bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative Assessment of Protons During the Solar Proton Events of September 2017
Authors: Pandya Megha , Bhaskara Veenadhari 
Published: September 2021

AbstractWe present multi‐spacecraft observations of the proton fluxes spanning from 1.5 to 433 MeV for the largest solar proton event of solar cycle 24, i.e., September 7 and 10, 2017. In September 2017, M5.5 flare on September 4, X9.3 flare on September 6 and X8.2 flare on September 10 gave rise to solar proton event when observed by near‐Earth spacecrafts. On September 7 and September 10, 2017, a strong enhancement in the proton intensities was observed by Advanced Composition Explorer (ACE) and WIND at L1 and Van Allen Probes, GOES‐15 and POES‐19 in the Earth's inner magnetosphere. Below geosynchronous orbit, Van Allen Probes and POES‐19 show that no significant proton flux was observed with energies 25 MeV on September 4, while the fluxes peaked 3 to 7‐times during September 7 and by times during the third proton flux event on September 10, 2017. Van Allen Probe‐A observation shows that the closest distance that solar proton fluxes could approach the Earth is ∼4.4 for 102.6 MeV energies on September 2017, while lower energy protons i.e., 25 MeV are observed deep up to ∼3.4 on September 2017. POES‐19 observations show that there is no particular magnetic local time (MLT) dependence of the solar proton flux and is symmetric everywhere at high and low latitudes. The measurements from multiple spacecrafts located in the different regions of the Earth's magnetosphere show that the increased level of solar proton flux population persisted for ∼2 days. Thus, we quantify the temporal flux variability in terms of ‐value, energy and MLT.
On the Westward Quasi‐8‐Day Planetary Waves in the Middle Atmosphere During Arctic Sudden Stratospheric Warmings
Authors: Qin Yusong , Gu Sheng‐Yang , Dou Xiankang , Teng Chen‐Ke‐Min , Li Huijun 
Published: September 2021

AbstractUsing the geopotential height measurements from the Aura Microwave Limb Sounder and the Sounding of the Atmosphere using Broadband Emission Radiometry instrument on the Thermosphere‐Ionosphere‐Mesosphere Energetics and Dynamics satellite, we found eight westward quasi‐8‐day wave (Q8DW) events with zonal wavenumber 1 (W1) during the Arctic sudden stratospheric warmings (SSWs) in 2005–2020. The W1 Q8DW perturbations are mainly confined to the middle and high latitudes in the Northern Hemisphere, and peak at ∼50–80 km. Specified Dynamics Whole Atmosphere Community Climate Model eXtended version simulations are utilized to reproduce the Q8DW activities. The diagnostic results indicate that the W1 Q8DWs originate from the high latitudes in the Northern Hemisphere stratosphere. Their excitation, propagation, and amplification are primarily influenced by the critical layers and baroclinic/barotropic instability, which are dependent on the background conditions during SSWs. Our statistical results show that the W1 planetary waves with periods shorter than 12 days during the Arctic SSWs are most frequently observed at the period of ∼8 days, which is significantly different from the climatological periods of the Rossby (1, 1) and (1, 2) normal modes (6.14 and 9.81 days, respectively). These results indicate that the W1 Q8DW may be a new wave mode. Finally, we found that the reversal (or deceleration) and the recovery of the zonal mean flow during SSWs can result in a zonally symmetric Q8DW, and the W1 Q8DW is likely the child wave generated by the nonlinear interaction between the stationary planetary wave with zonal wavenumber 1 and zonally symmetric Q8DW.
TCF7L2 lncRNA: a link between bipolar disorder and body mass index through glucocorticoid signaling
Authors: Liu Duan , Nguyen Thanh Thanh Le , Gao Huanyao , Huang Huaizhi , Kim Daniel C. , Sharp Brenna , Ye Zhenqing , Lee Jeong-Heon , Coombes Brandon J. , Ordog Tamas , Wang Liewei , Biernacka Joanna M. , Frye Mark A. , Weinshilboum Richard M. 
Published: September 2021

