bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating the precision of EBF1 SNP x stress interaction association: sex, race, and age differences in a big harmonized data set of 28,026 participants
Authors: Singh Abanish , Babyak Michael A. , Sims Mario , Musani Solomon K. , Brummett Beverly H. , Jiang Rong , Kraus William E. , Shah Svati H. , Siegler Ilene C. , Hauser Elizabeth R. , Williams Redford B. 
Published: October 2020

AbstractIn prior work, we identified a novel gene-by-stress association of EBF1’s common variation (SNP rs4704963) with obesity (i.e., hip, waist) in Whites, which was further strengthened through multiple replications using our synthetic stress measure. We now extend this prior work in a precision medicine framework to find the risk group using harmonized data from 28,026 participants by evaluating the following: (a) EBF1 SNPxSTRESS interaction in Blacks; (b) 3-way interaction of EBF1 SNPxSTRESS with sex, race, and age; and (c) a race and sex-specific path linking EBF1 and stress to obesity to fasting glucose to the development of cardiometabolic disease risk. Our findings provided additional confirmation that genetic variation in EBF1 may contribute to stress-induced human obesity, including in Blacks (P = 0.022) that mainly resulted from race-specific stress due to “racism/discrimination” (P = 0.036) and “not meeting basic needs” (P = 0.053). The EBF1 gene-by-stress interaction differed significantly (P = 1.01e−03) depending on the sex of participants in Whites. Race and age also showed tentative associations (Ps = 0.103, 0.093, respectively) with this interaction. There was a significant and substantially larger path linking EBF1 and stress to obesity to fasting glucose to type 2 diabetes for the EBF1 minor allele group (coefficient = 0.28, P = 0.009, 95% CI = 0.07-0.49) compared with the same path for the EBF1 major allele homozygotes in White females and also a similar pattern of the path in Black females. Underscoring the race-specific key life-stress indicators (e.g., racism/discrimination) and also the utility of our synthetic stress, we identified the potential risk group of EBF1 and stress-induced human obesity and cardiometabolic disease.
Emerging role of the Hippo pathway in autophagy
Authors: Wang Dongying , He Jiaxing , Huang Bingyu , Liu Shanshan , Zhu Hongming , Xu Tianmin 
Published: October 2020

AbstractAutophagy is a dynamic circulatory system that occurs in all eukaryotic cells. Cytoplasmic material is transported to lysosomes for degradation and recovery through autophagy. This provides energy and macromolecular precursors for cell renewal and homeostasis. The Hippo-YAP pathway has significant biological properties in controlling organ size, tissue homeostasis, and regeneration. Recently, the Hippo-YAP axis has been extensively referred to as the pathophysiological processes regulating autophagy. Understanding the cellular and molecular basis of these processes is crucial for identifying disease pathogenesis and novel therapeutic targets. Here we review recent findings from Drosophila models to organisms. We particularly emphasize the regulation between Hippo core components and autophagy, which is involved in normal cellular regulation and the pathogenesis of human diseases, and its application to disease treatment.
Immunomodulatory activity of IR700-labelled affibody targeting HER2
Authors: Mączyńska Justyna , Da Pieve Chiara , Burley Thomas A. , Raes Florian , Shah Anant , Saczko Jolanta , Harrington Kevin J. , Kramer-Marek Gabriela 
Published: October 2020

AbstractThere is an urgent need to develop therapeutic approaches that can increase the response rate to immuno-oncology agents. Photoimmunotherapy has recently been shown to generate anti-tumour immunological responses by releasing tumour-associated antigens from ablated tumour cell residues, thereby enhancing antigenicity and adjuvanticity. Here, we investigate the feasibility of a novel HER2-targeted affibody-based conjugate (ZHER2:2395-IR700) selectively to induce cancer cell death in vitro and in vivo. The studies in vitro confirmed the specificity of ZHER2:2395-IR700 binding to HER2-positive cells and its ability to produce reactive oxygen species upon light irradiation. A conjugate concentration- and light irradiation-dependent decrease in cell viability was also demonstrated. Furthermore, light-activated ZHER2:2395-IR700 triggered all hallmarks of immunogenic cell death, as defined by the translocation of calreticulin to the cell surface, and the secretion of ATP, HSP70/90 and HMGB1 from dying cancer cells into the medium. Irradiating a co-culture of immature dendritic cells (DCs) and cancer cells exposed to light-activated ZHER2:2395-IR700 enhanced DC maturation, as indicated by augmented expression of CD86 and HLA-DR. In SKOV-3 xenografts, the ZHER2:2395-IR700-based phototherapy delayed tumour growth and increased median overall survival. Collectively, our results strongly suggest that ZHER2:2395-IR700 is a promising new therapeutic conjugate that has great potential to be applicable for photoimmunotherapy-based regimens.
Selective knockdown of hexokinase 2 in rods leads to age-related photoreceptor degeneration and retinal metabolic remodeling
Authors: Zhang Rui , Shen Weiyong , Du Jianhai , Gillies Mark C. 
Published: October 2020

