bluuebunny/crossref_metadata_2025_split huggingface dataset:
RNA-sequencing data-driven dissection of human plasma cell differentiation reveals new potential transcription regulators
Authors: Kassambara Alboukadel , Herviou Laurie , Ovejero Sara , Jourdan Michel , Thibaut Coraline , Vikova Veronika , Pasero Philippe , Elemento Olivier , Moreaux Jérôme 
Published: April 2021

AbstractPlasma cells (PCs) play an important role in the adaptive immune system through a continuous production of antibodies. We have demonstrated that PC differentiation can be modeled in vitro using complex multistep culture systems reproducing sequential differentiation process occurring in vivo. Here we present a comprehensive, temporal program of gene expression data encompassing human PC differentiation (PCD) using RNA sequencing (RNA-seq). Our results reveal 6374 differentially expressed genes classified into four temporal gene expression patterns. A stringent pathway enrichment analysis of these gene clusters highlights known pathways but also pathways largely unknown in PCD, including the heme biosynthesis and the glutathione conjugation pathways. Additionally, our analysis revealed numerous novel transcriptional networks with significant stage-specific overexpression and potential importance in PCD, including BATF2, BHLHA15/MIST1, EZH2, WHSC1/MMSET, and BLM. We have experimentally validated a potent role for BLM in regulating cell survival and proliferation during human PCD. Taken together, this RNA-seq analysis of PCD temporal stages helped identify coexpressed gene modules with associated up/downregulated transcription regulator genes that could represent major regulatory nodes for human PC maturation. These data constitute a unique resource of human PCD gene expression programs in support of future studies for understanding the underlying mechanisms that control PCD.
Telomere length and telomere repeat-binding protein in children with sickle cell disease
Authors: Suliman Mohamed E. , Ansari Mohammed G. A. , Rayis Mohamed A. , Hamza Muaawia A. , Saeed Abdullah A. , Mohammed Abdul Khader , Al-Daghri Nasser M. 
Published: April 2021

Abstract
Background
This study aimed to assess the telomere length and plasma telomere repeat-binding factor 2 (TRF2) levels in addition to other inflammatory markers in children with sickle cell disease (SCD).

Methods
We enrolled 106 children (90 SCD and 26 controls) aged 1–15 years from the Hematology unit of King Fahad Medical City (KFMC), Saudi Arabia. Genomic DNA extracted from blood and leukocyte TL was determined using quantitative reverse transcription PCR, whereas TRF2, C-reactive protein, interleukin-6, and DNA oxidative damage were determined by using respective commercially available assays.

Results
Leukocyte TL was inversely correlated with age in the SCD patients (r = −0.24, P = 0.02) and the controls (r = −0.68, P < 0.0001). In addition, SCD patients had significantly shorter TL (7.74 ± 0.81 kb) (P = 0.003) than controls (8.28 ± 0.73 kb). In contrast, no significant difference in TL among the SCD genotypes (HbSS and HbSβ0) has been observed. A modest, positive correlation was seen between TL and reticulocyte % (r = 0.21; P = 0.06). There were no significant differences in the TL and TRF2 concentrations between subjects with HbSS and HbSβ0 genotypes.

Conclusions
Short leukocyte TL was significantly associated with SCD. An inverse association was observed between TL and hemoglobin. Hydroxyurea treatment revealed no impact on TL.

Impact

This study explored the TL and plasma TRF2 in Saudi children with SCD. This is the first documentation that SCD children have shorter TL than their healthy counterparts, and no association between TL and TRF2 has been observed.

Hydroxyurea treatment showed no impact on TL in children with SCD.

This study is the first of its kind in children with SCD.

It will pave the way for another study with a larger sample size in a diverse population to scrutinize these findings better.
“GrimAge,” an epigenetic predictor of mortality, is accelerated in major depressive disorder
Authors: Protsenko Ekaterina , Yang Ruoting , Nier Brent , Reus Victor , Hammamieh Rasha , Rampersaud Ryan , Wu Gwyneth W. Y. , Hough Christina M. , Epel Elissa , Prather Aric A. , Jett Marti , Gautam Aarti , Mellon Synthia H. , Wolkowitz Owen M. 
Published: April 2021

