bluuebunny/crossref_metadata_2025_split huggingface dataset:
ZNF582 overexpression restrains the progression of clear cell renal cell carcinoma by enhancing the binding of TJP2 and ERK2 and inhibiting ERK2 phosphorylation
Authors: Yang Wuping , Zhang Zedan , Li Lei , Zhang Kenan , Xu Yawei , Xia Mancheng , Zhou Jingcheng , Gong Yanqing , Chen Jinchao , Gong Kan 
Published: March 2023

AbstractRecent evidences have suggested that Zinc finger protein 582 (ZNF582) plays different important roles in various tumors, but its clinical role, biological function and regulatory mechanism in clear cell renal cell carcinoma (ccRCC) are still vague. Through analyzing GEO and TCGA-KIRC data and validation with local samples, we identified the low expression pattern of ZNF582 in ccRCC. Decreased ZNF582 expression is correlated with higher tumor stage and grade, distant metastasis and poor prognosis. By analyzing the DNA methylation data of ccRCC in TCGA-KIRC and using Massarray DNA methylation and demethylation analysis, we confirmed the hypermethylation status of ZNF582 in ccRCC and its negative regulation on ZNF582 expression. Using cell phenotype experiments and orthotopic kidney tumor growth models, we determined the inhibitory effect of ZNF582 overexpression on ccRCC growth and metastasis in vivo and in vitro. Mechanistically, using TMT (Tandem mass tags) quantitative proteomics test, Co-IP (Co-immunoprecipitation) and Western Blot experiments, we clarified that ZNF582 binds to TJP2 and up-regulates TJP2 protein expression. Increased TJP2 protein combines with ERK2 to promote ERK2 protein expression and suppresses the phosphorylation of ERK2, thereby inhibiting the growth and metastasis of ccRCC. In general, our findings provide the first solid theoretical rationale for targeting ZNF582/TJP2/ERK2 axis to improve ccRCC treatment.
The endocannabinoid system promotes hepatocyte progenitor cell proliferation and maturation by modulating cellular energetics
Authors: Mukhopadhyay Bani , Holovac Kellie , Schuebel Kornel , Mukhopadhyay Partha , Cinar Resat , Iyer Sindhu , Marietta Cheryl , Goldman David , Kunos George 
Published: March 2023

AbstractThe proliferation and differentiation of hepatic progenitor cells (HPCs) drive the homeostatic renewal of the liver under diverse conditions. Liver regeneration is associated with an increase in Axin2+Cnr1+ HPCs, along with a marked increase in the levels of the endocannabinoid anandamide (AEA). But the molecular mechanism linking AEA signaling to HPC proliferation and/or differentiation has not been explored. Here, we show that in vitro exposure of HPCs to AEA triggers both cell cycling and differentiation along with increased expression of Cnr1, Krt19, and Axin2. Mechanistically, we found that AEA promotes the nuclear localization of the transcription factor β-catenin, with subsequent induction of its downstream targets. Systemic analyses of cells after CRISPR-mediated knockout of the β-catenin-regulated transcriptome revealed that AEA modulates β-catenin-dependent cell cycling and differentiation, as well as interleukin pathways. Further, we found that AEA promotes OXPHOS in HPCs when amino acids and glucose are readily available as substrates, but AEA inhibits it when the cells rely primarily on fatty acid oxidation. Thus, the endocannabinoid system promotes hepatocyte renewal and maturation by stimulating the proliferation of Axin2+Cnr1+ HPCs via the β-catenin pathways while modulating the metabolic activity of their precursor cells.
Genomic characterization of DICER1-associated neoplasms uncovers molecular classes
Authors: Kommoss Felix K. F. , Chong Anne-Sophie , Chong Anne-Laure , Pfaff Elke , Jones David T. W. , Hiemcke-Jiwa Laura S. , Kester Lennart A. , Flucke Uta , Gessler Manfred , Schrimpf Daniel , Sahm Felix , Clarke Blaise A. , Stewart Colin J. R. , Wang Yemin , Gilks C. Blake , Kommoss Friedrich , Huntsman David G. , Schüller Ulrich , Koelsche Christian , McCluggage W. Glenn , von Deimling Andreas , Foulkes William D. 
Published: March 2023