AbstractPhotoreceptors, the primary site of phototransduction in the retina, require energy and metabolites to constantly renew their outer segments. They preferentially consume most glucose through aerobic glycolysis despite possessing abundant mitochondria and enzymes for oxidative phosphorylation (OXPHOS). Exactly how photoreceptors balance aerobic glycolysis and mitochondrial OXPHOS to regulate their survival is still unclear. We crossed rhodopsin-Cre mice with hexokinase 2 (HK2)-floxed mice to study the effect of knocking down HK2, the first rate-limiting enzyme in glycolysis, on retinal health and metabolic remodeling. Immunohistochemistry and Western blots were performed to study changes in photoreceptor-specific proteins and key enzymes in glycolysis and the tricarboxylic acid (TCA) cycle. Changes in retinal structure and function were studied by optical coherence tomography and electroretinography. Mass spectrometry was performed to profile changes in 13C-glucose-derived metabolites in glycolysis and the TCA cycle. We found that knocking down HK2 in rods led to age-related photoreceptor degeneration, evidenced by reduced expression of photoreceptor-specific proteins, age-related reductions of the outer nuclear layer, photoreceptor inner and outer segments and impaired electroretinographic responses. Loss of HK2 in rods led to upregulation of HK1, phosphorylation of pyruvate kinase muscle isozyme 2, mitochondrial stress proteins and enzymes in the TCA cycle. Mass spectrometry found that the deletion of HK2 in rods resulted in accumulation of 13C-glucose along with decreased pyruvate and increased metabolites in the TCA cycle. Our data suggest that HK2-mediated aerobic glycolysis is indispensable for the maintenance of photoreceptor structure and function and that long-term inhibition of glycolysis leads to photoreceptor degeneration.
setd2 knockout zebrafish is viable and fertile: differential and developmental stress-related requirements for Setd2 and histone H3K36 trimethylation in different vertebrate animals
Authors: Liu Dian-Jia , Zhang Fan , Chen Yi , Jin Yi , Zhang Yuan-Liang , Chen Shu-Bei , Xie Yin-Yin , Huang Qiu-Hua , Zhao Wei-Li , Wang Lan , Xu Peng-Fei , Chen Zhu , Chen Sai-Juan , Li Bing , Zhang Aijun , Sun Xiao-Jian 
Published: October 2020

AbstractSetd2 is the only enzyme that catalyzes histone H3 lysine 36 trimethylation (H3K36me3) on virtually all actively transcribed protein-coding genes, and this mechanism is evolutionarily conserved from yeast to human. Despite this widespread and conserved activity, Setd2 and H3K36me3 are dispensable for normal growth of yeast but are absolutely required for mammalian embryogenesis, such as oocyte maturation and embryonic vasculogenesis in mice, raising a question of how the functional requirements of Setd2 in specific developmental stages have emerged through evolution. Here, we explored this issue by studying the essentiality and function of Setd2 in zebrafish. Surprisingly, the setd2-null zebrafish are viable and fertile. They show Mendelian birth ratio and normal embryogenesis without vascular defect as seen in mice; however, they have a small body size phenotype attributed to insufficient energy metabolism and protein synthesis, which is reversable in a nutrition-dependent manner. Unlike the sterile Setd2-null mice, the setd2-null zebrafish can produce functional sperms and oocytes. Nonetheless, related to the requirement of maternal Setd2 for oocyte maturation in mice, the second generation of setd2-null zebrafish that carry no maternal setd2 show decreased survival rate and a developmental delay at maternal-to-zygotic transition. Taken together, these results indicate that, while the phenotypes of the setd2-null zebrafish and mice are apparently different, they are matched in parallel as the underlying mechanisms are evolutionarily conserved. Thus, the differential requirements of Setd2 may reflect distinct viability thresholds that associate with intrinsic and/or extrinsic stresses experienced by the organism through development, and these epigenetic regulatory mechanisms may serve as a reserved source supporting the evolution of life from simplicity to complexity.
Genome-wide association study of smoking trajectory and meta-analysis of smoking status in 842,000 individuals
Authors: Xu Ke , Li Boyang , McGinnis Kathleen A. , Vickers-Smith Rachel , Dao Cecilia , Sun Ning , Kember Rachel L. , Zhou Hang , Becker William C. , Gelernter Joel , Kranzler Henry R. , Zhao Hongyu , Justice Amy C. ,   VA Million Veteran Program
Published: October 2020

