bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNMT3a-dermatopontin axis suppresses breast cancer malignancy via inactivating YAP
Authors: Ye Danrong , Wang Yuying , Deng Xiaochong , Zhou Xiqian , Liu Diya , Zhou Baian , Zheng Wenfang , Wang Xuehui , Fang Lin 
Published: February 2023

AbstractBreast cancer (BC) is the most common malignant tumor in women worldwide, and its recurrence and metastasis negatively affect patient prognosis. However, the mechanisms underlying its tumorigenesis and progression remain unclear. Recently, the influence of dermatopontin (DPT), which is an extracellular matrix protein, has been proposed in the development of cancer. Here we found that DNMT3a-mediated DPT, promoter hypermethylation results in the downregulation of DPT expression in breast cancer and its low expression correlated with poor prognosis. Notably, DPT directly interacted with YAP to promote YAP Ser127 phosphorylation, and restricted the translocation of endogenous YAP from the cytoplasm to the nucleus, thereby suppressing malignant phenotypes in BC cells. In addition, Ectopic YAP overexpression reversed the inhibitory effects of DPT on BC growth and metastasis. Our study showed the critical role of DPT in regulating BC progression, making it easier to explore the clinical potential of modulating DPT/YAP activity in BC targeted therapies.
Actin polymerisation and crosslinking drive left-right asymmetry in single cell and cell collectives
Authors: Tee Yee Han , Goh Wei Jia , Yong Xianbin , Ong Hui Ting , Hu Jinrong , Tay Ignacius Yan Yun , Shi Shidong , Jalal Salma , Barnett Samuel F. H. , Kanchanawong Pakorn , Huang Wenmao , Yan Jie , Lim Yong Ann Ben , Thiagarajan Visalatchi , Mogilner Alex , Bershadsky Alexander D. 
Published: February 2023

AbstractDeviations from mirror symmetry in the development of bilateral organisms are common but the mechanisms of initial symmetry breaking are insufficiently understood. The actin cytoskeleton of individual cells self-organises in a chiral manner, but the molecular players involved remain essentially unidentified and the relationship between chirality of an individual cell and cell collectives is unclear. Here, we analysed self-organisation of the chiral actin cytoskeleton in individual cells on circular or elliptical patterns, and collective cell alignment in confined microcultures. Screening based on deep-learning analysis of actin patterns identified actin polymerisation regulators, depletion of which suppresses chirality (mDia1) or reverses chirality direction (profilin1 and CapZβ). The reversed chirality is mDia1-independent but requires the function of actin-crosslinker α−actinin1. A robust correlation between the effects of a variety of actin assembly regulators on chirality of individual cells and cell collectives is revealed. Thus, actin-driven cell chirality may underlie tissue and organ asymmetry.
Enzyme-like polyene cyclizations catalyzed by dynamic, self-assembled, supramolecular fluoro alcohol-amine clusters
Authors: Arnold Andreas M. , Dullinger Philipp , Biswas Aniruddha , Jandl Christian , Horinek Dominik , Gulder Tanja 
Published: February 2023

AbstractTerpene cyclases catalyze one of the most powerful transformations with respect to efficiency and selectivity in natural product (bio)synthesis. In such polyene cyclizations, structurally highly complex carbon scaffolds are built by the controlled ring closure of linear polyenes. Thereby, multiple C,C bonds and stereocenters are simultaneously created with high precision. Structural pre-organization of the substrate carbon chain inside the active center of the enzyme is responsible for the product- and stereoselectivity of this cyclization. Here, we show that in-situ formed fluorinated-alcohol-amine supramolecular clusters serve as artificial cyclases by triggering enzyme-like reactivity and selectivity by controlling substrate conformation in solution. Because of the dynamic nature of these supramolecular assemblies, a broad range of terpenes can be produced diastereoselectively. Mechanistic studies reveal a finely balanced interplay of fluorinated solvent, catalyst, and substrate as key to establishing nature’s concept of a shape-selective polyene cyclization in organic synthesis.
T cell-independent eradication of experimental glioma by intravenous TLR7/8-agonist-loaded nanoparticles
Authors: Turco Verena , Pfleiderer Kira , Hunger Jessica , Horvat Natalie K. , Karimian-Jazi Kianush , Schregel Katharina , Fischer Manuel , Brugnara Gianluca , Jähne Kristine , Sturm Volker , Streibel Yannik , Nguyen Duy , Altamura Sandro , Agardy Dennis A. , Soni Shreya S. , Alsasa Abdulrahman , Bunse Theresa , Schlesner Matthias , Muckenthaler Martina U. , Weissleder Ralph , Wick Wolfgang , Heiland Sabine , Vollmuth Philipp , Bendszus Martin , Rodell Christopher B. , Breckwoldt Michael O. , Platten Michael 
Published: February 2023

