bluuebunny/crossref_metadata_2025_split huggingface dataset:
EDDM3A drives gastric cancer progression by promoting HIF-1α-dependent aerobic glycolysis
Authors: Wu Tao , Yang Ying , Zhang Bo , Zhang Zhan-sheng , Zhou Shuai , Jia Guo-zhan , Liu Shi-qi , He Xian-li , He Jia-xing , Wang Nan 
Published: January 2022

AbstractEpididymal protein 3A (EDDM3A) is a protein involved in sperm maturation. It has been demonstrated that EDDM3A expression is upregulated and promotes cell proliferation in non-small cell lung cancer (NSCLC). However, the role of EDDM3A in other types of human cancers, including gastric cancer (GC), is still unexplored. Here, we show that the expression of EDDM3A is significantly upregulated in gastric cancer (GC) tissues and its upregulation correlates with poorer survival in patients with gastric cancer. Knockdown of EDDM3A inhibited growth and metastasis of GC cells, whereas overexpression of EDDM3A exhibited the opposite effect. Mechanistically, enhanced aerobic glycolysis mediated by upregulation of HIF-1α and subsequently increased target glycolytic genes and decreased mitochondrial biogenesis was found to contribute to the promotion of tumor growth and metastasis by EDDM3A in GC cells. Additionally, upregulation of EDDM3A in GC is at least partially mediated by downregulation of miR-618. In conclusion, elevated EDDM3A plays a pivotal oncogenic role in gastric carcinogenesis, suggesting it as a potential therapeutic target for treatment of GC.
POLE2 facilitates the malignant phenotypes of glioblastoma through promoting AURKA-mediated stabilization of FOXM1
Authors: Zhang Peng , Chen Xu , Zhang LingYun , Cao Dan , Chen Yong , Guo ZhengQian , Chen Jian 
Published: January 2022

AbstractGlioblastoma (GBM) is a type of brain cancer with high morbidity and mortality worldwide. The clinical significance, biological roles, and underlying molecular mechanisms of DNA poly ε-B subunit (POLE2) in GBM were investigated in the study. Firstly, the Cancer Genome Atlas (TCGA) database found that POLE2 was highly expressed in GBM. Immunohistochemistry (IHC) results further confirmed that POLE2 was abnormally elevated in GBM. In addition, loss-of-function assays revealed that POLE2 knockdown could inhibit the malignant behaviors of GBM, especially reduce cell viability, weaken cell clone formation, enhance the sensitivity of apoptosis, restrain migration and inhibit epithelial-mesenchymal transition (EMT) in vitro. In vivo experiments further clarified the suppressive effects of reduced POLE2 expression on tumors. Mechanically, POLE2 knockdown promoted the ubiquitination as well as reduced the stability of Forkhead transcription factor (FOXM1), which is a known tumor promotor in GBM, through Aurora kinase A (AURKA). Moreover, the knockdown of FOXM1 could weaken the promoting effects of POLE2 on malignant behaviors of GBM. In conclusion, our study revealed crucial roles and a novel mechanism of POLE2 involved in GBM through AURKA-mediated stability of FOXM1 and may provide the theoretical basis of molecular therapy for GBM.
Pathological and therapeutic roles of bioactive peptide trefoil factor 3 in diverse diseases: recent progress and perspective
Authors: Yang Yiqi , Lin Ziyang , Lin Quanyou , Bei Weijian , Guo Jiao 
Published: January 2022

AbstractTrefoil factor 3 (TFF3) is the last small-molecule peptide found in the trefoil factor family, which is mainly secreted by intestinal goblet cells and exerts mucosal repair effect in the gastrointestinal tract. Emerging evidence indicated that the TFF3 expression profile and biological effects changed significantly in pathological states such as cancer, colitis, gastric ulcer, diabetes mellitus, non-alcoholic fatty liver disease, and nervous system disease. More importantly, mucosal protection would no longer be the only effect of TFF3, it gradually exhibits carcinogenic activity and potential regulatory effect of nervous and endocrine systems, but the inner mechanisms remain unclear. Understanding the molecular function of TFF3 in specific diseases might provide a new insight for the clinical development of novel therapeutic strategies. This review provides an up-to-date overview of the pathological effects of TFF3 in different disease and discusses the binding proteins, signaling pathways, and clinical application.
Cathelicidin hCAP18/LL-37 promotes cell proliferation and suppresses antitumor activity of 1,25(OH)2D3 in hepatocellular carcinoma
Authors: Zhang Huidan , Zhen Junai , Zhang Rong , Wanyan Yangke , Liu Kehang , Yuan Xueli , Tao Liping , Chen Yuqing 
Published: January 2022