AbstractHere we report a large genome-wide association study (GWAS) for longitudinal smoking phenotypes in 286,118 individuals from the Million Veteran Program (MVP) where we identified 18 loci for smoking trajectory of current versus never in European Americans, one locus in African Americans, and one in Hispanic Americans. Functional annotations prioritized several dozen genes where significant loci co-localized with either expression quantitative trait loci or chromatin interactions. The smoking trajectories were genetically correlated with 209 complex traits, for 33 of which smoking was either a causal or a consequential factor. We also performed European-ancestry meta-analyses for smoking status in the MVP and GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN) (Ntotal = 842,717) and identified 99 loci for smoking initiation and 13 loci for smoking cessation. Overall, this large GWAS of longitudinal smoking phenotype in multiple populations, combined with a meta-GWAS for smoking status, adds new insights into the genetic vulnerability for smoking behavior.
AKAP5 complex facilitates purinergic modulation of vascular L-type Ca2+ channel CaV1.2
Authors: Prada Maria Paz , Syed Arsalan U. , Reddy Gopireddy R. , Martín-Aragón Baudel Miguel , Flores-Tamez Víctor A. , Sasse Kent C. , Ward Sean M. , Sirish Padmini , Chiamvimonvat Nipavan , Bartels Peter , Dickson Eamonn J. , Hell Johannes W. , Scott John D. , Santana Luis F. , Xiang Yang K. , Navedo Manuel F. , Nieves-Cintrón Madeline 
Published: October 2020

AbstractThe L-type Ca2+ channel CaV1.2 is essential for arterial myocyte excitability, gene expression and contraction. Elevations in extracellular glucose (hyperglycemia) potentiate vascular L-type Ca2+ channel via PKA, but the underlying mechanisms are unclear. Here, we find that cAMP synthesis in response to elevated glucose and the selective P2Y11 agonist NF546 is blocked by disruption of A-kinase anchoring protein 5 (AKAP5) function in arterial myocytes. Glucose and NF546-induced potentiation of L-type Ca2+ channels, vasoconstriction and decreased blood flow are prevented in AKAP5 null arterial myocytes/arteries. These responses are nucleated via the AKAP5-dependent clustering of P2Y11/ P2Y11-like receptors, AC5, PKA and CaV1.2 into nanocomplexes at the plasma membrane of human and mouse arterial myocytes. Hence, data reveal an AKAP5 signaling module that regulates L-type Ca2+ channel activity and vascular reactivity upon elevated glucose. This AKAP5-anchored nanocomplex may contribute to vascular complications during diabetic hyperglycemia.
Prevalent and sex-biased breathing patterns modify functional connectivity MRI in young adults
Authors: Lynch Charles J. , Silver Benjamin M. , Dubin Marc J. , Martin Alex , Voss Henning U. , Jones Rebecca M. , Power Jonathan D. 
Published: October 2020

AbstractResting state functional connectivity magnetic resonance imaging (fMRI) is a tool for investigating human brain organization. Here we identify, visually and algorithmically, two prevalent influences on fMRI signals during 440 h of resting state scans in 440 healthy young adults, both caused by deviations from normal breathing which we term deep breaths and bursts. The two respiratory patterns have distinct influences on fMRI signals and signal covariance, distinct timescales, distinct cardiovascular correlates, and distinct tendencies to manifest by sex. Deep breaths are not sex-biased. Bursts, which are serial taperings of respiratory depth typically spanning minutes at a time, are more common in males. Bursts share features of chemoreflex-driven clinical breathing patterns that also occur primarily in males, with notable neurological, psychiatric, medical, and lifespan associations. These results identify common breathing patterns in healthy young adults with distinct influences on functional connectivity and an ability to differentially influence resting state fMRI studies.
Lithium systematics in global arc magmas and the importance of crustal thickening for lithium enrichment
Authors: Chen Chen , Lee Cin-Ty A. , Tang Ming , Biddle Kevin , Sun Weidong 
Published: October 2020