AbstractGlioblastoma, the most common and aggressive primary brain tumor type, is considered an immunologically “cold” tumor with sparse infiltration by adaptive immune cells. Immunosuppressive tumor-associated myeloid cells are drivers of tumor progression. Therefore, targeting and reprogramming intratumoral myeloid cells is an appealing therapeutic strategy. Here, we investigate a β-cyclodextrin nanoparticle (CDNP) formulation encapsulating the Toll-like receptor 7 and 8 (TLR7/8) agonist R848 (CDNP-R848) to reprogram myeloid cells in the glioma microenvironment. We show that intravenous monotherapy with CDNP-R848 induces regression of established syngeneic experimental glioma, resulting in increased survival rates compared with unloaded CDNP controls. Mechanistically, CDNP-R848 treatment reshapes the immunosuppressive tumor microenvironment and orchestrates tumor clearing by pro-inflammatory tumor-associated myeloid cells, independently of T cells and NK cells. Using serial magnetic resonance imaging, we identify a radiomic signature in response to CDNP-R848 treatment and ultrasmall superparamagnetic iron oxide (USPIO) imaging reveals that immunosuppressive macrophage recruitment is reduced by CDNP-R848. In conclusion, CDNP-R848 induces tumor regression in experimental glioma by targeting blood-borne macrophages without requiring adaptive immunity.
Interpretable design of Ir-free trimetallic electrocatalysts for ammonia oxidation with graph neural networks
Authors: Pillai Hemanth Somarajan , Li Yi , Wang Shih-Han , Omidvar Noushin , Mu Qingmin , Achenie Luke E. K. , Abild-Pedersen Frank , Yang Juan , Wu Gang , Xin Hongliang 
Published: February 2023

AbstractThe electrochemical ammonia oxidation to dinitrogen as a means for energy and environmental applications is a key technology toward the realization of a sustainable nitrogen cycle. The state-of-the-art metal catalysts including Pt and its bimetallics with Ir show promising activity, albeit suffering from high overpotentials for appreciable current densities and the soaring price of precious metals. Herein, the immense design space of ternary Pt alloy nanostructures is explored by graph neural networks trained on ab initio data for concurrently predicting site reactivity, surface stability, and catalyst synthesizability descriptors. Among a few Ir-free candidates that emerge from the active learning workflow, Pt3Ru-M (M: Fe, Co, or Ni) alloys were successfully synthesized and experimentally verified to be more active toward ammonia oxidation than Pt, Pt3Ir, and Pt3Ru. More importantly, feature attribution analyses using the machine-learned representation of site motifs provide fundamental insights into chemical bonding at metal surfaces and shed light on design strategies for high-performance catalytic systems beyond the d-band center metric of binding sites.
Subduction initiation triggered the Caribbean large igneous province
Authors: Riel Nicolas , Duarte João C. , Almeida Jaime , Kaus Boris J. P. , Rosas Filipe , Rojas-Agramonte Yamirka , Popov Anton 
Published: February 2023

AbstractSubduction provides the primary driving force for plate tectonics. However, the mechanisms leading to the formation of new subduction zones remain debated. An example is the Lesser Antilles Arc in the Atlantic. Previous initiation mechanisms have implied the transmission of subduction from the Pacific Ocean or the impact of a plume head. Here, we use geodynamic models to simulate the evolution of the Caribbean region during the Cretaceous, where the eastern Pacific subduction triggered the formation of a new subduction zone in the Atlantic. The simulations show how the collision of the old Caribbean plateau with the Central America margin lead to the formation of a new Atlantic subduction zone by polarity reversal. The results further show how subduction renewal on the back of the old Caribbean plateau (present-day Central America) resulted in a major mantle flow reorganization that generated a subduction-induced plume consistent with the formation of the Caribbean Large Igneous Province.
Genomic and microenvironmental heterogeneity shaping epithelial-to-mesenchymal trajectories in cancer
Authors: Malagoli Tagliazucchi Guidantonio , Wiecek Anna J. , Withnell Eloise , Secrier Maria 
Published: February 2023