AbstractCathelicidin hCAP18/LL-37 can resist infection from various pathogens and is an essential component of the human immune system. Accumulating evidence has indicated that hCAP18/LL-37 plays a tissue-specific role in human cancer. However, its function in hepatocellular carcinoma (HCC) is poorly understood. The present study investigated the effects of hCAP18/LL-37 on HCC in vitro and in vivo. Results showed that hCAP18/LL-37 overexpression significantly promoted the proliferation of cultured HCC cells and the growth of PLC/PRF-5 xenograft tumor. Transcriptome sequencing analyses revealed that the PI3K/Akt pathway was the most significant upregulated pathway induced by LL-37 overexpression. Further analysis demonstrated that hCAP18/LL-37 stimulated the phosphorylation of EGFR/HER2 and activated the PI3K/Akt pathway in HCC cells. Furthermore, stronger EGFR/HER2/Akt signals were observed in the PLC/PRF-5LL-37 xenograft tumor. Interestingly, even though the expression of hCAP18/LL-37 was significantly downregulated in HCC cells and tumors, 1,25(OH)2D3 treatment significantly upregulated the hCAP18/LL-37 level both in HCC cells and xenograft tumors. Moreover, 1,25(OH)2D3 together with si-LL-37 significantly enhanced the antitumor activity of 1,25(OH)2D3 in the PLC/PRF-5 xenograft tumor. Collectively, these data suggest that hCAP18/LL-37 promotes HCC cells proliferation through stimulation of the EGFR/HER2/Akt signals and appears to suppress the antitumor activity of 1,25(OH)2D3 in HCC xenograft tumor. This implies that hCAP18/LL-37 may be an important target when aiming to improve the antitumor activity of 1,25(OH)2D3 supplementation therapy in HCC.
Idebenone improves motor dysfunction, learning and memory by regulating mitophagy in MPTP-treated mice
Authors: Yan Junqiang , Sun Wenjie , Shen Mengmeng , Zhang Yongjiang , Jiang Menghan , Liu Anran , Ma Hongxia , Lai Xiaoyi , Wu Jiannan 
Published: January 2022

AbstractThe progression of Parkinson’s disease (PD) is often accompanied by the loss of substantia nigra dopaminergic neurons, mitophagy damage, learning, and memory impairment. Idebenone is a therapeutic drug that targets the mitochondria of neurodegenerative diseases, but its role in Parkinson’s disease and its pathological mechanism are still unclear. The purpose of this study was to investigate whether idebenone could improve behavioral disorders, especially motor, learning, and memory disorders, in mouse PD models and to explore its molecular mechanism. In the present study, C57BL-6 mice underwent intraperitoneal injection of MPTP (30 mg/kg) once a day for five consecutive days. Then, a 200 mg/kg dose was given as a single daily gavage of idebenone dissolved in water for 21 days after the successful establishment of the subacute MPTP model. Motor, learning, and memory were measured by a water maze and a rotarod test. Our results showed that idebenone could reduce MPTP-induced dopaminergic neuron damage and improve movement disorders, memory, and learning ability, which may be associated with upregulating mitochondrial autophagy-related outer membrane proteins VDAC1 and BNIP3 and activating the Parkin/PINK1 mitochondrial autophagy pathway. To confirm whether idebenone promotes the smooth progression of autophagy, we used eGFP-mCherry-LC3 mice to construct a subacute model of Parkinson’s disease and found that idebenone can increase autophagy in dopaminergic neurons in Parkinson’s disease. In summary, our results confirm that idebenone can regulate the expression of the mitochondrial outer membrane proteins VDAC1 and BNIP3, activate Parkin/PINK1 mitophagy, promote the degradation of damaged mitochondria, reduce dopaminergic neuron damage, and improve behavioral disorders in Parkinson’s disease mice.
Neutrophils in chronic inflammatory diseases
Authors: Herrero-Cervera Andrea , Soehnlein Oliver , Kenne Ellinor 
Published: January 2022