AbstractMuch of the world’s Li deposits occurs as basinal brines in magmatic orogens, particularly in continental volcanic arcs. However, the exact origin of Li enrichment in arc magmatic systems is not clear. Here, we show that, globally, primitive arc magmas have Li contents and Li/Y ratios similar to mid-ocean ridge basalts, indicating that the subducting slab has limited contribution to Li enrichment in arc magmas. Instead, we find that Li enrichment is enhanced by lower degrees of sub-arc mantle melting and higher extents of intracrustal differentiation. These enrichment effects are favored in arcs with thick crust, which explains why magmatism and differentiation in continental arcs, like the Andes, reach greater Li contents than their island arc counterparts. Weathering of these enriched source rocks mobilizes and transports such Li into the hydrologic system, ultimately developing Li brines with the combination of arid climate and the presence of landlocked extensional basins in thickened orogenic settings.
Twisted-Planar-Twisted expanded porphyrinoid dimer as a rudimentary reaction-based methanol indicator
Authors: Li Qizhao , Li Chengjie , Baryshnikov Glib , Ding Yubin , Zhao Chengxi , Gu Tingting , Sha Feng , Liang Xu , Zhu Weihua , Wu Xinyan , Ågren Hans , Sessler Jonathan L. , Xie Yongshu 
Published: October 2020

AbstractDirectly linked porphyrin dimers have attracted considerable attention because of their intriguing electronic features. Most emphasis has been placed on either dimers with large dihedral angles between the constituent planar monomeric subunits or those with overall planarity, referred to as “Planar-Twisted-Planar” and “Planar-Planar-Planar”, respectively. Herein, we report a “Twisted-Planar-Twisted” framework, the hexaphyrin dimer D that exists in a trans configuration. Treatment of D with MeOH affords two isomeric dimers, MD1 and MD2, both of which incorporate a methoxy moiety and exist in cis orientations with respect to the tethering linkage. The methanol-promoted conversion is accompanied by a readily discernible color change from green to brown and is not induced to an appreciable level by other alcohols. Dimer D thus acts as a rudimentary, albeit highly selective, reaction-based methanol indicator. This work provides a promising approach for constructing reaction-based chemosensors using porphyrinoid dimers of nonplanar subunits with biased reactivity.
Telomere damage induces internal loops that generate telomeric circles
Authors: Mazzucco Giulia , Huda Armela , Galli Martina , Piccini Daniele , Giannattasio Michele , Pessina Fabio , Doksani Ylli 
Published: October 2020

AbstractExtrachromosomal telomeric circles are commonly invoked as important players in telomere maintenance, but their origin has remained elusive. Using electron microscopy analysis on purified telomeres we show that, apart from known structures, telomeric repeats accumulate internal loops (i-loops) that occur in the proximity of nicks and single-stranded DNA gaps. I-loops are induced by single-stranded damage at normal telomeres and represent the majority of telomeric structures detected in ALT (Alternative Lengthening of Telomeres) tumor cells. Our data indicate that i-loops form as a consequence of the exposure of single-stranded DNA at telomeric repeats. Finally, we show that these damage-induced i-loops can be excised to generate extrachromosomal telomeric circles resulting in loss of telomeric repeats. Our results identify damage-induced i-loops as a new intermediate in telomere metabolism and reveal a simple mechanism that links telomere damage to the accumulation of extrachromosomal telomeric circles and to telomere erosion.
Subtle metastability of the layered magnetic topological insulator MnBi2Te4 from weak interactions
Authors: Ning Jinliang , Zhu Yanglin , Kidd Jamin , Guan Yingdong , Wang Yu , Mao Zhiqiang , Sun Jianwei 
Published: October 2020

AbstractLayered quantum materials can host interesting properties, including magnetic and topological, for which enormous computational predictions have been done. Their thermodynamic stability is much less visited computationally, which however determines the existence of materials and can be used to guide experimental synthesis. MnBi2Te4 is one of such layered quantum materials that was predicted to be an intrinsic antiferromagnetic topological insulator, and later experimentally realized but in a thermodynamically metastable state. Here, using a combined first-principles-based approach that considers lattice, charge, and spin degrees of freedom, we investigate the metastability of MnBi2Te4 by calculating the Helmholtz free energy for the reaction Bi2Te3 + MnTe → MnBi2Te4. We identify a temperature range (~500–873 K) in which the compound is stable with respect to the competing binary phases, consistent with experimental observation. We validate the predictions by comparing the calculated specific heats contributed from different degrees of freedom with experimental results. Our findings indicate that the degrees of freedom responsible for the van der Waals interaction, lattice vibration, magnetic coupling, and nontrivial band topology in MnBi2Te4 not only enable emergent phenomena but also play a crucial role in determining its thermodynamic stability. This conclusion lays the foundation for the future computational material synthesis of novel layered systems.
Towards a passive limitation of particle surface contamination in the Columbus module (ISS) during the MATISS experiment of the Proxima Mission
Authors: Lemelle Laurence , Campagnolo Lucie , Mottin Eléonore , Le Tourneau Denis , Garre Emmanuel , Marcoux Pierre , Thévenot Cécile , Maillet Alain , Barde Sébastien , Teisseire Jérémie , Nonglaton Guillaume , Place Christophe 
Published: October 2020