AbstractBipolar disorder (BD) and obesity are highly comorbid. We previously performed a genome-wide association study (GWAS) for BD risk accounting for the effect of body mass index (BMI), which identified a genome-wide significant single-nucleotide polymorphism (SNP) in the gene encoding the transcription factor 7 like 2 (TCF7L2). However, the molecular function of TCF7L2 in the central nervous system (CNS) and its possible role in the BD and BMI interaction remained unclear. In the present study, we demonstrated by studying human induced pluripotent stem cell (hiPSC)-derived astrocytes, cells that highly express TCF7L2 in the CNS, that the BD-BMI GWAS risk SNP is associated with glucocorticoid-dependent repression of the expression of a previously uncharacterized TCF7L2 transcript variant. That transcript is a long non-coding RNA (lncRNA-TCF7L2) that is highly expressed in the CNS but not in peripheral tissues such as the liver and pancreas that are involved in metabolism. In astrocytes, knockdown of the lncRNA-TCF7L2 resulted in decreased expression of the parent gene, TCF7L2, as well as alterations in the expression of a series of genes involved in insulin signaling and diabetes. We also studied the function of TCF7L2 in hiPSC-derived astrocytes by integrating RNA sequencing data after TCF7L2 knockdown with TCF7L2 chromatin-immunoprecipitation sequencing (ChIP-seq) data. Those studies showed that TCF7L2 directly regulated a series of BD risk genes. In summary, these results support the existence of a CNS-based mechanism underlying BD-BMI genetic risk, a mechanism based on a glucocorticoid-dependent expression quantitative trait locus that regulates the expression of a novel TCF7L2 non-coding transcript.
CRISPR/Cas9 mediated gene correction ameliorates abnormal phenotypes in spinocerebellar ataxia type 3 patient-derived induced pluripotent stem cells
Authors: He Lang , Wang Shang , Peng Linliu , Zhao Huifang , Li Shuai , Han Xiaobo , Habimana Jean de Dieu , Chen Zhao , Wang Chunrong , Peng Yun , Peng Huirong , Xie Yue , Lei Lijing , Deng Qi , Wan Linlin , Wan Na , Yuan Hongyu , Gong Yiqing , Zou Guangdong , Li Zhiyuan , Tang Beisha , Jiang Hong 
Published: September 2021

AbstractSpinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) is a progressive autosomal dominant neurodegenerative disease caused by abnormal CAG repeats in the exon 10 ofATXN3. The accumulation of the mutant ataxin-3 proteins carrying expanded polyglutamine (polyQ) leads to selective degeneration of neurons. Since the pathogenesis of SCA3 has not been fully elucidated, and no effective therapies have been identified, it is crucial to investigate the pathogenesis and seek new therapeutic strategies of SCA3. Induced pluripotent stem cells (iPSCs) can be used as the ideal cell model for the molecular pathogenesis of polyQ diseases. Abnormal CAG expansions mediated by CRISPR/Cas9 genome engineering technologies have shown promising potential for the treatment of polyQ diseases, including SCA3. In this study, SCA3-iPSCs can be corrected by the replacement of the abnormal CAG expansions (74 CAG) with normal repeats (17 CAG) using CRISPR/Cas9-mediated homologous recombination (HR) strategy. Besides, corrected SCA3-iPSCs retained pluripotent and normal karyotype, which can be differentiated into a neural stem cell (NSCs) and neuronal cells, and maintained electrophysiological characteristics. The expression of differentiation markers and electrophysiological characteristics were similar among the neuronal differentiation from normal control iPSCs (Ctrl-iPSCs), SCA3-iPSCs, and isogenic control SCA3-iPSCs. Furthermore, this study proved that the phenotypic abnormalities in SCA3 neurons, including aggregated IC2-polyQ protein, decreased mitochondrial membrane potential (MMP) and glutathione expressions, increased reactive oxygen species (ROS), intracellular Ca2+concentrations, and lipid peroxidase malondialdehyde (MDA) levels, all were rescued in the corrected SCA3-NCs. For the first time, this study demonstrated the feasibility of CRISPR/Cas9-mediated HR strategy to precisely repair SCA3-iPSCs, and reverse the corresponding abnormal disease phenotypes. In addition, the importance of genetic control using CRISPR/Cas9-mediated iPSCs for disease modeling. Our work may contribute to providing a potential ideal model for molecular mechanism research and autologous stem cell therapy of SCA3 or other polyQ diseases, and offer a good gene therapy strategy for future treatment.
CHIP promotes the activation of NF-κB signaling through enhancing the K63-linked ubiquitination of TAK1
Authors: Liu Yuchun , Sun Yao , Han Shaoming , Guo Yanan , Tian Qingnan , Ma Qiang , Zhang Shoutao 
Published: September 2021

