bluuebunny/crossref_metadata_2025_split huggingface dataset:
On Use of Low Cost, Compact GNSS Receiver Modules for Ionosphere Monitoring
Authors: Dan Sukabya , Santra Atanu , Mahato Somnath , Koley Chaitali , Banerjee P. , Bose Anindya 
Published: December 2021

AbstractGeodetic or special purpose Global Navigation Satellite System (GNSS) receivers are used for ionosphere monitoring and research. Dual frequency, compact, low‐cost commercial GNSS modules can provide raw GNSS data and are commonly used for positioning applications. This paper presents the applicability of these compact modules for monitoring ionospheric activities. A comparative study between Javad Triumph LS, a costly geodetic receiver, and an Ublox ZED‐F9P, a low‐cost, dual‐frequency, compact module is carried out to explore the potential of the low‐cost devices for ionosphere probing. Studies are carried out on signal strength values (C/N0) and vertical total electron content (VTEC) values. From the concurrently collected GPS data, a bias of 2.2–4.9 dBHz in signal strength values are observed between the two types of receivers depending on the signal frequency band. The VTEC values calculated from the Ublox module are in close agreement with the values obtained from the Triumph LS receiver. Therefore, the compact module shows the potential for use in ionosphere monitoring with clear advantages in cost, size, and power consumption. However, the signal strength values obtained from such compact modules need to be calibrated using standard GNSS receivers. A GNSS‐based Ionosphere Monitoring Unit (GIMU) is also proposed in this manuscript by the integration of a compact, low‐cost GNSS module with a single‐board computer and a wireless data communication module. Real‐time, cost‐effective, concurrent ionosphere monitoring over a geographically distributed network is possible using a network of such units.
Radiation Belt Model Including Semi‐Annual Variation and Solar Driving (Sentinel)
Authors: Katsavrias C. , Aminalragia‐Giamini S. , Papadimitriou C. , Daglis I. A. , Sandberg I. , Jiggens P. 
Published: December 2021

AbstractThe Earth's outer radiation belt response to geospace disturbances is extremely variable spanning from a few hours to several months. In addition, the numerous physical mechanisms, which control this response depend on the electron energy, the timescale, and the various types of geospace disturbances. As a consequence, various models that currently exist are either specialized, orbit‐specific data‐driven models, or sophisticated physics‐based ones. In this paper, we present a new approach for radiation belt modeling using Machine Learning methods driven solely by Solar wind speed and pressure, Solar flux at 10.7 cm, and the angle controlling the Russell‐McPherron effect (θRM). We show that the model can successfully reproduce and predict the electron fluxes of the outer radiation belt in a broad energy (0.033–4.062 MeV) and L‐shell (2.5–5.9) range, and moreover, it can capture the long‐term modulation of the semi‐annual variation. We also show that the model can generalize well and provide successful predictions, even outside of the spatio‐temporal range it has been trained with, using 0.8 MeV electron flux measurements from GOES‐15/EPEAD at a geostationary orbit.
The Relationship Between Delta Form and Nitrate Retention Revealed by Numerical Modeling Experiments
Authors: Knights Deon , Sawyer Audrey H. , Edmonds Douglas A. , Olliver Elizabeth A. , Barnes Rebecca T. 
Published: December 2021

AbstractRiver deltas display a wide range of morphologic patterns that influence how nutrients interact in channels and wetlands on their way to the coast. To quantify the role of delta morphology on nitrate fate, we simulated reactive nitrate transport over steady base flow conditions for six synthetic, morphologically unique river‐dominated deltas created in Delft3D by varying incoming grain size distributions. We parameterized nitrate removal kinetics using an observed relationship with elevation from Wax Lake Delta (Louisiana, USA). Total nitrate retention across the six synthetic deltas and Wax Lake Delta ranged from 1.3%‐13%, suggesting that these river‐dominated deltas have limited ability to remove nitrate from incoming river water. Nitrate removal is constrained by limited hydrologic connectivity with the areas of greatest nitrate demand, which are found at higher elevation. In these synthetic numerical experiments, the efficiency of nitrate removal is greatest for deltas with more topologic complexity and greater proportions of the delta plain at higher elevation, which are both common characteristics of coarser‐grained deltas. The positive relationship between grain size and nitrate removal may help guide land reclamation projects if project goals include minimizing nitrate export to the sea.
Antibiotics in critically ill children—a narrative review on different aspects of a rational approach
Authors: Bruns Nora , Dohna-Schwake Christian 
Published: December 2021

Abstract
Especially critically ill children are exposed to antibiotic overtreatment, mainly caused by the fear of missing out a severe bacterial infection. Potential adverse effects and selection of multi-drug resistant bacteria play minor roles in decision making. This narrative review first describes harm from antibiotics and second focuses on different aspects that could help to reduce antibiotic overtreatment without harming the patient: harm from antibiotic treatment, diagnostic approaches, role of biomarkers, timing of antibiotic therapy, empiric therapy, targeted therapy, and therapeutic drug monitoring. Wherever possible, we linked the described evidence to the current Surviving Sepsis Campaign guidelines. Antibiotic stewardship programs should help guiding antibiotic therapy for critically ill children.

Impact

Critically ill children can be harmed by inadequate or overuse of antibiotics.

Hemodynamically unstable children with a suspicion of infection should be immediately treated with broad-spectrum antibiotics. In contrast, in hemodynamically stable children with sepsis and organ dysfunction, a time frame of 3 h for proper diagnostics may be adequate before starting antibiotics if necessary.

Less and more targeted antibiotic treatment can be achieved via antibiotic stewardship programs.
Genetically regulated expression in late-onset Alzheimer’s disease implicates risk genes within known and novel loci
Authors: Chen Hung-Hsin , Petty Lauren E. , Sha Jin , Zhao Yi , Kuzma Amanda , Valladares Otto ,   Alzheimer’s Disease Genetics Consortium, International Genomics of Alzheimer’s Project, Bush William , Naj Adam C. , Gamazon Eric R. , