bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery, in-vitro and in-vivo efficacy of an anti-inflammatory small molecule inhibitor of C-reactive protein
Authors: Zeller Johannes , Shing Karen Cheung Tung , Nero Tracy , Krippner Guy , McFadyen James , Bogner Balazs , Kreuzaler Sheena , Kiefer Jurij , Horner Verena , Braig David , Kather Michel , Kammerer Bernd , Woollard Kevin , Sharma Prerna , Morton Craig , Pietersz Geoffrey , Parker Michael , Peter Karlheinz , Eisenhardt Steffen 
Published: October 2021

Abstract
C-reactive protein (CRP) is an acute phase protein. We recently identified a novel mechanism that leads to a conformational change from the native, pentameric structure (pCRP) to a pentameric intermediate (pCRP*) and ultimately to the monomeric form, mCRP, both being highly pro-inflammatory. This ‘CRP activation’ is mediated by binding of pCRP to activated/damaged cell membranes via exposed phosphocholine (PC) lipid head groups. We designed a low molecular weight pCRP – PC inhibitor, C10M. Binding assays and X-ray crystallography revealed direct, competitive binding of C10M to pCRP, blocking interaction with PC and thereby inhibiting formation of pCRP*/mCRP and their pro-inflammatory effects. The anti-inflammatory potential of C10M was confirmed in-vitro by various measures of leukocyte and endothelial cell activation and in-vivo in rat models of acute ischemia/reperfusion injury and hindlimb transplantation. In conclusion, inhibition of pCRP*/mCRP generation via the PC-mimicking compound C10M represents a promising, potentially broadly applicable anti-inflammatory therapy.
Microarray Analysis And Functional Prediction Of Differentially-Expressed Circular RNAs In Acquired Middle Ear Choleateatoma
Authors: Xie Shumin , Jin Li , Yin Tuanfang , Ren Jihao , Liu Wei 
Published: October 2021

Abstract
Background: Middle ear cholesteatoma is characterized by hyper-proliferation of keratinocytes. Circular RNA (circRNA) plays an essential role in the pathogenesis of many proliferative diseases. However, the role of circRNA in the etiopathogenesis of middle ear cholesteatoma is rarely investigated so far. Our aim was to investigate the differential expression profiling of circRNAs between acquired middle ear cholesteatoma and normal skin, and to indentify potential circRNAs contributing to the etiopathogenesis of middle ear cholesteatoma. Microarray analysis and functional prediction were performed to investigate the circRNA expression profiling between middle ear cholesteatoma and normal skin. Validation of differentially expressed circRNAs was conducted by qRT-PCR. Prediction of m6A modification was also carried out. Results: Microarray analysis displayed that totally 93 up-regulated and 85 down-regulated circRNAs were identified in middle ear cholesteatoma. Through validation, expressions of hsa_circRNA_104327 and hsa_circRNA_404655 were significantly higher, while hsa_circRNA_000319 was significantly down-regulated in cholesteatoma. GO classification, KEGG pathway, and ceRNA network analyses suggested that these differentially expressed circRNAs might play importantant roles in the etiopathogenesis of middle ear cholesteatoma. Prediction of m6A modification exhibited that hsa_circRNA_000319 possessed 4 m6A sites with very high confidence, and hsa_circRNA_404655 had 3 m6A sites with high confidence.Conclusions: Our study indicated possible roles of differentially expressed circRNAs in the etiopathogenesis of middle ear cholesteatoma. Targeting on these differentially expressed circRNAs may provide a new and effective treatment for middle ear cholesteatoma in the future.
PGM1 Suppresses Colorectal Cancer Cell Migration And Invasion by Regulating PI3K/ AKT Pathway
Authors: Zheng Zhewen , Zhang Xue , Bai Jian , Long Long , Liu Di , Zhou Yunfeng 
Published: October 2021

