bluuebunny/crossref_metadata_2025_split huggingface dataset:
Salt-inducible kinases inhibitor HG-9-91-01 targets RIPK3 kinase activity to alleviate necroptosis-mediated inflammatory injury
Authors: Huang Dongxuan , Chen Pengfei , Huang Guoqing , Sun Huimin , Luo Xiaohua , He Chaowen , Chen Fei , Wang Yong , Zeng Changchun , Su Lianhui , Zeng Xiaobin , Lu Jiachun , Li Shiyue , Huang Dongsheng , Gao Hanchao , Cao Mengtao 
Published: February 2022

AbstractReceptor-interacting protein kinase 3 (RIPK3) functions as a central regulator of necroptosis, mediating signaling transduction to activate pseudokinase mixed lineage kinase domain-like protein (MLKL) phosphorylation. Increasing evidences show that RIPK3 contributes to the pathologies of inflammatory diseases including multiple sclerosis, infection and colitis. Here, we identified a novel small molecular compound Salt-inducible Kinases (SIKs) inhibitor HG-9-91-01 inhibiting necroptosis by targeting RIPK3 kinase activity. We found that SIKs inhibitor HG-9-91-01 could block TNF- or Toll-like receptors (TLRs)-mediated necroptosis independent of SIKs. We revealed that HG-9-91-01 dramatically decreased cellular activation of RIPK3 and MLKL. Meanwhile, HG-9-91-01 inhibited the association of RIPK3 with MLKL and oligomerization of downstream MLKL. Interestingly, we found that HG-9-91-01 also trigger RIPK3-RIPK1-caspase 1-caspase 8-dependent apoptosis, which activated cleavage of GSDME leading to its dependent pyroptosis. Mechanistic studies revealed that SIKs inhibitor HG-9-91-01 directly inhibited RIPK3 kinase activity to block necroptosis and interacted with RIPK3 and recruited RIPK1 to activate caspases leading to cleave GSDME. Importantly, mice pretreated with HG-9-91-01 showed resistance to TNF-induced systemic inflammatory response syndrome. Consistently, HG-9-91-01 treatment protected mice against Staphylococcus aureus-mediated lung damage through targeting RIPK3 kinase activity. Overall, our results revealed that SIKs inhibitor HG-9-91-01 is a novel inhibitor of RIPK3 kinase and a potential therapeutic target for the treatment of necroptosis-mediated inflammatory diseases.
Oxethazaine inhibits esophageal squamous cell carcinoma proliferation and metastasis by targeting aurora kinase A
Authors: Bao Zhuo , Li Ang , Lu Xuebo , Wang Zitong , Yu Yin , Wu Wenjie , Zhao Lili , Li Bo , Wu Xiangyu , Laster Kyle Vaughn , Zhang Chengjuan , Jiang Yanan , Dong Zigang , Liu Kangdong 
Published: February 2022

AbstractEsophageal squamous cell carcinoma (ESCC), a malignant neoplasm with high incidence, is a severe global public health threat. The current modalities used for treating ESCC include surgery, chemotherapy, and radiotherapy. Although ESCC management and treatment strategies have improved over the last decade, the overall 5-year survival rate remains <20%. Therefore, the identification of novel therapeutic strategies that can increase ESCC patient survival rates is urgently needed. Oxethazaine, an amino-amide anesthetic agent, is mainly prescribed in combination with antacids to relieve esophagitis, dyspepsia, and other gastric disorders. In the present study, we found that oxethazaine inhibited the proliferation and migration of esophageal cancer cells. According to the results of in vitro screening and binding assays, oxethazaine binds directly to AURKA, suppresses AURKA activity, and inhibits the downstream effectors of AURKA. Notably, we found that oxethazaine suppressed tumor growth in three patient-derived esophageal xenograft mouse models and tumor metastasis in vivo. Our findings suggest that oxethazaine can inhibit ESCC proliferation and metastasis in vitro and in vivo by targeting AURKA.
m6A methyltransferase KIAA1429 acts as an oncogenic factor in colorectal cancer by regulating SIRT1 in an m6A-dependent manner
Authors: Zhou Yuan , Pei Zhengda , Maimaiti Aizezi , Zheng Linyi , Zhu Zhongcheng , Tian Mengxiang , Zhou Zhongyi , Tan Fengbo , Pei Qian , Li Yuqiang , Liu Wenxue 
Published: February 2022

