap, establishing a fundamental link between the dielectric response and the quantum metric of insulators. We demonstrate that quantum geometry is responsible for the electronic contribution to the dielectric constant in a wide range of insulators, including the free electron gas in a quantizing magnetic field, for which we show the capacitance is quantized. We also study gapped bands of hBN-aligned twisted bilayer graphene and obstructed atomic insulators such as diamond. In the latter, we find its abnormally large refractive index to have a topological origin.
Atroposelective synthesis of biaxial bridged eight-membered terphenyls via a Co/SPDO-catalyzed aerobic oxidative coupling/desymmetrization of phenols
Authors: Wang Shuang-Hu , Wei Shi-Qiang , Zhang Ye , Zhang Xiao-Ming , Zhang Shu-Yu , Dai Kun-Long , Tu Yong-Qiang , Lu Ka , Ding Tong-Mei 
Published: May 2024

AbstractBridged chiral biaryls are axially chiral compounds with a medium-sized ring connecting the two arenes. Compared with plentiful methods for the enantioselective synthesis of biaryl compounds, synthetic approaches for this subclass of bridged atropisomers are limited. Here we show an atroposelective synthesis of 1,3-diaxial bridged eight-membered terphenyl atropisomers through an Co/SPDO (spirocyclic pyrrolidine oxazoline)-catalyzed aerobic oxidative coupling/desymmetrization reaction of prochiral phenols. This catalytic desymmetric process is enabled by combination of an earth-abundant Co(OAc)2 and a unique SPDO ligand in the presence of DABCO (1,4-diaza[2.2.2]bicyclooctane). An array of diaxial bridged terphenyls embedded in an azocane can be accessed in high yields (up to 99%) with excellent enantio- (>99% ee) and diastereoselectivities (>20:1 dr).
Targeted suppression of siRNA biogenesis in Arabidopsis pollen promotes triploid seed viability
Authors: Pachamuthu Kannan , Simon Matthieu , Borges Filipe 
Published: May 2024

AbstractIn plants, small-interfering RNAs (siRNAs) mediate epigenetic silencing via the RNA-directed DNA methylation (RdDM) pathway, which is particularly prominent during reproduction and seed development. However, there is limited understanding of the origins and dynamics of reproductive siRNAs acting in different cellular and developmental contexts. Here, we used the RNaseIII-like protein RTL1 to suppress siRNA biogenesis in Arabidopsis pollen, and found distinct siRNA subsets produced during pollen development. We demonstrate that RTL1 expression in the late microspore and vegetative cell strongly impairs epigenetic silencing, and resembles RdDM mutants in their ability to bypass interploidy hybridization barriers in the seed. However, germline-specific RTL1 expression did not impact transgenerational inheritance of triploid seed lethality. These results reveal the existence of multiple siRNA subsets accumulated in mature pollen, and suggest that mobile siRNAs involved in the triploid block are produced in germline precursor cells after meiosis, or in the vegetative cell during pollen mitosis.
Structures of co-transcriptional RNA capping enzymes on paused transcription complex
Authors: Li Yan , Wang Qianmin , Xu Yanhui , Li Ze 
Published: May 2024

AbstractThe 5′-end capping of nascent pre-mRNA represents the initial step in RNA processing, with evidence demonstrating that guanosine addition and 2′-O-ribose methylation occur in tandem with early steps of transcription by RNA polymerase II, especially at the pausing stage. Here, we determine the cryo-EM structures of the paused elongation complex in complex with RNGTT, as well as the paused elongation complex in complex with RNGTT and CMTR1. Our findings show the simultaneous presence of RNGTT and the NELF complex bound to RNA polymerase II. The NELF complex exhibits two conformations, one of which shows a notable rearrangement of NELF-A/D compared to that of the paused elongation complex. Moreover, CMTR1 aligns adjacent to RNGTT on the RNA polymerase II stalk. Our structures indicate that RNGTT and CMTR1 directly bind the paused elongation complex, illuminating the mechanism by which 5’-end capping of pre-mRNA during transcriptional pausing.
High-speed optical imaging with sCMOS pixel reassignment
Authors: Mandracchia Biagio , Zheng Corey , Rajendran Suraj , Liu Wenhao , Forghani Parvin , Xu Chunhui , Jia Shu 
Published: May 2024

AbstractFluorescence microscopy has undergone rapid advancements, offering unprecedented visualization of biological events and shedding light on the intricate mechanisms governing living organisms. However, the exploration of rapid biological dynamics still poses a significant challenge due to the limitations of current digital camera architectures and the inherent compromise between imaging speed and other capabilities. Here, we introduce sHAPR, a high-speed acquisition technique that leverages the operating principles of sCMOS cameras to capture fast cellular and subcellular processes. sHAPR harnesses custom fiber optics to convert microscopy images into one-dimensional recordings, enabling acquisition at the maximum camera readout rate, typically between 25 and 250 kHz. We have demonstrated the utility of sHAPR with a variety of phantom and dynamic systems, including high-throughput flow cytometry, cardiomyocyte contraction, and neuronal calcium waves, using a standard epi-fluorescence microscope. sHAPR is highly adaptable and can be integrated into existing microscopy systems without requiring extensive platform modifications. This method pushes the boundaries of current fluorescence imaging capabilities, opening up new avenues for investigating high-speed biological phenomena.