AbstractChronic inflammation is a component of many disease conditions that affect a large group of individuals worldwide. Chronic inflammation is characterized by persistent, low-grade inflammation and is increased in the aging population. Neutrophils are normally the first responders to acute inflammation and contribute to the resolution of inflammation. However, in chronic inflammation, the role of neutrophils is less well understood and has been described as either beneficial or detrimental, causing tissue damage and enhancing the immune response. Emerging evidence suggests that neutrophils are important players in several chronic diseases, such as atherosclerosis, diabetes mellitus, nonalcoholic fatty liver disease and autoimmune disorders. This review will highlight the interaction of neutrophils with other cells in the context of chronic inflammation, the contribution of neutrophils to selected chronic inflammatory diseases, and possible future therapeutic strategies.
Microenvironmental influences on T cell immunity in cancer and inflammation
Authors: Heintzman Darren R. , Fisher Emilie L. , Rathmell Jeffrey C. 
Published: January 2022

AbstractT cell metabolism is dynamic and highly regulated. While the intrinsic metabolic programs of T cell subsets are integral to their distinct differentiation and functional patterns, the ability of cells to acquire nutrients and cope with hostile microenvironments can limit these pathways. T cells must function in a wide variety of tissue settings, and how T cells interpret these signals to maintain an appropriate metabolic program for their demands or if metabolic mechanisms of immune suppression restrain immunity is an area of growing importance. Both in inflamed and cancer tissues, a wide range of changes in physical conditions and nutrient availability are now acknowledged to shape immunity. These include fever and increased temperatures, depletion of critical micro and macro-nutrients, and accumulation of inhibitory waste products. Here we review several of these factors and how the tissue microenvironment both shapes and constrains immunity.
AI Pontryagin or how artificial neural networks learn to control dynamical systems
Authors: Böttcher Lucas , Antulov-Fantulin Nino , Asikis Thomas 
Published: January 2022

AbstractThe efficient control of complex dynamical systems has many applications in the natural and applied sciences. In most real-world control problems, both control energy and cost constraints play a significant role. Although such optimal control problems can be formulated within the framework of variational calculus, their solution for complex systems is often analytically and computationally intractable. To overcome this outstanding challenge, we present AI Pontryagin, a versatile control framework based on neural ordinary differential equations that automatically learns control signals that steer high-dimensional dynamical systems towards a desired target state within a specified time interval. We demonstrate the ability of AI Pontryagin to learn control signals that closely resemble those found by corresponding optimal control frameworks in terms of control energy and deviation from the desired target state. Our results suggest that AI Pontryagin is capable of solving a wide range of control and optimization problems, including those that are analytically intractable.
Premature commitment to uncertain decisions during human NMDA receptor hypofunction
Authors: Salvador Alexandre , Arnal Luc H. , Vinckier Fabien , Domenech Philippe , Gaillard Raphaël , Wyart Valentin 
Published: January 2022

AbstractMaking accurate decisions based on unreliable sensory evidence requires cognitive inference. Dysfunction of n-methyl-d-aspartate (NMDA) receptors impairs the integration of noisy input in theoretical models of neural circuits, but whether and how this synaptic alteration impairs human inference and confidence during uncertain decisions remains unknown. Here we use placebo-controlled infusions of ketamine to characterize the causal effect of human NMDA receptor hypofunction on cognitive inference and its neural correlates. At the behavioral level, ketamine triggers inference errors and elevated decision uncertainty. At the neural level, ketamine is associated with imbalanced coding of evidence and premature response preparation in electroencephalographic (EEG) activity. Through computational modeling of inference and confidence, we propose that this specific pattern of behavioral and neural impairments reflects an early commitment to inaccurate decisions, which aims at resolving the abnormal uncertainty generated by NMDA receptor hypofunction.
The three-dimensional structure of Epstein-Barr virus genome varies by latency type and is regulated by PARP1 enzymatic activity
Authors: Morgan Sarah M. , Tanizawa Hideki , Caruso Lisa Beatrice , Hulse Michael , Kossenkov Andrew , Madzo Jozef , Keith Kelsey , Tan Yinfei , Boyle Sarah , Lieberman Paul M. , Tempera Italo 
Published: January 2022