AbstractDICER1 syndrome is a tumor predisposition syndrome that is associated with up to 30 different neoplastic lesions, usually affecting children and adolescents. Here we identify a group of mesenchymal tumors which is highly associated with DICER1 syndrome, and molecularly distinct from other DICER1-associated tumors. This group of DICER1-associated mesenchymal tumors encompasses multiple well-established clinicopathological tumor entities and can be further divided into three clinically meaningful classes designated “low-grade mesenchymal tumor with DICER1 alteration” (LGMT DICER1), “sarcoma with DICER1 alteration” (SARC DICER1), and primary intracranial sarcoma with DICER1 alteration (PIS DICER1). Our study not only provides a combined approach to classify DICER1-associated neoplasms for improved clinical management but also suggests a role for global hypomethylation and other recurrent molecular events in sarcomatous differentiation in mesenchymal tumors with DICER1 alteration. Our results will facilitate future investigations into prognostication and therapeutic approaches for affected patients.
Coastal El Niño triggers rapid marine silicate alteration on the seafloor
Authors: Geilert Sonja , Frick Daniel A. , Garbe-Schönberg Dieter , Scholz Florian , Sommer Stefan , Grasse Patricia , Vogt Christoph , Dale Andrew W. 
Published: March 2023

AbstractMarine silicate alteration plays a key role in the global carbon and cation cycles, although the timeframe of this process in response to extreme weather events is poorly understood. Here we investigate surface sediments across the Peruvian margin before and after extreme rainfall and runoff (coastal El Niño) using Ge/Si ratios and laser-ablated solid and pore fluid Si isotopes (δ30Si). Pore fluids following the rainfall show elevated Ge/Si ratios (2.87 µmol mol−1) and δ30Si values (3.72‰), which we relate to rapid authigenic clay formation from reactive terrigenous minerals delivered by continental runoff. This study highlights the direct coupling of terrestrial erosion and associated marine sedimentary processes. We show that marine silicate alteration can be rapid and highly dynamic in response to local weather conditions, with a potential impact on marine alkalinity and CO2-cycling on short timescales of weeks to months, and thus element turnover on human time scales.
Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics
Authors: Zhang Danyang , Lape Remigijus , Shaikh Saher A. , Kohegyi Bianka K. , Watson Jake F. , Cais Ondrej , Nakagawa Terunaga , Greger Ingo H. 
Published: March 2023

AbstractAMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an opportunity for the development of selective therapeutics. AMPARs associated with TARP γ8 are enriched in the hippocampus, and are targets of emerging anti-epileptic drugs. To understand their therapeutic activity, we determined cryo-EM structures of the GluA1/2-γ8 receptor associated with three potent, chemically diverse ligands. We find that despite sharing a lipid-exposed and water-accessible binding pocket, drug action is differentially affected by binding-site mutants. Together with patch-clamp recordings and MD simulations we also demonstrate that ligand-triggered reorganisation of the AMPAR-TARP interface contributes to modulation. Unexpectedly, one ligand (JNJ-61432059) acts bifunctionally, negatively affecting GluA1 but exerting positive modulatory action on GluA2-containing AMPARs, in a TARP stoichiometry-dependent manner. These results further illuminate the action of TARPs, demonstrate the sensitive balance between positive and negative modulatory action, and provide a mechanistic platform for development of both positive and negative selective AMPAR modulators.
Unnatural activities and mechanistic insights of cytochrome P450 PikC gained from site-specific mutagenesis by non-canonical amino acids
Authors: Pan Yunjun , Li Guobang , Liu Ruxin , Guo Jiawei , Liu Yunjie , Liu Mingyu , Zhang Xingwang , Chi Luping , Xu Kangwei , Wu Ruibo , Zhang Yuzhong , Li Yuezhong , Gao Xiang , Li Shengying 
Published: March 2023

AbstractCytochrome P450 enzymes play important roles in the biosynthesis of macrolide antibiotics by mediating a vast variety of regio- and stereoselective oxidative modifications, thus improving their chemical diversity, biological activities, and pharmaceutical properties. Tremendous efforts have been made on engineering the reactivity and selectivity of these useful biocatalysts. However, the 20 proteinogenic amino acids cannot always satisfy the requirement of site-directed/random mutagenesis and rational protein design of P450 enzymes. To address this issue, herein, we practice the semi-rational non-canonical amino acid mutagenesis for the pikromycin biosynthetic P450 enzyme PikC, which recognizes its native macrolide substrates with a 12- or 14-membered ring macrolactone linked to a deoxyamino sugar through a unique sugar-anchoring mechanism. Based on a semi-rationally designed substrate binding strategy, non-canonical amino acid mutagenesis at the His238 position enables the unnatural activities of several PikC mutants towards the macrolactone precursors without any sugar appendix. With the aglycone hydroxylating activities, the pikromycin biosynthetic pathway is rewired by the representative mutant PikCH238pAcF carrying a p-acetylphenylalanine residue at the His238 position and a promiscuous glycosyltransferase. Moreover, structural analysis of substrate-free and three different enzyme-substrate complexes of PikCH238pAcF provides significant mechanistic insights into the substrate binding and catalytic selectivity of this paradigm biosynthetic P450 enzyme.
Quantum structural fluxion in superconducting lanthanum polyhydride
Authors: Wang Hui , Salzbrenner Pascal T. , Errea Ion , Peng Feng , Lu Ziheng , Liu Hanyu , Zhu Li , Pickard Chris J. , Yao Yansun 
Published: March 2023

AbstractThe discovery of 250-kelvin superconducting lanthanum polyhydride under high pressure marked a significant advance toward the realization of a room‐temperature superconductor. X-ray diffraction (XRD) studies reveal a nonstoichiometric LaH9.6 or LaH10±δ polyhydride responsible for the superconductivity, which in the literature is commonly treated as LaH10 without accounting for stoichiometric defects. Here, we discover significant nuclear quantum effects (NQE) in this polyhydride, and demonstrate that a minor amount of stoichiometric defects will cause quantum proton diffusion in the otherwise rigid lanthanum lattice in the ground state. The diffusion coefficient reaches ~10−7 cm2/s in LaH9.63 at 150 gigapascals and 240 kelvin, approaching the upper bound value of interstitial hydrides at comparable temperatures. A puzzling phenomenon observed in previous experiments, the positive pressure dependence of the superconducting critical temperature Tc below 150 gigapascals, is explained by a modulation of the electronic structure due to a premature distortion of the hydrogen lattice in this quantum fluxional structure upon decompression, and resulting changes of the electron-phonon coupling. This finding suggests the coexistence of the quantum proton fluxion and hydrogen-induced superconductivity in this lanthanum polyhydride, and leads to an understanding of the structural nature and superconductivity of nonstoichiomectric hydrogen-rich materials.
An aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer’s disease
Authors: Lau Victor , Ramer Leanne , Tremblay Marie-Ève 
Published: March 2023

AbstractAlzheimer’s disease (AD) predominantly occurs as a late onset (LOAD) form involving neurodegeneration and cognitive decline with progressive memory loss. Risk factors that include aging promote accumulation of AD pathologies, such as amyloid-beta and tau aggregates, as well as inflammation and oxidative stress. Homeostatic glial states regulate and suppress pathology buildup; inflammatory states exacerbate pathology by releasing pro-inflammatory cytokines. Multiple stresses likely induce glial senescence, which could decrease supportive functions and reinforce inflammation. In this perspective, we hypothesize that aging first drives AD pathology burden, whereafter AD pathology putatively induces glial senescence in LOAD. We hypothesize that increasing glial senescence, particularly local senescent microglia accumulation, sustains and drives perpetuating buildup and spread of AD pathologies, glial aging, and further senescence. We predict that increasing glial senescence, particularly local senescent microglia accumulation, also transitions individuals from healthy cognition into mild cognitive impairment and LOAD diagnosis. These pathophysiological underpinnings may centrally contribute to LOAD onset, but require further mechanistic investigation.
Continuous Spatiotemporal Therapy of A Full-API Nanodrug via Multi-Step Tandem Endogenous Biosynthesis
Authors: Fang Fang , Wang Sa , Song Yueyue , Sun Meng , Chen Wen-Cheng , Zhao Dongxu , Zhang Jinfeng 
Published: March 2023