AbstractMajor depressive disorder (MDD) is associated with premature mortality and is an independent risk factor for a broad range of diseases, especially those associated with aging, such as cardiovascular disease, diabetes, and Alzheimer’s disease. However, the pathophysiology underlying increased rates of somatic disease in MDD remains unknown. It has been proposed that MDD represents a state of accelerated cellular aging, and several measures of cellular aging have been developed in recent years. Among such metrics, estimators of biological age based on predictable age-related patterns of DNA methylation (DNAm), so-called ‘epigenetic clocks’, have shown particular promise for their ability to capture accelerated aging in psychiatric disease. The recently developed DNAm metric known as ‘GrimAge’ is unique in that it was trained on time-to-death data and has outperformed its predecessors in predicting both morbidity and mortality. Yet, GrimAge has not been investigated in MDD. Here we measured GrimAge in 49 somatically healthy unmedicated individuals with MDD and 60 age-matched healthy controls. We found that individuals with MDD exhibited significantly greater GrimAge relative to their chronological age (‘AgeAccelGrim’) compared to healthy controls (p = 0.001), with a median of 2 years of excess cellular aging. This difference remained significant after controlling for sex, current smoking status, and body-mass index (p = 0.015). These findings are consistent with prior suggestions of accelerated cellular aging in MDD, but are the first to demonstrate this with an epigenetic metric predictive of premature mortality.
Transcriptomic signaling pathways involved in a naturalistic model of inflammation-related depression and its remission
Authors: Moisan Marie-Pierre , Foury Aline , Dexpert Sandra , Cole Steve W. , Beau Cédric , Forestier Damien , Ledaguenel Patrick , Magne Eric , Capuron Lucile 
Published: April 2021

AbstractThis study aimed at identifying molecular biomarkers of inflammation-related depression in order to improve diagnosis and treatment. For this, we performed whole-genome expression profiling from peripheral blood in a naturalistic model of inflammation-associated major depressive disorder (MDD) represented by comorbid depression in obese patients. We took advantage of the marked reduction of depressive symptoms and inflammation following bariatric surgery to test the robustness of the identified biomarkers. Depression was assessed during a clinical interview using Mini-International Neuropsychiatric Interview and the 10-item, clinician-administered, Montgomery–Asberg Depression Rating Scale. From a cohort of 100 massively obese patients, we selected 33 of them for transcriptomic analysis. Twenty-four of them were again analyzed 4–12 months after bariatric surgery. We conducted differential gene expression analyses before and after surgery in unmedicated MDD and non-depressed obese subjects. We found that TP53 (Tumor Protein 53), GR (Glucocorticoid Receptor), and NFκB (Nuclear Factor kappa B) pathways were the most discriminating pathways associated with inflammation-related MDD. These signaling pathways were processed in compositez-scores of gene expression that were used as biomarkers in regression analyses. Results showed that these transcriptomic biomarkers highly predicted depressive symptom intensity at baseline and their remission after bariatric surgery. While inflammation was present in all patients, GR signaling over-activation was found only in depressed ones where it may further increase inflammatory and apoptosis pathways. In conclusion, using an original model of inflammation-related depression and its remission without antidepressants, we provide molecular predictors of inflammation-related MDD and new insights in the molecular pathways involved.
ZEB1-induced LINC01559 expedites cell proliferation, migration and EMT process in gastric cancer through recruiting IGF2BP2 to stabilize ZEB1 expression
Authors: Shen Huojian , Zhu Hongyi , Chen Yuanwen , Shen Zhiyong , Qiu Weiqing , Qian Changlin , Zhang Jie 
Published: April 2021

AbstractGastric cancer (GC) is a common type of tumor that is characterized with high metastatic rate. In recent years, increasing studies have indicated that lncRNAs are involved in the regulation on cancer cell proliferation and migration. However, the functional role of long intergenic non-protein coding RNA 1559 (LINC01559) in GC is still unclear. In this study, we applied quantitative real-time polymerase chain reaction (RT-qPCR) and examined that LINC01559 expression was significantly enhanced in GC cells. Functional assays such as EdU, colony formation, JC-1 and transwell assays displayed that silencing LINC01559 inhibited cell proliferation and migration while promoted cell apoptosis in GC. Besides, western blot analysis and immunofluorescence assays examined the expression of factors related to epithelial-mesenchymal transition (EMT) and indicated that EMT process was blocked by LINC01559 knockdown in GC cells. Besides, LINC01559 silencing inhibited tumor growth in vivo. In addition, Chromatin immunoprecipitation (ChIP) assays demonstrated that zinc finger E-box binding homeobox 1 (ZEB1) served as a transcription factor to combine with LINC01559 promoter and activated the expression of LINC01559 in GC cells. In return, LINC01559 recruited insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) to stabilize ZEB1 mRNA to up-regulate ZEB1 in GC cells. In short, the findings in this research might provide a novel target for GC treatment.
MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity
Authors: Zheng Jun-Yi , Wang Chen-Yu , Gao Chuan , Xiao Qiong , Huang Cheng-Wei , Wu Min , Li Lian-Yun 
Published: April 2021