Abstract
BackgroundPhosphoglucomutase 1(PGM1) is known for its involvement in cancer pathogenesis. However, its biological role in colorectal cancer (CRC) is unknown. Here, we studied the functions and mechanisms of PGM1 in CRC.Methods We verified PGM-1 as a DEG by a comprehensive strategy of the TCGA-COAD dataset mining and computational biology. Relative levels of PGM-1 in CRC tumors and adjoining peritumoral tissue were identified by qRT-PCR, WB, and IHC staining in a tissue microarray. PGM1 functions were analyzed using CCK8, EdU, colony formation, cell cycle, apoptosis, and Transwell migration and invasion assays. The influence of PGM1 was further investigated using tumor formation in vivo.ResultsPGM1 mRNA and protein were both reduced in CRC and the reduction was related to CRC pathology and overall survival. PGM1 knockdown stimulated both proliferation and colony formation, promoting cell cycle arrest and apoptosis while overexpression has opposite effects in CRC cells both in vivo and in vitro. Furthermore, we lined the actions of PGM1 to the PI3K/ AKT pathway. ConclusionWe verified that PGM1 suppresses CRC through the PI3K/ AKT pathway. These results suggest the potential for targeting PGM1 in CRC therapies.
Mutation analysis of second primary tumors in head and neck cancer in Taiwanese patients through next-generation sequencing
Authors: Liu Ting-Yuan , Lee Chien-Chin , Chen Yu-Chia , Chang Ya-Sian , Huang Hsi-Yuan , Lee Ya-Ting , Yen Ju-Chen , Chao Dysan , Chang Jan-Gowth 
Published: October 2021

Abstract
Head and neck cancer has poor overall survival. Patients with head and neck cancer more frequently develop second primary tumors than do patients with other cancers, leading to a poor prognosis. In this study, we used next-generation sequencing to analyze and compare mutations between first tumors and second tumors in head and neck cancer. We retrieved tumor tissues collected from 15 patients who were diagnosed twice as having cancer. We used driver gene and trunk mutations to distinguish between recurrent cancer and primary cancer in oral cancer. We observed unique driver gene mutations in three patients with an initial clinical diagnosis of recurrent cancer; hence, we believe that the corresponding patients had primary cancer. Four patients with an initial clinical diagnosis of primary cancer were found to actually have recurrent cancer according to our results. Three (75%) patients with recurrent cancer demonstrated NUP98 mutations. NUP98 mutations may be a new biomarker for diagnosing recurrent oral cancer. Genetic testing can be used to enhance the accuracy of clinical diagnosis.
Improving Genetic Knowledge Among Physicians: A Necessity in the Era of Genomic Medicine
Authors: Hureaux Marguerite , Watson Sarah 
Published: October 2021

Abstract
Background: Genetic analyses have experienced rapid development over the past decades. This evolution is accompanied by a considerable increase in indications in clinical practice. As a result, physicians are exposed to prescribing and understanding genetics results in their daily practice. The objective was to assess the knowledge of young physicians on new genetic techniques and their expectations concerning molecular biology education. Methods: This study is based on the results of an anonymized questionnaire on genetics knowledge sent to young French physicians specialized in medical oncology, radiation therapy, and clinical hematology in France; and on a retrospective analysis of nonconformities to requirements of the ISO 15189 accreditation standard in genetics samples from a Parisian university hospital center. Results: Of the 87 young physicians (median age 29, 58.6% female) who responded to the survey, 60.3% did not differentiate several standard molecular biology techniques. Median Visual Analog Scale for theoretical knowledge of standard genetic technics was 35/100 (IQR 20-56). Median Visual Analogical Scale for genetics diagnostic and theragnostic indications knowledge were 50/100 (IQR 31.2-70) and 43/100 (IQR 19.2-65), respectively. Proficiency in genetics results interpretation was assessed with a Median Visual Analog Scale of 47/100 (IQR 23.25-69). Finally, 82.4% of young physicians believed that the current teaching of molecular biology was not suited to their current practice and 91.9% requested a specific training implementation. These results were supported by the high rate of nonconformities regarding the prescription (43%) among the different types of nonconformities of genetics samples.Conclusion: Medical education on new techniques of genetics by young French physicians appears to be insufficient, and a specific training should be considered. A better knowledge of this discipline is necessary in order to control the clinical, ethical and financial issues associated with the exponential use of molecular biology in medicine.
pKAI: a fast and interpretable deep learning approach for accurate electrostatics-driven pKa predictions
Authors: Reis Pedro , Bertolini Marco , Montanari Floriane , Rocchia Walter , Machuqueiro Miguel , Clevert Djork-Arné 
Published: October 2021