AbstractNanomedicine holds great promise to enhance cancer therapy. However, low active pharmaceutical ingredient (API) loading content, unpredictable drug release, and potential toxicity from excipients limit their translational capability. We herein report a full-API nanodrug composed of FDA-approved 5-aminolevulinic acid (ALA), human essential element Fe3+, and natural bioactive compound curcumin with an ideal API content and pH-responsive release profile for continuous spatiotemporal cancer therapy achieved by multi-step tandem endogenous biosynthesis. First, ALA enzymatically converts into photosensitizer protoporphyrin IX (PpIX). Afterward, multiple downstream products including carbon monoxide (CO), Fe2+, biliverdin (BV), and bilirubin (BR) are individually biosynthesized through the PpIX-heme-CO/Fe2+/BV-BR metabolic pathway, further cooperating with released Fe3+ and curcumin, ultimately eliciting mitochondria damage, membrane disruption, and intracytoplasmic injury. This work not only provides a paradigm for exploiting diversified metabolites for tumor suppression, but also presents a safe and efficient full-API nanodrug, facilitating the practical translation of nanodrugs.
Lacking mechanistic disease definitions and corresponding association data hamper progress in network medicine and beyond
Authors: Sadegh Sepideh , Skelton James , Anastasi Elisa , Maier Andreas , Adamowicz Klaudia , Möller Anna , Kriege Nils M. , Kronberg Jaanika , Haller Toomas , Kacprowski Tim , Wipat Anil , Baumbach Jan , Blumenthal David B. 
Published: March 2023

AbstractA long-term objective of network medicine is to replace our current, mainly phenotype-based disease definitions by subtypes of health conditions corresponding to distinct pathomechanisms. For this, molecular and health data are modeled as networks and are mined for pathomechanisms. However, many such studies rely on large-scale disease association data where diseases are annotated using the very phenotype-based disease definitions the network medicine field aims to overcome. This raises the question to which extent the biases mechanistically inadequate disease annotations introduce in disease association data distort the results of studies which use such data for pathomechanism mining. We address this question using global- and local-scale analyses of networks constructed from disease association data of various types. Our results indicate that large-scale disease association data should be used with care for pathomechanism mining and that analyses of such data should be accompanied by close-up analyses of molecular data for well-characterized patient cohorts.
Clonal origin and development of high hyperdiploidy in childhood acute lymphoblastic leukaemia
Authors: Woodward Eleanor L. , Yang Minjun , Moura-Castro Larissa H. , van den Bos Hilda , Gunnarsson Rebeqa , Olsson-Arvidsson Linda , Spierings Diana C. J. , Castor Anders , Duployez Nicolas , Zaliova Marketa , Zuna Jan , Johansson Bertil , Foijer Floris , Paulsson Kajsa 
Published: March 2023

AbstractHigh hyperdiploid acute lymphoblastic leukemia (HeH ALL), one of the most common childhood malignancies, is driven by nonrandom aneuploidy (abnormal chromosome numbers) mainly comprising chromosomal gains. In this study, we investigate how aneuploidy in HeH ALL arises. Single cell whole genome sequencing of 2847 cells from nine primary cases and one normal bone marrow reveals that HeH ALL generally display low chromosomal heterogeneity, indicating that they are not characterized by chromosomal instability and showing that aneuploidy-driven malignancies are not necessarily chromosomally heterogeneous. Furthermore, most chromosomal gains are present in all leukemic cells, suggesting that they arose early during leukemogenesis. Copy number data from 577 primary cases reveals selective pressures that were used for in silico modeling of aneuploidy development. This shows that the aneuploidy in HeH ALL likely arises by an initial tripolar mitosis in a diploid cell followed by clonal evolution, in line with a punctuated evolution model.
Neutron-encoded diubiquitins to profile linkage selectivity of deubiquitinating enzymes
Authors: van Tol Bianca D. M. , van Doodewaerd Bjorn R. , Lageveen-Kammeijer Guinevere S. M. , Jansen Bas C. , Talavera Ormeño Cami M. P. , Hekking Paul J. M. , Sapmaz Aysegul , Kim Robbert Q. , Moutsiopoulou Angeliki , Komander David , Wuhrer Manfred , van der Heden van Noort Gerbrand J. , Ovaa Huib , Geurink Paul P. 
Published: March 2023

AbstractDeubiquitinating enzymes are key regulators in the ubiquitin system and an emerging class of drug targets. These proteases disassemble polyubiquitin chains and many deubiquitinases show selectivity for specific polyubiquitin linkages. However, most biochemical insights originate from studies of single diubiquitin linkages in isolation, whereas in cells all linkages coexist. To better mimick this diubiquitin substrate competition, we develop a multiplexed mass spectrometry-based deubiquitinase assay that can probe all ubiquitin linkage types simultaneously to quantify deubiquitinase activity in the presence of all potential diubiquitin substrates. For this, all eight native diubiquitins are generated and each linkage type is designed with a distinct molecular weight by incorporating neutron-encoded amino acids. Overall, 22 deubiquitinases are profiled, providing a three-dimensional overview of deubiquitinase linkage selectivity over time and enzyme concentration.
Atmospheric CO2 forcing on Mediterranean biomes during the past 500 kyrs
Authors: Koutsodendris Andreas , Dakos Vasilis , Fletcher William J. , Knipping Maria , Kotthoff Ulrich , Milner Alice M. , Müller Ulrich C. , Kaboth-Bahr Stefanie , Kern Oliver A. , Kolb Laurin , Vakhrameeva Polina , Wulf Sabine , Christanis Kimon , Schmiedl Gerhard , Pross Jörg 
Published: March 2023