AbstractN6-methyladenosine (m6A) modifications of RNAs are involved in various aspects of colorectal carcinogenesis via regulation of mRNA stability, splicing, and translation. KIAA1429, an m6A methyltransferase, was found deregulated in multiple cancer types. However, its role in colorectal cancer remains elusive. By analyzing TCGA and GEPIA database, we found that KIAA1429 in colorectal cancer was highly expressed. In addition, we used immunohistochemistry, western blotting, and QRT-PCR to detect the expression of KIAA1429 in colorectal cancer samples and cell lines, and we found that KIAA1429 was overexpressed in colorectal cancer sample and cell line. Functionally, silencing of KIAA1429 by shRNA in colorectal cancer cell lines resulted in decreased cell proliferation, colony formation, and migration. On the contrary, overexpression of KIAA1429 increased cell proliferation, colony formation, and migration. Further mechanism analysis demonstrated that KIAA1429 increased the expression of SIRT1 via regulating its mRNA stability in an m6A-dependent manner. More importantly, in vivo experiment showed that depletion of KIAA1429 significantly inhibited colorectal tumor growth. In conclusion, our results suggested that the m6A methyltransferase KIAA1429 promotes the growth and motility of colorectal cancer and could be a potent therapeutic target.
Growth of two-dimensional Janus MoSSe by a single in situ process without initial or follow-up treatments
Authors: Jang Chan Wook , Lee Won Jun , Kim Jae Kuk , Park Sang Minh , Kim Sung , Choi Suk-Ho 
Published: February 2022

AbstractTwo-dimensional (2D) Janus transition metal dichalcogenides (TMDCs) are highly attractive as an emerging class of 2D materials, but only a few methods are available for fabricating them. These methods rely on the initial growth of 2D TMDCs in one process, followed by an additional plasma or high-temperature (T) process. To overcome these drawbacks, we employ the new approach of NaCl-assisted single-process chemical vapor deposition, which consists of three steps that proceed only by altering the temperature in situ. In the first step, MoS2 is deposited onto a SiO2/Si substrate with the Mo and S atoms activated in different temperature zones. In the second step, S vacancies are formed in the upper layer of the grown MoS2 by annealing. In the third step, the vacancies are filled with activated Se atoms. Throughout the steps, NaCl lowers the melting point of the constituent atoms, while the T in each zone is properly controlled. The growth mechanism is clarified by a separate annealing experiment that does not involve a supply of activated atoms. These results highlight a simple and cost-effective approach for growing Janus MoSSe, which is more useful for fundamental studies and device applications.
Ferroelastic oligocrystalline microwire with unprecedented high-temperature superelastic and shape memory effects
Authors: Chen Zhen , Cong Daoyong , Ren Yang , Zhang Yin , Yan Haile , You Li , Song Chao , Li Shaohui , Cao Yuxian , Li Shengwei , Zuo Changchang , Wang Li , Gao Zhiyong , Cai Wei , Wang Yandong 
Published: February 2022

AbstractA compelling demand exists for high-performance high-temperature shape memory alloys (HTSMAs) that can be applied as intelligent components in the rapidly developing aerospace, robotics, manufacturing, and energy exploration industries. However, existing HTSMAs are handicapped by their high cost and unsatisfactory functional properties, which impede their practical application. Here, by using the strategy of creating an oligocrystalline structure, we have developed a high-performance, cost-effective high-temperature shape memory microwire exhibiting an exceptional combination of superb superelasticity with a large recoverable strain of up to 15%, an outstanding one-way shape memory effect with a maximum recoverable strain as high as 13% and a remarkable two-way shape memory effect with a large recoverable strain of 6.3%. These unparalleled comprehensive properties provide this microwire with a high potential for use in high-temperature actuation, sensing, and energy conversion applications, especially in miniature intelligent devices, such as high-temperature microelectromechanical systems. The present strategy may be universally applicable to other brittle phase-transforming alloys for achieving outstanding functional properties at high temperatures.
Hemoglobinopathy prevention in primary care: a reflection of underdetection and difficulties with accessibility of medical care, a quantitative study
Authors: van Vliet Margo E. , Kerkhoffs Jean-Louis H. , Harteveld Cornelis L. , Houwink Elisa J. F. 
Published: February 2022