Abstract
The pKa values of ionizable residues influence protein folding, stability and biological function. The pKa in bulk water is known for all residues, however, in a protein environment, it can significantly be affected by confinement and electrostatics. Existing computational methods to estimate pKa shifts rely on theoretical approximations and lengthy computations. Furthermore, the amount of experimentally determined pKa values is still very limited, hindering the development of faster machine learning-based methods. In this work, we use a data set of 6 million pKa shifts — determined by PypKa, a continuum electrostatics method — to train deep learning models that are shown to rival the physics-based predictor. On ~750 experimentally determined data points, our model displays the best accuracy and it is the only one that breaks the 1 pK unit RMSE barrier of this considerably difficult test set. Although trained using a very simplified view of the surroundings of the titratable group (namely, atom types and distances to other titratable groups within a given radius), the models are shown to assign proper electrostatic charges to chemical groups, to keep the known correlation between solvent exposure and pKa shift magnitude, and to grasp the importance of close interactions, including hydrogen bonds. Inference times allow speedups of more than 1000 times faster than physics-based methods, especially for large proteins. By combining speed, accuracy and a reasonable understanding of the theoretical basis for pKa shifts, our models provide a game-changing solution for fast estimations of macroscopic pKa from ensembles of microscopic (pKhalf) values as well as for many downstream applications such as molecular docking and constant-pH molecular dynamics simulations.
Psychological Stress of Parents of Children With Atopic Dermatitis: The Korea National Health and Nutrition Examination Survey
Authors: Lee Hyun Ji , Lee Gyu-Na , Lee Ji Hyun , Han Ju Hee , Han Kyungdo , Park Young Min 
Published: October 2021

Abstract
Background: Atopic dermatitis (AD) is a chronically relapsing inflammatory skin condition that has profound impacts on patient and family quality of life.Objectives: To investigate the psychological stress of parents of children with AD in Korea using data from the Korean National Health and Nutrition Examination Survey (KNHANES).Methods: The cross-sectional study included parents of 8,575 participants under age 19 (970 with AD and 5,733 without AD) from the 2009–2012 KNHANES. Self-perception of stress, depressed mood, suicidal ideation, and diagnosis of depression by a physician were assessed for determination of psychological distress. Results: After adjusting for age, gender, education level, occupation, and marital status, logistic regression analyses indicated that mothers of children with AD showed higher frequency of stress perception (adjusted odds ratio [aOR] 1.458 [95% confidence interval (CI), 1.223-1.739], p < 0.0001) and suicide ideation (aOR 1.403 [95% CI 1.099-1.791], p = 0.0066) than those without AD. In contrast, fathers of children with AD did not show a significant difference compared to those of children without AD.Conclusions: Understanding the psychological stress of parents of children with AD is important for clinicians as evaluation, management, and support for parents, especially mothers, of children with AD are required.
Ketogenic Diet Ameliorates Lipid Dysregulation in Type 2 Diabetic Mice by Downregulating Hepatic Pescadillo 1
Authors: Zhou Jielin , Lu Yao , Jia Yajing , Lu Jing , Jiang Zhengxuan , Chen Keyang 
Published: October 2021

Abstract
Background: Previous reports implied a possible link between PES1 and lipid metabolism. However, the role of PES1 in regulation of T2DM related lipid metabolism and the effect of KD on PES1 have not been reported. The aim of present study is to explore the role of PES1 in effects of ketogenic diet (KD) on diabetic mice and its mediated mechanism.Methods: Male C57BL/6J and KKAy mice were fed with standard diet (SD) and KD, respectively. Simultaneously, McArdle 7777 cells were treated by β-hydroxybutyric acid (β-HB), Pes1 siRNA or Pes1 overexpression plasmid, respectively. Additionally, liver-conditional knockout (CKO) of Pes1 in vivo were used.Results: We unexpectedly found that hepatic PES1 expression in T2DM patients was markedly elevated, but the elevated PES1 was suppressed by KD feeding in T2DM mice with the reduction of hepatic and plasma triglycerides (TG). In mice with CKO of Pes1, the protein levels of p300, SREBP1c, FASN, SCD1, caspase1, NLRP3 and GSDMD were dramatically downregulated in livers, and the plasma and hepatic TG, IL-1β and IL-18 were decreased as well. The similar phenomena were also observed in β-HB and Pes1 knockdown treated hepatocytes. By contrast, Pes1 overexpression in cultured hepatocytes showed that these levels were significantly enhanced, which however were reduced under β-HB treatment. Mechanistically, we discovered that β-HB decreased CHOP binding to the Pes1 promoters, resulting in the downregulation of PES1, thereby reducing PES1 binding to p300 and caspase1 promoters. The inhibition of p300 and caspase1 expressions elicited the dramatic suppression of acetylation of SREBP1c via its interaction with p300, and the decreased GSDMD levels. Besides, knockdown of caspase1 also alleviated the TG levels in cultured hepatocytes.Conclusion: KD may improve lipid dysregulation in type 2 diabetic mice by downregulating hepatic PES1 expression.
Simultaneous Determination of Eight New Generation Amide Insecticide Residues in Complex Matrix Agri-food by Multi-walled Carbon Nanotube Cleanup and UPLC-MS/MS
Authors: Lin Tao , Chen Xinglian , Wang Li , Fang Haixian , Li Maoxuan , Li Yangang , Liu Hongcheng 
Published: October 2021