AbstractThere is growing concern on the survival of Mediterranean forests under the projected near-future droughts as a result of anthropogenic climate change. Here we determine the resilience of Mediterranean forests across the entire range of climatic boundary conditions realized during the past 500 kyrs based on continuous pollen and geochemical records of (sub)centennial-scale resolution from drillcores from Tenaghi Philippon, Greece. Using convergent cross-mapping we provide empirical confirmation that global atmospheric carbon dioxide (CO2) may affect Mediterranean vegetation through forcing on moisture availability. Our analysis documents two stable vegetation regimes across the wide range of CO2and moisture levels realized during the past four glacial-interglacial cycles, with abrupt shifts from forest to steppe biomes occurring when a threshold in precipitation is crossed. Our approach highlights that a CO2-driven moisture decrease in the near future may bear an impending risk for abrupt vegetation regime shifts prompting forest loss in the Mediterranean region.
The genomic landscape of reference genomes of cultivated human gut bacteria
Authors: Lin Xiaoqian , Hu Tongyuan , Chen Jianwei , Liang Hewei , Zhou Jianwei , Wu Zhinan , Ye Chen , Jin Xin , Xu Xun , Zhang Wenwei , Jing Xiaohuan , Yang Tao , Wang Jian , Yang Huanming , Kristiansen Karsten , Xiao Liang , Zou Yuanqiang 
Published: March 2023

AbstractCulture-independent metagenomic studies have revolutionized our understanding of the gut microbiota. However, the lack of full genomes from cultured species is still a limitation for in-depth studies of the gut microbiota. Here we present a substantially expanded version of our Cultivated Genome Reference (CGR), termed CGR2, providing 3324 high-quality draft genomes from isolates selected from a large-scale cultivation of bacterial isolates from fecal samples of healthy Chinese individuals. The CGR2 classifies 527 species (179 previously unidentified species) from 8 phyla, and uncovers a genomic and functional diversity of Collinsella aerofaciens. The CGR2 genomes match 126 metagenome-assembled genomes without cultured representatives in the Unified Human Gastrointestinal Genome (UHGG) collection and harbor 3767 unidentified secondary metabolite biosynthetic gene clusters, providing a source of natural compounds with pharmaceutical potentials. We uncover accurate phage–bacterium linkages providing information on the evolutionary characteristics of interaction between bacteriophages and bacteria at the strain level.
Organic electrochemical transistors as on-site signal amplifiers for electrochemical aptamer-based sensing
Authors: Ji Xudong , Lin Xuanyi , Rivnay Jonathan 
Published: March 2023

AbstractElectrochemical aptamer-based sensors are typically deployed as individual, passive, surface-functionalized electrodes, but they exhibit limited sensitivity especially when the area of the electrode is reduced for miniaturization purposes. We demonstrate that organic electrochemical transistors (electrolyte gated transistors with volumetric gating) can serve as on-site amplifiers to improve the sensitivity of electrochemical aptamer-based sensors. By monolithically integrating an Au working/sensing electrode, on-chip Ag/AgCl reference electrode, and Poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) counter electrode — also serving as the channel of an organic electrochemical transistor— we can simultaneously perform testing of organic electrochemical transistors and traditional electroanalytical measurement on electrochemical aptamer-based sensors including cyclic voltammetry and square-wave voltammetry. This device can directly amplify the current from the electrochemical aptamer-based sensor via the in-plane current modulation in the counter electrode/transistor channel. The integrated sensor can sense transforming growth factor beta 1 with 3 to 4 orders of magnitude enhancement in sensitivity compared to that in an electrochemical aptamer-based sensor (292 μA/dec vs. 85 nA/dec). This approach is believed to be universal, and can be applied to a wide range of tethered electrochemical reporter-based sensors to enhance sensitivity, aiding in sensor miniaturization and easing the burden on backend signal processing.