AbstractEpstein-Barr virus (EBV) persists in human B-cells by maintaining its chromatinized episomes within the nucleus. We have previously shown that cellular factor Poly [ADP-ribose] polymerase 1 (PARP1) binds the EBV genome, stabilizes CTCF binding at specific loci, and that PARP1 enzymatic activity correlates with maintaining a transcriptionally active latency program. To better understand PARP1’s role in regulating EBV latency, here we functionally characterize the effect of PARP enzymatic inhibition on episomal structure through in situ HiC mapping, generating a complete 3D structure of the EBV genome. We also map intragenomic contact changes after PARP inhibition to global binding of chromatin looping factors CTCF and cohesin across the EBV genome. We find that PARP inhibition leads to fewer total unique intragenomic interactions within the EBV episome, yet new chromatin loops distinct from the untreated episome are also formed. This study also illustrates that PARP inhibition alters gene expression at the regions where chromatin looping is most effected. We observe that PARP1 inhibition does not alter cohesin binding sites but does increase its frequency of binding at those sites. Taken together, these findings demonstrate that PARP has an essential role in regulating global EBV chromatin structure and latent gene expression.
Interfacial compatibility critically controls Ru/TiO2 metal-support interaction modes in CO2 hydrogenation
Authors: Zhou Jun , Gao Zhe , Xiang Guolei , Zhai Tianyu , Liu Zikai , Zhao Weixin , Liang Xin , Wang Leyu 
Published: January 2022

AbstractSupports can widely affect or even dominate the catalytic activity, selectivity, and stability of metal nanoparticles through various metal-support interactions (MSIs). However, underlying principles have not been fully understood yet, because MSIs are influenced by the composition, size, and facet of both metals and supports. Using Ru/TiO2 supported on rutile and anatase as model catalysts, we demonstrate that metal-support interfacial compatibility can critically control MSI modes and catalytic performances in CO2 hydrogenation. Annealing Ru/rutile-TiO2 in air can enhance CO2 conversion to methane resulting from enhanced interfacial coupling driven by matched lattices of RuOx with rutile-TiO2; annealing Ru/anatase-TiO2 in air decreases CO2 conversion and converts the product into CO owing to strong metal-support interaction (SMSI). Although rutile and anatase share the same chemical composition, we show that interfacial compatibility can basically modify metal-support coupling strength, catalyst morphology, surface atomic configuration, MSI mode, and catalytic performances of Ru/TiO2 in heterogeneous catalysis.
Land transpiration-evaporation partitioning errors responsible for modeled summertime warm bias in the central United States
Authors: Dong Jianzhi , Lei Fangni , Crow Wade T. 
Published: January 2022

AbstractEarth system models (ESMs) from the Coupled Model Intercomparison Project Phase 6 (CMIP6) experiment exhibit a well-known summertime warm bias in mid-latitude land regions – most notably in the central contiguous United States (CUS). The dominant source of this bias is still under debate. Using validated datasets and both coupled and off-line modeling, we find that the CUS summertime warm bias is driven by the incorrect partitioning of evapotranspiration (ET) into its canopy transpiration and soil evaporation components. Specifically, CMIP6 ESMs do not effectively use available rootzone soil moisture for summertime transpiration and instead rely excessively on shallow soil and canopy-intercepted water storage to supply ET. As such, expected summertime precipitation deficits in CUS induce a negative ET bias into CMIP6 ESMs and a corresponding positive temperature bias via local land-atmosphere coupling. This tendency potentially biases CMIP6 projections of regional water stress and summertime air temperature variability under elevated CO2 conditions.
Unprotected peptide macrocyclization and stapling via a fluorine-thiol displacement reaction
Authors: Islam Md Shafiqul , Junod Samuel L. , Zhang Si , Buuh Zakey Yusuf , Guan Yifu , Zhao Mi , Kaneria Kishan H. , Kafley Parmila , Cohen Carson , Maloney Robert , Lyu Zhigang , Voelz Vincent A. , Yang Weidong , Wang Rongsheng E. 
Published: January 2022