AbstractThe epithelial to mesenchymal transition (EMT) is a key cellular process underlying cancer progression, with multiple intermediate states whose molecular hallmarks remain poorly characterised. To fill this gap, we present a method to robustly evaluate EMT transformation in individual tumours based on transcriptomic signals. We apply this approach to explore EMT trajectories in 7180 tumours of epithelial origin and identify three macro-states with prognostic and therapeutic value, attributable to epithelial, hybrid E/M and mesenchymal phenotypes. We show that the hybrid state is relatively stable and linked with increased aneuploidy. We further employ spatial transcriptomics and single cell datasets to explore the spatial heterogeneity of EMT transformation and distinct interaction patterns with cytotoxic, NK cells and fibroblasts in the tumour microenvironment. Additionally, we provide a catalogue of genomic events underlying distinct evolutionary constraints on EMT transformation. This study sheds light on the aetiology of distinct stages along the EMT trajectory, and highlights broader genomic and environmental hallmarks shaping the mesenchymal transformation of primary tumours.
Integrative proteomic characterization of adenocarcinoma of esophagogastric junction
Authors: Li Shengli , Yuan Li , Xu Zhi-Yuan , Xu Jing-Li , Chen Gui-Ping , Guan Xiaoqing , Pan Guang-Zhao , Hu Can , Dong Jinyun , Du Yi-An , Yang Li-Tao , Ni Mao-Wei , Jiang Rui-Bin , Zhu Xiu , Lv Hang , Xu Han-Dong , Zhang Sheng-Jie , Qin Jiang-Jiang , Cheng Xiang-Dong 
Published: February 2023

AbstractThe incidence of adenocarcinoma of the esophagogastric junction (AEG) has been rapidly increasing in recent decades, but its molecular alterations and subtypes are still obscure. Here, we conduct proteomics and phosphoproteomics profiling of 103 AEG tumors with paired normal adjacent tissues (NATs), whole exome sequencing of 94 tumor-NAT pairs, and RNA sequencing in 83 tumor-NAT pairs. Our analysis reveals an extensively altered proteome and 252 potential druggable proteins in AEG tumors. We identify three proteomic subtypes with significant clinical and molecular differences. The S-II subtype signature protein, FBXO44, is demonstrated to promote tumor progression and metastasis in vitro and in vivo. Our comparative analyses reveal distinct genomic features in AEG subtypes. We find a specific decrease of fibroblasts in the S-III subtype. Further phosphoproteomic comparisons reveal different kinase-phosphosubstrate regulatory networks among AEG subtypes. Our proteogenomics dataset provides valuable resources for understanding molecular mechanisms and developing precision treatment strategies of AEG.
Small molecule inhibitors of 15-PGDH exploit a physiologic induced-fit closing system
Authors: Huang Wei , Li Hongyun , Kiselar Janna , Fink Stephen P. , Regmi Sagar , Day Alexander , Yuan Yiyuan , Chance Mark , Ready Joseph M. , Markowitz Sanford D. , Taylor Derek J. 
Published: February 2023

Abstract15-prostaglandin dehydrogenase (15-PGDH) is a negative regulator of tissue stem cells that acts via enzymatic activity of oxidizing and degrading PGE2, and related eicosanoids, that support stem cells during tissue repair. Indeed, inhibiting 15-PGDH markedly accelerates tissue repair in multiple organs. Here we have used cryo-electron microscopy to solve the solution structure of native 15-PGDH and of 15-PGDH individually complexed with two distinct chemical inhibitors. These structures identify key 15-PGDH residues that mediate binding to both classes of inhibitors. Moreover, we identify a dynamic 15-PGDH lid domain that closes around the inhibitors, and that is likely fundamental to the physiologic 15-PGDH enzymatic mechanism. We furthermore identify two key residues, F185 and Y217, that act as hinges to regulate lid closing, and which both inhibitors exploit to capture the lid in the closed conformation, thus explaining their sub-nanomolar binding affinities. These findings provide the basis for further development of 15-PGDH targeted drugs as therapeutics for regenerative medicine.
Histone variant H2A.Z modulates nucleosome dynamics to promote DNA accessibility
Authors: Li Shuxiang , Wei Tiejun , Panchenko Anna R. 
Published: February 2023