AbstractTranscriptional factor nuclear factor κB (NF-κB) can be activated by various intracellular or extracellular stimuli and its dysregulation leads to pathological conditions, such as neurodegenerative disorders, infection, and cancer. The carboxyl terminus of HSC70-interacting protein (CHIP), a pathogenic gene of spinocerebellar autosomal recessive 16 (SCAR16), plays an important roles in protein degradation, trafficking, and multiple signaling transductions. It has been reported that CHIP participates in the regulation of NF-κB signaling, and the mutant of CHIP (p.T246M) leads to the occurrence of SCAR16. However, the detailed mechanism of CHIP and CHIP (p.T246M) in the regulation of NF-κB signaling in neurological disorders remains unclear. Here, we found that CHIP promoted the activation of NF-κB signaling, while the knockdown had the opposite effect. Furthermore, CHIP interacted with TAK1 and targeted it for K63-linked ubiquitination. Finally, CHIP enhanced the interaction between TAK1 and NEMO. However, CHIP (p.T246M) couldn’t upregulate NF-κB signaling, potentiate the ubiquitination of TAK1, and enhance the interactions. Taken together, our study demonstrated for the first time that CHIP positively regulates NF-κB signaling by targeting TAK1 and enhancing its K63-linked ubiquitination.
Recurrence biomarkers of triple negative breast cancer treated with neoadjuvant chemotherapy and anti-EGFR antibodies
Authors: Radosevic-Robin Nina , Selenica Pier , Zhu Yingjie , Won Helen H. , Berger Michael F. , Ferrando Lorenzo , Cocco Emiliano , Privat Maud , Ponelle-Chachuat Flora , Abrial Catherine , Nabholtz Jean-Marc , Penault-Llorca Frederique , Reis-Filho Jorge S. , Scaltriti Maurizio 
Published: September 2021

AbstractTo find metastatic recurrence biomarkers of triple-negative breast cancer (TNBC) treated by neoadjuvant chemotherapy and anti-EGFR antibodies (NAT), we evaluated tumor genomic, transcriptomic, and immune features, using MSK-IMPACT assay, gene arrays, Nanostring technology, and TIL assessment on H&E. Six patients experienced a rapid fatal recurrence (RR) and other 6 had later non-fatal recurrences (LR). Before NAT, RR had low expression of 6 MHC class I and 13 MHC class II genes but were enriched in upregulated genes involved in the cell cycle-related pathways. Their TIL number before NAT in RR was very low (<5%) and did not increase after treatment. In post-NAT residual tumors, RR cases showed high expression of SOX2 and CXCR4. Our results indicate that high expression of cell cycle genes, combined with cold immunological phenotype, may predict strong TNBC resistance to NAT and rapid progression after it. This biomarker combination is worth validation in larger studies.
Comprehensive subtyping of Parkinson’s disease patients with similarity fusion: a case study with BioFIND data
Authors: Brendel Matthew , Su Chang , Hou Yu , Henchcliffe Claire , Wang Fei 
Published: September 2021

AbstractParkinson’s disease (PD) is a complex neurodegenerative disorder with diverse clinical manifestations. To better understand this disease, research has been done to categorize, or subtype, patients, using an array of criteria derived from clinical assessments and biospecimen analyses. In this study, using data from the BioFIND cohort, we aimed at identifying subtypes of moderate-to-advanced PD via comprehensively considering motor and non-motor manifestations. A total of 103 patients were included for analysis. Through the use of a patient-wise similarity matrix fusion technique and hierarchical agglomerative clustering analysis, three unique subtypes emerged from the clustering results. Subtype I, comprised of 60 patients (~58.3%), was characterized by mild symptoms, both motor and non-motor. Subtype II, comprised of 20 (~19.4%) patients, was characterized by an intermediate severity, with a high tremor score and mild non-motor symptoms. Subtype III, comprised of 23 (~22.3%) patients, was characterized by more severe motor and non-motor symptoms. These subtypes show statistically significant differences when looking at motor (on and off medication) clinical features and non-motor clinical features, while there was no clear difference in demographics, biomarker levels, and genetic risk scores.
The study of Dominican amber-bearing sediments from Siete Cañadas and La Cumbre with a discussion on their origin
Authors: Stach Paweł , Natkaniec-Nowak Lucyna , Dumańska-Słowik Magdalena , Kosakowski Paweł , Naglik Beata , Drzewicz Przemysław , Misiak Jacek , Pršek Jaroslav , George Carlos , Ramírez Gómez Ramón Elías 
Published: September 2021