AbstractMLL3 is a histone H3K4 methyltransferase that is frequently mutated in cancer, but the underlying molecular mechanisms remain elusive. Here, we found that MLL3 depletion by CRISPR/sgRNA significantly enhanced cell migration, but did not elevate the proliferation rate of cancer cells. Through RNA-Seq and ChIP-Seq approaches, we identified TNS3 as the potential target gene for MLL3. MLL3 depletion caused downregulation of H3K4me1 and H3K27ac on an enhancer ~ 7 kb ahead of TNS3. 3C assay indicated the identified enhancer interacts with TNS3 promoter and repression of enhancer activity by dCas9-KRAB system impaired TNS3 expression. Exogenous expression of TNS3 in MLL3 deficient cells completely blocked the enhanced cell migration phenotype. Taken together, our study revealed a novel mechanism for MLL3 in suppressing cancer, which may provide novel targets for diagnosis or drug development.
AMPK activation by ASP4132 inhibits non-small cell lung cancer cell growth
Authors: Xia Ying-chen , Zha Jian-hua , Sang Yong-Hua , Yin Hui , Xu Guo-qiu , Zhen Jie , Zhang Yan , Yu Ben-tong 
Published: April 2021

AbstractActivation of adenosine monophosphate-activated protein kinase (AMPK) is able to produce significant anti-non-small cell lung cancer (NSCLC) cell activity. ASP4132 is an orally active and highly effective AMPK activator. The current study tested its activity against NSCLC cells. In primary NSCLC cells and established cell lines (A549 and NCI-H1944) ASP4132 potently inhibited cell growth, proliferation and cell cycle progression as well as cell migration and invasion. Robust apoptosis activation was detected in ASP4132-treated NSCLC cells. Furthermore, ASP4132 treatment in NSCLC cells induced programmed necrosis, causing mitochondrial p53-cyclophilin D (CyPD)-adenine nucleotide translocase 1 (ANT1) association, mitochondrial depolarization and medium lactate dehydrogenase release. In NSCLC cells ASP4132 activated AMPK signaling, induced AMPKα1-ACC phosphorylation and increased AMPK activity. Furthermore, AMPK downstream events, including mTORC1 inhibition, receptor tyrosine kinases (PDGFRα and EGFR) degradation, Akt inhibition and autophagy induction, were detected in ASP4132-treated NSCLC cells. Importantly, AMPK inactivation by AMPKα1 shRNA, knockout (using CRISPR/Cas9 strategy) or dominant negative mutation (T172A) almost reversed ASP4132-induced anti-NSCLC cell activity. Conversely, a constitutively active AMPKα1 (T172D) mimicked and abolished ASP4132-induced actions in NSCLC cells. In vivo, oral administration of a single dose of ASP4132 largely inhibited NSCLC xenograft growth in SCID mice. AMPK activation, mTORC1 inhibition and EGFR-PDGFRα degradation as well as Akt inhibition and autophagy induction were detected in ASP4132-treated NSCLC xenograft tumor tissues. Together, activation of AMPK by ASP4132 potently inhibits NSCLC cell growth in vitro and in vivo.
CircHIPK3 regulates the autophagy and apoptosis of hypoxia/reoxygenation-stimulated cardiomyocytes via the miR-20b-5p/ATG7 axis
Authors: Qiu Zhimei , Wang Yan , Liu Weiwei , Li Chaofu , Zhao Ranzun , Long Xianping , Rong Jidong , Deng Wengweng , Shen Changyin , Yuan Jinson , Chen Wengming , Shi Bei 
Published: April 2021