Abstract
The simultaneous determination method of 8 amide pesticides by multi-walled carbon nanotubes (MWCNs) cleanup, combined with QuEChERS method and ultra-high performance liquid chromatography-triple quadrupole tandem mass spectrometry has been developed and successfully applied in complex matrix such as green onions, celery, leeks, citrus, lychees, avocado. The matric effect of MWCNs is optimized and compared with QuEChERS materials. The results show that MWCNs can effectively reduce the matrix effect in sample extraction. The mass spectrometry is optimized, through their chemical structure skeletons, the ESI+ and ESI- mode are simultaneously scanned in the method. The coefficient (r) is greater than 0.9990, the limit of quantification ranges from 0.03 to 0.80 μg/kg, the recovery rate ranges from 71.2% to 120%, and the relative standard deviation (RSD) ranges from 3.8% to 9.4%. The method is fast, simple, sensitive, and has good purification effect. It is suitable for the rapid determination of amide pesticides in complex matrix agri-food.
A universal framework for featurization of atomistic systems
Authors: Lei Xiangyun , Medford Andrew 
Published: October 2021

Abstract
Molecular dynamics simulations are an invaluable tool in numerous scientific fields. However, the ubiquitous classical force fields cannot describe reactive systems, and quantum molecular dynamics are too computationally demanding to treat large systems or long timescales. Reactive force fields based on physics or machine learning can be used to bridge the gap in time and length scales, but these force fields require substantial effort to construct and are highly specific to a given chemical composition and application. A significant limitation of machine learning models is the use of element-specific features, leading to models that scale poorly with the number of elements. This work introduces the Gaussian multipole (GMP) featurization scheme that utilizes physically-relevant multipole expansions of the electron density around atoms to yield feature vectors that interpolate between element types and have a fixed dimension regardless of the number of elements present. We combine GMP with neural networks to directly compare it to the widely used Behler-Parinello symmetry functions for the MD17 dataset, revealing that it exhibits improved accuracy and computational efficiency. Further, we demonstrate that GMP-based models can achieve chemical accuracy for the QM9 dataset, and their accuracy remains reasonable even when extrapolating to new elements. Finally, we test GMP-based models for the Open Catalysis Project (OCP) dataset, revealing comparable performance to graph convolutional deep learning models. The results indicate that this featurization scheme fills a critical gap in the construction of efficient and transferable machine-learned force fields.
Base Editing of Human Pluripotent Stem Cells for modeling Long QT syndrome
Authors: Wu Fujian , Guo Tianwei , Sun Lixiang , Li Furong , Yang Xiaofei 
Published: October 2021