AbstractNucleosomes, containing histone variants H2A.Z, are important for gene transcription initiation and termination, chromosome segregation and DNA double-strand break repair, among other functions. However, the underlying mechanisms of how H2A.Z influences nucleosome stability, dynamics and DNA accessibility are not well understood, as experimental and computational evidence remains inconclusive. Our modeling efforts of human nucleosome stability and dynamics, along with comparisons with experimental data show that the incorporation of H2A.Z results in a substantial decrease of the energy barrier for DNA unwrapping. This leads to the spontaneous DNA unwrapping of about forty base pairs from both ends, nucleosome gapping and increased histone plasticity, which otherwise is not observed for canonical nucleosomes. We demonstrate that both N- and C-terminal tails of H2A.Z play major roles in these events, whereas the H3.3 variant exerts a negligible impact in modulating the DNA end unwrapping. In summary, our results indicate that H2A.Z deposition makes nucleosomes more mobile and DNA more accessible to transcriptional machinery and other chromatin components.
Controlled sequential in situ self-assembly and disassembly of a fluorogenic cisplatin prodrug for cancer theranostics
Authors: Wen Xidan , Zhang Rui , Hu Yuxuan , Wu Luyan , Bai He , Song Dongfan , Wang Yanfeng , An Ruibing , Weng Jianhui , Zhang Shuren , Wang Rong , Qiu Ling , Lin Jianguo , Gao Guandao , Liu Hong , Guo Zijian , Ye Deju 
Published: February 2023

AbstractTemporal control of delivery and release of drugs in tumors are important in improving therapeutic outcomes to patients. Here, we report a sequential stimuli-triggered in situ self-assembly and disassembly strategy to direct delivery and release of theranostic drugs in vivo. Using cisplatin as a model anticancer drug, we design a stimuli-responsive small-molecule cisplatin prodrug (P-CyPt), which undergoes extracellular alkaline phosphatase-triggered in situ self-assembly and succeeding intracellular glutathione-triggered disassembly process, allowing to enhance accumulation and elicit burst release of cisplatin in tumor cells. Compared with cisplatin, P-CyPt greatly improves antitumor efficacy while mitigates off-target toxicity in mice with subcutaneous HeLa tumors and orthotopic HepG2 liver tumors after systemic administration. Moreover, P-CyPt also produces activated near-infrared fluorescence (at 710 nm) and dual photoacoustic imaging signals (at 700 and 750 nm), permitting high sensitivity and spatial-resolution delineation of tumor foci and real-time monitoring of drug delivery and release in vivo. This strategy leverages the advantages offered by in situ self-assembly with those of intracellular disassembly, which may act as a general platform for the design of prodrugs capable of improving drug delivery for cancer theranostics.
Creation of chiral interface channels for quantized transport in magnetic topological insulator multilayer heterostructures
Authors: Zhao Yi-Fan , Zhang Ruoxi , Cai Jiaqi , Zhuo Deyi , Zhou Ling-Jie , Yan Zi-Jie , Chan Moses H. W. , Xu Xiaodong , Chang Cui-Zu 
Published: February 2023

AbstractOne-dimensional chiral interface channels can be created at the boundary of two quantum anomalous Hall (QAH) insulators with different Chern numbers. Such a QAH junction may function as a chiral edge current distributer at zero magnetic field, but its realization remains challenging. Here, by employing an in-situ mechanical mask, we use molecular beam epitaxy to synthesize QAH insulator junctions, in which two QAH insulators with different Chern numbers are connected along a one-dimensional junction. For the junction between Chern numbers of 1 and −1, we observe quantized transport and demonstrate the appearance of the two parallel propagating chiral interface channels along the magnetic domain wall at zero magnetic field. For the junction between Chern numbers of 1 and 2, our quantized transport shows that a single chiral interface channel appears at the interface. Our work lays the foundation for the development of QAH insulator-based electronic and spintronic devices and topological chiral networks.
A latitudinal gradient of deep-sea invasions for marine fishes
Authors: Friedman Sarah T. , Muñoz Martha M. 
Published: February 2023

AbstractAlthough the tropics harbor the greatest species richness globally, recent work has demonstrated that, for many taxa, speciation rates are faster at higher latitudes. Here, we explore lability in oceanic depth as a potential mechanism for this pattern in the most biodiverse vertebrates – fishes. We demonstrate that clades with the highest speciation rates also diversify more rapidly along the depth gradient, drawing a fundamental link between evolutionary and ecological processes on a global scale. Crucially, these same clades also inhabit higher latitudes, creating a prevailing latitudinal gradient of deep-sea invasions concentrated in poleward regions. We interpret these findings in the light of classic ecological theory, unifying the latitudinal variation of oceanic features and the physiological tolerances of the species living there. This work advances the understanding of how niche lability sculpts global patterns of species distributions and underscores the vulnerability of polar ecosystems to changing environmental conditions.
Photonic comb-rooted synthesis of ultra-stable terahertz frequencies
Authors: Shin Dong-Chel , Kim Byung Soo , Jang Heesuk , Kim Young-Jin , Kim Seung-Woo 
Published: February 2023