AbstractAutophagy and apoptosis are involved in myocardial ischemia/reperfusion (I/R) injury. Research indicates that circular RNA HIPK3 (circHIPK3) is crucial to cell autophagy and apoptosis in various cancer types. However, the role of circHIPK3 in the regulation of cardiomyocyte autophagy and apoptosis during I/R remains unknown. Our study aimed to examine the regulatory effect of circHIPK3 during myocardial I/R and investigate its mechanism in cardiomyocyte autophagy and apoptosis. Methods and results. The expression of circHIPK3 was upregulated during myocardial I/R injury and hypoxia/reoxygenation (H/R) injury of cardiomyocytes. To study the potential role of circHIPK3 in myocardial H/R injury, we performed gain-of-function and loss-of-function analyses of circHIPK3 in cardiomyocytes. Overexpression of circHIPK3 significantly promoted H/R-induced cardiomyocyte autophagy and cell injury (increased intracellular reactive oxygen species (ROS) and apoptosis) compared to those in the control group, while silencing of circHIPK3 showed the opposite effect. Further research found that circHIPK3 acted as an endogenous miR-20b-5p sponge to sequester and inhibit miR-20b-5p activity, resulting in increased ATG7 expression. In addition, miR-20b-5p inhibitors reversed the decrease in ATG7 induced by silencing circHIPK3. Conclusions. CircHIPK3 can accelerate cardiomyocyte autophagy and apoptosis during myocardial I/R injury through the miR-20b-5p/ATG7 axis. These data suggest that circHIPK3 may serve as a potential therapeutic target for I/R.
Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide
Authors: Jamsen Joonas A. , Sassa Akira , Shock David D. , Beard William A. , Wilson Samuel H. 
Published: April 2021

AbstractOxidized dGTP (8-oxo-7,8-dihydro-2´-deoxyguanosine triphosphate, 8-oxodGTP) insertion by DNA polymerases strongly promotes cancer and human disease. How DNA polymerases discriminate against oxidized and undamaged nucleotides, especially in error-prone double strand break (DSB) repair, is poorly understood. High-resolution time-lapse X-ray crystallography snapshots of DSB repair polymerase μ undergoing DNA synthesis reveal that a third active site metal promotes insertion of oxidized and undamaged dGTP in the canonical anti-conformation opposite template cytosine. The product metal bridged O8 with product oxygens, and was not observed in the syn-conformation opposite template adenine (At). Rotation of At into the syn-conformation enabled undamaged dGTP misinsertion. Exploiting metal and substrate dynamics in a rigid active site allows 8-oxodGTP to circumvent polymerase fidelity safeguards to promote pro-mutagenic double strand break repair.
Normal tissue architecture determines the evolutionary course of cancer
Authors: West Jeffrey , Schenck Ryan O. , Gatenbee Chandler , Robertson-Tessi Mark , Anderson Alexander R. A. 
Published: April 2021

AbstractCancer growth can be described as a caricature of the renewal process of the tissue of origin, where the tissue architecture has a strong influence on the evolutionary dynamics within the tumor. Using a classic, well-studied model of tumor evolution (a passenger-driver mutation model) we systematically alter spatial constraints and cell mixing rates to show how tissue structure influences functional (driver) mutations and genetic heterogeneity over time. This approach explores a key mechanism behind both inter-patient and intratumoral tumor heterogeneity: competition for space. Time-varying competition leads to an emergent transition from Darwinian premalignant growth to subsequent invasive neutral tumor growth. Initial spatial constraints determine the emergent mode of evolution (Darwinian to neutral) without a change in cell-specific mutation rate or fitness effects. Driver acquisition during the Darwinian precancerous stage may be modulated en route to neutral evolution by the combination of two factors: spatial constraints and limited cellular mixing. These two factors occur naturally in ductal carcinomas, where the branching topology of the ductal network dictates spatial constraints and mixing rates.
Efficiency stagnation in global steel production urges joint supply- and demand-side mitigation efforts
Authors: Wang Peng , Ryberg Morten , Yang Yi , Feng Kuishuang , Kara Sami , Hauschild Michael , Chen Wei-Qiang 
Published: April 2021