AbstractThe paper presents comprehensive mineralogical and geochemical characteristics of Dominican amber-bearing sediments from Siete Cañadas, Hato Mayor Province of the Eastern Mining District (EMD) in the Cordillera Oriental. The characteristics of rocks collected from the borehole in Siete Cañadas area (EMD) were compared with petrography of coaly shales from La Cumbre in the Northern Mining District (NMD). The mineralogy of the rocks was determined using transmitted and reflected light microscopy, scanning electron microscopy, Powder X-ray diffraction and Fourier Transform Raman Spectroscopy. Biomarker analyses by the gas chromatography–mass spectrometry were used to trace the genetic source and transformation stage of organic matter hosted in the core sediments. In this study, the characteristics of rocks from La Cumbre were supplemented with the petrographic data from our studies reported earlier. Based on the findings, it has been concluded that the basins in the investigated parts of the EMD and NMD regions were likely characterized by different, isolated palaeosettings. Transformation and maturation of terrigenous material were affected by locally occurring physicochemical conditions. In both amber deposits, the sedimentation of clastic and organic material proceeded in the presence of marine conditions. In case of the La Cumbre deposit (NMD area), the sedimentation underwent probably in the conditions of the lagoon environment, a shallow maritime lake or periodically flooded plain that facilitated organic matter decomposition and carbonation from meta-lignite to sub-bituminous coal (random reflectance of coal—Rro = 0.39%). In the Siete Cañadas (EMD region), the sedimentation took place in a shallow saltwater basin, where terrigenous material was likely mixed with material found in situ (fauna fossils, carbonate-group minerals) to form the mudstones enriched in bituminous substance of low maturity. The organic matter found in the rocks from both deposits is of mixed terrestrial/marine origin and was deposited in the presence of low oxygen concentration and reducing and/or dysoxic conditions.
Novel variants in Krueppel like factor 1 that cause persistence of fetal hemoglobin in In(Lu) individuals
Authors: Eernstman Jesse , Veldhuisen Barbera , Ligthart Peter , von Lindern Marieke , van der Schoot C. Ellen , van den Akker Emile 
Published: September 2021

AbstractBeta-hemoglobinopathies become prominent after birth due to a switch from γ-globin to the mutated β-globin. Haploinsufficiency for the erythroid specific indispensable transcription factor Krueppel-like factor 1 (KLF1) is associated with high persistence of fetal hemoglobin (HPFH). The In(Lu) phenotype, characterized by low to undetectable Lutheran blood group expression is caused by mutations within KLF1 gene. Here we screened a blood donor cohort of 55 Lutheran weak or negative donors for KLF1 variants and evaluated their effect on KLF1 target gene expression. To discriminate between weak and negative Lutheran expression, a flow cytometry (FCM) assay was developed to detect Lu antigen expression. The Lu(a−b−) (negative) donor group, showing a significant decreased CD44 (Indian blood group) expression, also showed increased HbF and HbA2 levels, with one individual expressing HbF as high as 5%. KLF1 exons and promoter sequencing revealed variants in 80% of the Lutheran negative donors. Thirteen different variants plus one high frequency SNP (c.304 T > C) were identified of which 6 were novel. In primary erythroblasts, knockdown of endogenous KLF1 resulted in decreased CD44, Lu and increased HbF expression, while KLF1 over-expressing cells were comparable to wild type (WT). In line with the pleiotropic effects of KLF1 during erythropoiesis, distinct KLF1 mutants expressed in erythroblasts display different abilities to rescue CD44 and Lu expression and/or to affect fetal (HbF) or adult (HbA) hemoglobin expression. With this study we identified novel KLF1 variants to be include into blood group typing analysis. In addition, we provide further insights into the regulation of genes by KLF1.
Cerebrospinal fluid markers in incident pediatric-onset multiple sclerosis: a nationwide study
Authors: McKay Kyla A. , Wickström Ronny , Hillert Jan , Karrenbauer Virginija Danylaite 
Published: September 2021