AbstractStable terahertz sources are required to advance high-precision terahertz applications such as molecular spectroscopy, terahertz radars, and wireless communications. Here, we demonstrate a photonic scheme of terahertz synthesis devised to bring the well-established feat of optical frequency comb stabilization down to the terahertz region. The source comb is stabilized to an ultra-low expansion optical cavity offering a frequency instability of 10−15 at 1-s integration. By photomixing a pair of comb lines extracted coherently from the source comb, terahertz frequencies of 0.10–1.10 THz are generated with an extremely low level of phase noise of –70 dBc/Hz at 1-Hz offset. The frequency instability measured for 0.66 THz is 4.4 × 10−15 at 1-s integration, which reduces to 5.1×10−17 at 65-s integration. Such unprecedented performance is expected to drastically improve the signal-to-noise ratio of terahertz radars, the resolving power of terahertz molecular spectroscopy, and the transmission capacity of wireless communications.
A cooperative nano-CRISPR scaffold potentiates immunotherapy via activation of tumour-intrinsic pyroptosis
Authors: Wang Ning , Liu Chao , Li Yingjie , Huang Dongxue , Wu Xinyue , Kou Xiaorong , Wang Xiye , Wu Qinjie , Gong Changyang 
Published: February 2023

AbstractEfficient cancer immunotherapy depends on selective targeting of high bioactivity therapeutic agents to the tumours. However, delivering exogenous medication might prove difficult in clinical practice. Here we report a cooperative Nano-CRISPR scaffold (Nano-CD) that utilizes a specific sgRNA, selected from a functional screen for triggering endogenous GDSME expression, while releasing cisplatin to initiate immunologic cell death. Mechanistically, cascade-amplification of the antitumor immune response is prompted by the adjuvantic properties of the lytic intracellular content and enhanced by the heightened GDSME expression, resulting in pyroptosis and the release of tumor associated antigens. Neither of the single components provide efficient tumour control, while tumor growth is efficiently inhibited in primary and recurrent melanomas due to the combinatorial effect of cisplatin and self-supplied GSDME. Moreover, Nano-CD in combination with checkpoint blockade creates durable immune memory and strong systemic anti-tumor immune response, leading to disease relapse prevention, lung metastasis inhibition and increased survival in mouse melanomas. Taken together, our therapeutic approach utilizes CRISPR-technology to enable cell-intrinsic protein expression for immunotherapy, using GDSME as prototypic immune modulator. This nanoplatform thus can be applied to modulate further immunological processes for therapeutic benefit.
Murine neonatal cardiac B cells promote cardiomyocyte proliferation and heart regeneration
Authors: Tan Yong , Duan Xuewen , Wang Bo , Liu Xingguang , Zhan Zhenzhen 
Published: February 2023

AbstractThe irreversible loss of cardiomyocytes in the adult heart following cardiac injury leads to adverse cardiac remodeling and ventricular dysfunction. However, the role of B cells in cardiomyocyte proliferation and heart regeneration has not been clarified. Here, we found that the neonatal mice with B cell depletion showed markedly reduced cardiomyocyte proliferation, leading to cardiac dysfunction, fibrosis scar formation, and the complete failure of heart regeneration after apical resection. B cell depletion also significantly impaired heart regeneration and cardiac function in neonatal mice following myocardial infarction (MI). However, B cell depletion in adult mice suppressed tissue inflammation, inhibited myocardial fibrosis, and improved cardiac function after MI. Interestingly, B cell depletion partially restricted cardiomyocyte proliferation in adult mice post-MI. Single-cell RNA sequencing showed that cardiac B cells possessed a more powerful ability to inhibit inflammatory responses and enhance angiogenesis in the postnatal day 1 (P1) mice compared with P7 and adult mice. Besides, the proportion of cardioprotective B cell clusters with high expression levels of S100a6 (S100 calcium-binding protein A6) and S100a4 (S100 calcium-binding protein A4) was greatly decreased in adult heart tissues compared with neonatal mice after cardiac damage. Thus, our study discovers that cardiac B cells in neonatal mice are required for cardiomyocyte proliferation and heart regeneration, while adult B cells promote inflammation and impair cardiac function after myocardial injury.