AbstractAs in most Northern European countries, the prevalence of hemoglobinopathies in The Netherlands is increasing due to migration. Although hemoglobinopathies are severe chronic diseases with few treatment options, timely detection of carriers allows at-risk couples to make informed reproductive choices such as pre-implantation diagnosis, prenatal diagnosis or termination of affected pregnancies. Using a quantitative design, we evaluated the prevalence of hemoglobinopathies in The Hague region, The Netherlands. Patient and carrier registries from hospital, laboratory and general practitioners allowed this quantitative analysis. The highest prevalence of hemoglobinopathies was seen in immigrant neighborhoods, and a large gap was noted between estimated carrier prevalence and the actual registration of carriers in electronic patient records. Carrier prevalence was estimated to be 13,704; however, the ELAN database contains only 1542 cases with ICPC codes for sickle cell disease or thalassemia. Although more research is needed to define the requirements of the healthcare system to address this challenge, this study clearly shows the gap between estimated carrier prevalence and registration and thereby the pressing need for action.
Quantifying arousal and awareness in altered states of consciousness using interpretable deep learning
Authors: Lee Minji , Sanz Leandro R. D. , Barra Alice , Wolff Audrey , Nieminen Jaakko O. , Boly Melanie , Rosanova Mario , Casarotto Silvia , Bodart Olivier , Annen Jitka , Thibaut Aurore , Panda Rajanikant , Bonhomme Vincent , Massimini Marcello , Tononi Giulio , Laureys Steven , Gosseries Olivia , Lee Seong-Whan 
Published: February 2022

AbstractConsciousness can be defined by two components: arousal (wakefulness) and awareness (subjective experience). However, neurophysiological consciousness metrics able to disentangle between these components have not been reported. Here, we propose an explainable consciousness indicator (ECI) using deep learning to disentangle the components of consciousness. We employ electroencephalographic (EEG) responses to transcranial magnetic stimulation under various conditions, including sleep (n = 6), general anesthesia (n = 16), and severe brain injury (n = 34). We also test our framework using resting-state EEG under general anesthesia (n = 15) and severe brain injury (n = 34). ECI simultaneously quantifies arousal and awareness under physiological, pharmacological, and pathological conditions. Particularly, ketamine-induced anesthesia and rapid eye movement sleep with low arousal and high awareness are clearly distinguished from other states. In addition, parietal regions appear most relevant for quantifying arousal and awareness. This indicator provides insights into the neural correlates of altered states of consciousness.
A putative cap binding protein and the methyl phosphate capping enzyme Bin3/MePCE function in telomerase biogenesis
Authors: Páez-Moscoso Diego J. , Ho David V. , Pan Lili , Hildebrand Katie , Jensen Kristi L. , Levy Michaella J. , Florens Laurence , Baumann Peter 
Published: February 2022

AbstractTelomerase reverse transcriptase (TERT) and the noncoding telomerase RNA (TR) subunit constitute the core of telomerase. Additional subunits are required for ribonucleoprotein complex assembly and in some cases remain stably associated with the active holoenzyme. Pof8, a member of the LARP7 protein family is such a constitutive component of telomerase in fission yeast. Using affinity purification of Pof8, we have identified two previously uncharacterized proteins that form a complex with Pof8 and participate in telomerase biogenesis. Both proteins participate in ribonucleoprotein complex assembly and are required for wildtype telomerase activity and telomere length maintenance. One factor we named Thc1 (Telomerase Holoenzyme Component 1) shares structural similarity with the nuclear cap binding complex and the poly-adenosine ribonuclease (PARN), the other is the ortholog of the methyl phosphate capping enzyme (Bin3/MePCE) in metazoans and was named Bmc1 (Bin3/MePCE 1) to reflect its evolutionary roots. Thc1 and Bmc1 function together with Pof8 in recognizing correctly folded telomerase RNA and promoting the recruitment of the Lsm2-8 complex and the catalytic subunit to assemble functional telomerase.
Molecular recognition of formylpeptides and diverse agonists by the formylpeptide receptors FPR1 and FPR2
Authors: Zhuang Youwen , Wang Lei , Guo Jia , Sun Dapeng , Wang Yue , Liu Weiyi , Xu H. Eric , Zhang Cheng 
Published: February 2022