Abstract
Human pluripotent stem cells (hPSCs) have great potential for disease modeling, drug discovery, and regenerative medicine as they can differentiate into many different functional cell types via directed differentiation. However, the application of disease modeling is limited due to a time-consuming and labor-intensive process of introducing known pathogenic mutations into hPSCs. Base editing is a newly developed technology that enables the facile introduction of point mutations into specific loci within the genome of living cells without unwanted genome injured. We describe an optimized stepwise protocol to introduce disease-specific mutations of long QT syndrome (LQTs) into hPSCs. We highlight technical issues, especially those associated with introducing a point mutation to obtain isogenic hPSCs without inserting any resistance cassette and reproducible cardiomyocyte differentiation. Based on the protocol, we succeeded in getting hPSCs carrying LQTs pathogenic mutation with excellent efficiency (21.7 % of heterozygous clones, 9.1 % of homozygous clones) in less than 20 days. In addition, we also provide protocols to analyze electrophysiological of hPSC-derived cardiomyocytes using multi-electrode arrays. This protocol is also applicable to introduce other disease-specific mutations into hPSCs.
Ultrafast Demagnetization Excited by Extreme Ultraviolet Light From a Free-Electron Laser
Authors: Philippi-Kobs André , Müller Leonard , Berntsen Magnus , Roseker Wojciech , Riepp Matthias , Bagschik Kai , Wagner Jochen , Frömter Robert , Danailov Miltcho , Capotondi Flavio , Pedersoli Emanuele , Manfredda Michele , Kiskinova Maya , Stransky Michal , Lipp Vladimir , Scherz Andreas , Ziaja Beata , Oepen Hans , Grübel Gerhard 
Published: October 2021

Abstract
Ultrashort and intense extreme ultraviolet (XUV) and X-ray pulses readily available at free-electron lasers (FELs) enable studying non-linear light−matter interactions on femtosecond timescales. Here, we report on the non-linear fluence dependence of magnetic scattering of Co/Pt multilayers, using FERMI FEL’s 70-fs-long single and double XUV pulses, the latter with a temporal separation of 200 fs, with a photon energy slightly detuned to the Co M2,3 absorption edge. We observe a quenching in magnetic scattering that sets-in already in the non-destructive fluence regime of a few mJ/cm² typically used for FEL-probe experiments on magnetic materials. Calculations of the transient electronic structure in tandem with a phenomenological modeling of the experimental data by means of ultrafast demagnetization unambiguously show that XUV-radiation-induced demagnetization is the dominant mechanism for the quenching in the investigated fluence regime of <50 mJ/cm², while light-induced changes of the electronic core levels are predicted to additionally occur at higher fluences. The modeling of the data further indicates that the demagnetization proceeds on the sub-20-fs timescale. This ultrashort timescale is consistent with non-coherent models for ultrafast demagnetization, considering the sub-femtosecond lifetime of hot electrons with energies of a few 10 eV generated by the XUV radiation.
Successful Management of a 29-Day-Old Infant with Severe Hyperlipidemia from a Novel Homozygous Variant of GPIHBP1 Gene
Authors: Liu Shu , Wang Zhiqing , Zheng Xianhua , Zhang Ye , Wei Sisi , OuYang Haimei , Liang Jinqun , Chen Nuan , Zeng Weihong , Jiang Jianhui 
Published: October 2021

Abstract
Background: Severe hyperlipidemia is characterized by markedly elevated blood triglyceride levels and severe early-onset cardiovascular diseases, pancreatitis, pancreatic necrosis or persistent multiple organ failure if left untreated. It is a rare autosomal recessive metabolic disorder originated from the variants of lipoprotein lipase gene, and previous studies have demonstrated that most cases with severe hyperlipidemia are closely related to the variants of some key genes for lipolysis, such as LPL, APOC2, APOA5, LMF1 and GPIHBP1. Meanwhile, other unidentified causes also exist and are equally worthy of attention.Methods: The 29-day-old infant was diagnosed with severe hyperlipidemia, registering a plasma triglyceride level as high as 25.46 mmol/L. Whole exome sequencing was conducted to explore the possible pathogenic gene variants for this patient.Results: The infant was put on a low-fat diet combined with pharmacological therapy, which was successful in restraining the level of serum triglyceride and total cholesterol to a low to medium range during the follow-ups. The patient was found to be a rare novel homozygous duplication variant—c.45_48dupGCGG (Pro17Alafs*22) in GPIHBP1 gene—leading to a frameshift which failed to form the canonical termination codon TGA. The mutant messenger RNA should presumably produce a peptide consisting of 16 amino acids at the N-terminus, with 21 novel amino acids on the heels of the wild-type protein.Conclusions: Our study expands on the spectrum of GPIHBP1 variants and contributes to a more comprehensive understanding of the genetic diagnosis, genetic counseling, and multimodality therapy of families with severe hyperlipidemia. Our experience gained in this study is also contributory to a deeper insight into severe hyperlipidemia and highlights the importance of molecular genetic tests.