AbstractWe report the discovery of a facile peptide macrocyclization and stapling strategy based on a fluorine thiol displacement reaction (FTDR), which renders a class of peptide analogues with enhanced stability, affinity, cellular uptake, and inhibition of cancer cells. This approach enabled selective modification of the orthogonal fluoroacetamide side chains in unprotected peptides in the presence of intrinsic cysteines. The identified benzenedimethanethiol linker greatly promoted the alpha helicity of a variety of peptide substrates, as corroborated by molecular dynamics simulations. The cellular uptake of benzenedimethanethiol stapled peptides appeared to be universally enhanced compared to the classic ring-closing metathesis (RCM) stapled peptides. Pilot mechanism studies suggested that the uptake of FTDR-stapled peptides may involve multiple endocytosis pathways in a distinct pattern in comparison to peptides stapled by RCM. Consistent with the improved cell permeability, the FTDR-stapled lead Axin and p53 peptide analogues demonstrated enhanced inhibition of cancer cells over the RCM-stapled analogues and the unstapled peptides.
Single-molecule analysis of specificity and multivalency in binding of short linear substrate motifs to the APC/C
Authors: Hartooni Nairi , Sung Jongmin , Jain Ankur , Morgan David O. 
Published: January 2022

AbstractRobust regulatory signals in the cell often depend on interactions between short linear motifs (SLiMs) and globular proteins. Many of these interactions are poorly characterized because the binding proteins cannot be produced in the amounts needed for traditional methods. To address this problem, we developed a single-molecule off-rate (SMOR) assay based on microscopy of fluorescent ligand binding to immobilized protein partners. We used it to characterize substrate binding to the Anaphase-Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that triggers chromosome segregation. We find that SLiMs in APC/C substrates (the D box and KEN box) display distinct affinities and specificities for the substrate-binding subunits of the APC/C, and we show that multiple SLiMs in a substrate generate a high-affinity multivalent interaction. The remarkably adaptable substrate-binding mechanisms of the APC/C have the potential to govern the order of substrate destruction in mitosis.
Visualizing the evolution from Mott insulator to Anderson insulator in Ti-doped 1T-TaS2
Authors: Zhang Wenhao , Gao Jingjing , Cheng Li , Bu Kunliang , Wu Zongxiu , Fei Ying , Zheng Yuan , Wang Li , Li Fangsen , Luo Xuan , Liu Zheng , Sun Yuping , Yin Yi 
Published: January 2022

AbstractThe electronic evolution of doped Mott insulators has been extensively studied for decades in search of exotic physical phases. The proposed Mott insulator 1T-TaS2 provides an intriguing platform to study the electronic evolution via doping. Here we apply scanning tunneling microscopy (STM) to study the evolution in Ti-doped 1T-TaS2 at different doping levels. The doping Ti atom locally perturbs the electronic and spin state inside the doped star of David and induces a clover-shaped orbital texture at low-doping levels (x < 0.01). The insulator to metal transition occurs around a critical point x = 0.01, in which small metallic and large insulating domains coexist. The clover-shaped orbital texture emerges at a broader energy range, revealing a competition with the electron correlation. It transforms to a disorder-induced Anderson insulating behavior as doping increases. We directly visualize the trapped electrons in dI/dV conductance maps. The comprehensive study of the series of Ti-doped 1T-TaS2 deepens our understanding of the electronic state evolution in a doped strong-correlated system.
Epicardial slices: an innovative 3D organotypic model to study epicardial cell physiology and activation
Authors: Maselli D. , Matos R. S. , Johnson R. D. , Chiappini C. , Camelliti P. , Campagnolo P. 
Published: January 2022

AbstractThe epicardium constitutes an untapped reservoir for cardiac regeneration. Upon heart injury, the adult epicardium re-activates, leading to epithelial-to-mesenchymal transition (EMT), migration, and differentiation. While interesting mechanistic and therapeutic findings arose from lower vertebrates and rodent models, the introduction of an experimental system representative of large mammals would undoubtedly facilitate translational advancements. Here, we apply innovative protocols to obtain living 3D organotypic epicardial slices from porcine hearts, encompassing the epicardial/myocardial interface. In culture, our slices preserve the in vivo architecture and functionality, presenting a continuous epicardium overlaying a healthy and connected myocardium. Upon thymosin β4 treatment of the slices, the epicardial cells become activated, upregulating epicardial and EMT genes, resulting in epicardial cell mobilization and differentiation into epicardial-derived mesenchymal cells. Our 3D organotypic model enables to investigate the reparative potential of the adult epicardium, offering an advanced tool to explore ex vivo the complex 3D interactions occurring within the native heart environment.