AbstractThe formylpeptide receptors (FPRs) mediate pattern recognition of formylated peptides derived from invading pathogens or mitochondria from dead host cells. They can also sense other structurally distinct native peptides and even lipid mediators to either promote or resolve inflammation. Pharmacological targeting of FPRs represents a novel therapeutic approach in treating inflammatory diseases. However, the molecular mechanisms underlying FPR ligand recognition are elusive. We report cryo-EM structures of Gi-coupled FPR1 and FPR2 bound to a formylpeptide and Gi-coupled FPR2 bound to two synthetic peptide and small-molecule agonists. Together with mutagenesis data, our structures reveal the molecular mechanism of formylpeptide recognition by FPRs and structural variations of FPR1 and FPR2 leading to their different ligand preferences. Structural analysis also suggests that diverse FPR agonists sample a conserved activation chamber at the bottom of ligand-binding pockets to activate FPRs. Our results provide a basis for rational drug design on FPRs.
The E3 ubiquitin-protein ligase Trim31 alleviates non-alcoholic fatty liver disease by targeting Rhbdf2 in mouse hepatocytes
Authors: Xu Minxuan , Tan Jun , Dong Wei , Zou Benkui , Teng Xuepeng , Zhu Liancai , Ge Chenxu , Dai Xianling , Kuang Qin , Zhong Shaoyu , Lai Lili , Yi Chao , Tang Tingting , Zhao Junjie , Wang Longyan , Liu Jin , Wei Hao , Sun Yan , Yang Qiufeng , Li Qiang , Lou Deshuai , Hu Linfeng , Liu Xi , Kuang Gang , Luo Jing , Xiong Mingxin , Feng Jing , Zhang Chufeng , Wang Bochu 
Published: February 2022

AbstractSystemic metabolic syndrome significantly increases the risk of morbidity and mortality in patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). However, no effective therapeutic strategies are available, practically because our understanding of its complicated pathogenesis is poor. Here we identify the tripartite motif-containing protein 31 (Trim31) as an endogenous inhibitor of rhomboid 5 homolog 2 (Rhbdf2), and we further determine that Trim31 directly binds to Rhbdf2 and facilitates its proteasomal degradation. Hepatocyte-specific Trim31 ablation facilitates NAFLD-associated phenotypes in mice. Inversely, transgenic or ex vivo gene therapy-mediated Trim31 gain-of-function in mice with NAFLD phenotypes virtually alleviates severe deterioration and progression of steatohepatitis. The current findings suggest that Trim31 is an endogenous inhibitor of Rhbdf2 and downstream cascades in the pathogenic process of steatohepatitis and that it may serve as a feasible therapeutical target for the treatment of NAFLD/NASH and associated metabolic disorders.
Cryo-EM structure of translesion DNA synthesis polymerase ζ with a base pair mismatch
Authors: Malik Radhika , Johnson Robert E. , Prakash Louise , Prakash Satya , Ubarretxena-Belandia Iban , Aggarwal Aneel K. 
Published: February 2022

AbstractThe B-family multi-subunit DNA polymerase ζ (Polζ) is important for translesion DNA synthesis (TLS) during replication, due to its ability to extend synthesis past nucleotides opposite DNA lesions and mismatched base pairs. We present a cryo-EM structure of Saccharomyces cerevisiae Polζ with an A:C mismatch at the primer terminus. The structure shows how the Polζ active site responds to the mismatched duplex DNA distortion, including the loosening of key protein-DNA interactions and a fingers domain in an “open” conformation, while the incoming dCTP is still able to bind for the extension reaction. The structure of the mismatched DNA-Polζ ternary complex reveals insights into mechanisms that either stall or favor continued DNA synthesis in eukaryotes.
Dark matter from axion strings with adaptive mesh refinement
Authors: Buschmann Malte , Foster Joshua W. , Hook Anson , Peterson Adam , Willcox Don E. , Zhang Weiqun , Safdi Benjamin R. 
Published: February 2022

AbstractAxions are hypothetical particles that may explain the observed dark matter density and the non-observation of a neutron electric dipole moment. An increasing number of axion laboratory searches are underway worldwide, but these efforts are made difficult by the fact that the axion mass is largely unconstrained. If the axion is generated after inflation there is a unique mass that gives rise to the observed dark matter abundance; due to nonlinearities and topological defects known as strings, computing this mass accurately has been a challenge for four decades. Recent works, making use of large static lattice simulations, have led to largely disparate predictions for the axion mass, spanning the range from 25 microelectronvolts to over 500 microelectronvolts. In this work we show that adaptive mesh refinement simulations are better suited for axion cosmology than the previously-used static lattice simulations because only the string cores require high spatial resolution. Using dedicated adaptive mesh refinement simulations we obtain an over three order of magnitude leap in dynamic range and provide evidence that axion strings radiate their energy with a scale-invariant spectrum, to within ~5% precision, leading to a mass prediction in the range (40,180) microelectronvolts.
A mechanism of origin licensing control through autoinhibition of S. cerevisiae ORC·DNA·Cdc6
Authors: Schmidt Jan Marten , Yang Ran , Kumar Ashish , Hunker Olivia , Seebacher Jan , Bleichert Franziska 
Published: February 2022