AbstractTo investigate whether cerebrospinal fluid (CSF) markers differ between pediatric-onset multiple sclerosis (PoMS, onset < 18 years) and adult-onset (AoMS), and whether these markers are associated with clinical outcomes among PoMS. Prospective nationwide registry study of incident MS, including persons with a CSF sample < 3 years post-MS onset. We compared CSF oligoclonal band (OCB) status, immunoglobulin G (IgG) index levels, and mononuclear cell count between PoMS and AoMS. Within the PoMS cohort we analyzed the association between CSF markers, relapse rate and Expanded Disability Status Scale (EDSS) score, using negative binomial regression and generalized estimating equations, respectively. The cohort consisted of 130 PoMS and 3228 AoMS cases. The PoMS group had higher odds of OCB-positivity (odds ratio: 2.70; 95% CI 1.21–7.67). None of the CSF markers were associated with relapse rate in the PoMS cohort; however, OCB-positivity was associated with higher EDSS scores. This study suggested that PoMS more commonly display CSF evidence for intrathecal IgG production than AoMS. Further, we found evidence of a relationship between OCB-positivity and subsequent disability, suggesting that they could play a role in the prognostication of MS in children.
Exploiting genomic surveillance to map the spatio-temporal dispersal of SARS-CoV-2 spike mutations in Belgium across 2020
Authors: Bollen Nena , Artesi Maria , Durkin Keith , Hong Samuel L. , Potter Barney , Boujemla Bouchra , Vanmechelen Bert , Martí-Carreras Joan , Wawina-Bokalanga Tony , Meex Cécile , Bontems Sébastien , Hayette Marie-Pierre , André Emmanuel , Maes Piet , Bours Vincent , Baele Guy , Dellicour Simon 
Published: September 2021

AbstractAt the end of 2020, several new variants of SARS-CoV-2—designated variants of concern—were detected and quickly suspected to be associated with a higher transmissibility and possible escape of vaccine-induced immunity. In Belgium, this discovery has motivated the initiation of a more ambitious genomic surveillance program, which is drastically increasing the number of SARS-CoV-2 genomes to analyse for monitoring the circulation of viral lineages and variants of concern. In order to efficiently analyse the massive collection of genomic data that are the result of such increased sequencing efforts, streamlined analytical strategies are crucial. In this study, we illustrate how to efficiently map the spatio-temporal dispersal of target mutations at a regional level. As a proof of concept, we focus on the Belgian province of Liège that has been consistently sampled throughout 2020, but was also one of the main epicenters of the second European epidemic wave. Specifically, we employ a recently developed phylogeographic workflow to infer the regional dispersal history of viral lineages associated with three specific mutations on the spike protein (S98F, A222V and S477N) and to quantify their relative importance through time. Our analytical pipeline enables analysing large data sets and has the potential to be quickly applied and updated to track target mutations in space and time throughout the course of an epidemic.
IIIG9 inhibition in adult ependymal cells changes adherens junctions structure and induces cellular detachment
Authors: Baeza Victor , Cifuentes Manuel , Martínez Fernando , Ramírez Eder , Nualart Francisco , Ferrada Luciano , Oviedo María José , De Lima Isabelle , Troncoso Ninoschka , Saldivia Natalia , Salazar Katterine 
Published: September 2021

AbstractEpendymal cells have multiple apical cilia that line the ventricular surfaces and the central canal of spinal cord. In cancer, the loss of ependymal cell polarity promotes the formation of different types of tumors, such as supratentorial anaplastic ependymomas, which are highly aggressive in children. IIIG9 (PPP1R32) is a protein restricted to adult ependymal cells located in cilia and in the apical cytoplasm and has unknown function. In this work, we studied the expression and localization of IIIG9 in the adherens junctions (cadherin/β-catenin-positive junctions) of adult brain ependymal cells using confocal and transmission electron microscopy. Through in vivo loss-of-function studies, ependymal denudation (single-dose injection experiments of inhibitory adenovirus) was observed, inducing the formation of ependymal cells with a “balloon-like” morphology. These cells had reduced cadherin expression (and/or delocalization) and cleavage of the cell death marker caspase-3, with “cilia rigidity” morphology (probably vibrational beating activity) and ventriculomegaly occurring prior to these events. Finally, after performing continuous infusions of adenovirus for 14 days, we observed total cell denudation and reactive parenchymal astrogliosis. Our data confirmed that IIIG9 is essential for the maintenance of adherens junctions of polarized ependymal cells. Eventually, altered levels of this protein in ependymal cell differentiation may increase ventricular pathologies, such as hydrocephalus or neoplastic transformation.