AbstractSteel production is a difficult-to-mitigate sector that challenges climate mitigation commitments. Efforts for future decarbonization can benefit from understanding its progress to date. Here we report on greenhouse gas emissions from global steel production over the past century (1900-2015) by combining material flow analysis and life cycle assessment. We find that ~45 Gt steel was produced in this period leading to emissions of ~147 Gt CO2-eq. Significant improvement in process efficiency (~67%) was achieved, but was offset by a 44-fold increase in annual steel production, resulting in a 17-fold net increase in annual emissions. Despite some regional technical improvements, the industry’s decarbonization progress at the global scale has largely stagnated since 1995 mainly due to expanded production in emerging countries with high carbon intensity. Our analysis of future scenarios indicates that the expected demand expansion in these countries may jeopardize steel industry’s prospects for following 1.5 °C emission reduction pathways. To achieve the Paris climate goals, there is an urgent need for rapid implementation of joint supply- and demand-side mitigation measures around the world in consideration of regional conditions.
Diurnal Fe(II)/Fe(III) cycling and enhanced O2 production in a simulated Archean marine oxygen oasis
Authors: Herrmann A. J. , Sorwat J. , Byrne J. M. , Frankenberg-Dinkel N. , Gehringer M. M. 
Published: April 2021

AbstractThe oxygenation of early Earth’s atmosphere during the Great Oxidation Event, is generally accepted to have been caused by oceanic Cyanobacterial oxygenic photosynthesis. Recent studies suggest that Fe(II) toxicity delayed the Cyanobacterial expansion necessary for the GOE. This study investigates the effects of Fe(II) on two Cyanobacteria, Pseudanabaena sp. PCC7367 and Synechococcus sp. PCC7336, in a simulated shallow-water marine Archean environment. A similar Fe(II) toxicity response was observed as reported for closed batch cultures. This toxicity was not observed in cultures provided with continuous gaseous exchange that showed significantly shorter doubling times than the closed-culture system, even with repeated nocturnal addition of Fe(II) for 12 days. The green rust (GR) formed under high Fe(II) conditions, was not found to be directly toxic to Pseudanabaena sp. PCC7367. In summary, we present evidence of diurnal Fe cycling in a simulated shallow-water marine environment for two ancestral strains of Cyanobacteria, with increased O2 production under anoxic conditions.
Identifying multiple sclerosis subtypes using unsupervised machine learning and MRI data
Authors: Eshaghi Arman , Young Alexandra L. , Wijeratne Peter A. , Prados Ferran , Arnold Douglas L. , Narayanan Sridar , Guttmann Charles R. G. , Barkhof Frederik , Alexander Daniel C. , Thompson Alan J. , Chard Declan , Ciccarelli Olga 
Published: April 2021

AbstractMultiple sclerosis (MS) can be divided into four phenotypes based on clinical evolution. The pathophysiological boundaries of these phenotypes are unclear, limiting treatment stratification. Machine learning can identify groups with similar features using multidimensional data. Here, to classify MS subtypes based on pathological features, we apply unsupervised machine learning to brain MRI scans acquired in previously published studies. We use a training dataset from 6322 MS patients to define MRI-based subtypes and an independent cohort of 3068 patients for validation. Based on the earliest abnormalities, we define MS subtypes as cortex-led, normal-appearing white matter-led, and lesion-led. People with the lesion-led subtype have the highest risk of confirmed disability progression (CDP) and the highest relapse rate. People with the lesion-led MS subtype show positive treatment response in selected clinical trials. Our findings suggest that MRI-based subtypes predict MS disability progression and response to treatment and may be used to define groups of patients in interventional trials.
Global influence of mantle temperature and plate thickness on intraplate volcanism
Authors: Ball P. W. , White N. J. , Maclennan J. , Stephenson S. N. 
Published: April 2021

AbstractThe thermochemical structure of lithospheric and asthenospheric mantle exert primary controls on surface topography and volcanic activity. Volcanic rock compositions and mantle seismic velocities provide indirect observations of this structure. Here, we compile and analyze a global database of the distribution and composition of Neogene-Quaternary intraplate volcanic rocks. By integrating this database with seismic tomographic models, we show that intraplate volcanism is concentrated in regions characterized by slow upper mantle shear-wave velocities and by thin lithosphere (i.e. <100 km). We observe a negative correlation between shear-wave velocities at depths of 125–175 km and melt fractions inferred from volcanic rock compositions. Furthermore, mantle temperature and lithospheric thickness estimates obtained by geochemical modeling broadly agree with values determined from tomographic models that have been converted into temperature. Intraplate volcanism often occurs in regions where uplifted (but undeformed) marine sedimentary rocks are exposed. Regional elevation of these rocks can be generated by a combination of hotter asthenosphere and lithospheric thinning. Therefore, the distribution and composition of intraplate volcanic rocks through geologic time will help to probe past mantle conditions and surface processes.