AbstractThe coordinated action of multiple replicative helicase loading factors is needed for the licensing of replication origins prior to DNA replication. Binding of the Origin Recognition Complex (ORC) to DNA initiates the ATP-dependent recruitment of Cdc6, Cdt1 and Mcm2-7 loading, but the structural details for timely ATPase site regulation and for how loading can be impeded by inhibitory signals, such as cyclin-dependent kinase phosphorylation, are unknown. Using cryo-electron microscopy, we have determined several structures of S. cerevisiae ORC·DNA·Cdc6 intermediates at 2.5–2.7 Å resolution. These structures reveal distinct ring conformations of the initiator·co-loader assembly and inactive ATPase site configurations for ORC and Cdc6. The Orc6 N-terminal domain laterally engages the ORC·Cdc6 ring in a manner that is incompatible with productive Mcm2-7 docking, while deletion of this Orc6 region alleviates the CDK-mediated inhibition of Mcm7 recruitment. Our findings support a model in which Orc6 promotes the assembly of an autoinhibited ORC·DNA·Cdc6 intermediate to block origin licensing in response to CDK phosphorylation and to avert DNA re-replication.
Understanding self-assembly at molecular level enables controlled design of DNA G-wires of different properties
Authors: Pavc Daša , Sebastian Nerea , Spindler Lea , Drevenšek-Olenik Irena , Podboršek Gorazd Koderman , Plavec Janez , Šket Primož 
Published: February 2022

AbstractA possible engineering of materials with diverse bio- and nano-applications relies on robust self-assembly of oligonucleotides. Bottom-up approach utilizing guanine-rich DNA oligonucleotides can lead to formation of G-wires, nanostructures consisting of continuous stacks of G-quartets. However, G-wire structure and self-assembly process remain poorly understood, although they are crucial for optimizing properties needed for specific applications. Herein, we use nuclear magnetic resonance to get insights at molecular level on how chosen short, guanine-rich oligonucleotides self-assemble into G-wires, whereas complementary methods are used for their characterization. Additionally, unravelling mechanistic details enable us to guide G-wire self-assembly in a controlled manner. MD simulations provide insight why loop residues with considerably different properties, i.e., hydrogen-bond affinity, stacking interactions, electronic effects and hydrophobicity extensively increase or decrease G-wire length. Our results provide fundamental understanding of G-wire self-assembly process useful for future design of nanomaterials with specific properties.
Winter wheat yield prediction using convolutional neural networks from environmental and phenological data
Authors: Srivastava Amit Kumar , Safaei Nima , Khaki Saeed , Lopez Gina , Zeng Wenzhi , Ewert Frank , Gaiser Thomas , Rahimi Jaber 
Published: February 2022

AbstractCrop yield forecasting depends on many interactive factors, including crop genotype, weather, soil, and management practices. This study analyzes the performance of machine learning and deep learning methods for winter wheat yield prediction using an extensive dataset of weather, soil, and crop phenology variables in 271 counties across Germany from 1999 to 2019. We proposed a Convolutional Neural Network (CNN) model, which uses a 1-dimensional convolution operation to capture the time dependencies of environmental variables. We used eight supervised machine learning models as baselines and evaluated their predictive performance using RMSE, MAE, and correlation coefficient metrics to benchmark the yield prediction results. Our findings suggested that nonlinear models such as the proposed CNN, Deep Neural Network (DNN), and XGBoost were more effective in understanding the relationship between the crop yield and input data compared to the linear models. Our proposed CNN model outperformed all other baseline models used for winter wheat yield prediction (7 to 14% lower RMSE, 3 to 15% lower MAE, and 4 to 50% higher correlation coefficient than the best performing baseline across test data). We aggregated soil moisture and meteorological features at the weekly resolution to address the seasonality of the data. We also moved beyond prediction and interpreted the outputs of our proposed CNN model using SHAP and force plots which provided key insights in explaining the yield prediction results (importance of variables by time). We found DUL, wind speed at week ten, and radiation amount at week seven as the most critical features in winter wheat yield prediction.