AbstractFuture long-duration human spaceflight calls for developments to limit biocontamination of the surface habitats. The MATISS experiment tests surface treatments in the ISS’s atmosphere. Four sample holders were mounted with glass lamella with hydrophobic coatings, and exposed in the Columbus module for ~6 months. About 7800 particles were detected by tile scanning optical microscopy (×3 and ×30 magnification) indicating a relatively clean environment (a few particles per mm2), but leading to a significant coverage-rate (>2% in 20 years). Varied shapes were displayed in the coarse (50–1500 µm2) and fine (0.5–50 µm2) area fractions, consistent with scale dices (tissue or skin) and microbial cells, respectively. The 200–900 µm2 fraction of the coarse particles was systematically higher on FDTS and SiOCH than on Parylene, while the opposite was observed for the <10 µm2 fraction of the fine particles. This trend suggests two biocontamination sources and a surface deposition impacted by hydrophobic coatings.
3D convolutional neural networks-based segmentation to acquire quantitative criteria of the nucleus during mouse embryogenesis
Authors: Tokuoka Yuta , Yamada Takahiro G. , Mashiko Daisuke , Ikeda Zenki , Hiroi Noriko F. , Kobayashi Tetsuya J. , Yamagata Kazuo , Funahashi Akira 
Published: October 2020

AbstractDuring embryogenesis, cells repeatedly divide and dynamically change their positions in three-dimensional (3D) space. A robust and accurate algorithm to acquire the 3D positions of the cells would help to reveal the mechanisms of embryogenesis. To acquire quantitative criteria of embryogenesis from time-series 3D microscopic images, image processing algorithms such as segmentation have been applied. Because the cells in embryos are considerably crowded, an algorithm to segment individual cells in detail and accurately is needed. To quantify the nuclear region of every cell from a time-series 3D fluorescence microscopic image of living cells, we developed QCANet, a convolutional neural network-based segmentation algorithm for 3D fluorescence bioimages. We demonstrated that QCANet outperformed 3D Mask R-CNN, which is currently considered as the best algorithm of instance segmentation. We showed that QCANet can be applied not only to developing mouse embryos but also to developing embryos of two other model species. Using QCANet, we were able to extract several quantitative criteria of embryogenesis from 11 early mouse embryos. We showed that the extracted criteria could be used to evaluate the differences between individual embryos. This study contributes to the development of fundamental approaches for assessing embryogenesis on the basis of extracted quantitative criteria.
Coastal sea level anomalies and associated trends from Jason satellite altimetry over 2002–2018
Authors:   The Climate Change Initiative Coastal Sea Level Team, Benveniste Jérôme , Birol Florence , Calafat Francisco , Cazenave Anny , Dieng Habib , Gouzenes Yvan , Legeais Jean François , Léger Fabien , Niño Fernando , Passaro Marcello , Schwatke Christian , Shaw Andrew 
Published: October 2020

AbstractClimate-related sea level changes in the world coastal zones result from the superposition of the global mean rise due to ocean warming and land ice melt, regional changes caused by non-uniform ocean thermal expansion and salinity changes, and by the solid Earth response to current water mass redistribution and associated gravity change, plus small-scale coastal processes (e.g., shelf currents, wind & waves changes, fresh water input from rivers, etc.). So far, satellite altimetry has provided global gridded sea level time series up to 10–15 km to the coast only, preventing estimation of sea level changes very close to the coast. Here we present a 16-year-long (June 2002 to May 2018), high-resolution (20-Hz), along-track sea level dataset at monthly interval, together with associated sea level trends, at 429 coastal sites in six regions (Northeast Atlantic, Mediterranean Sea, Western Africa, North Indian Ocean, Southeast Asia and Australia). This new coastal sea level product is based on complete reprocessing of raw radar altimetry waveforms from the Jason-1, Jason-2 and Jason-3 missions.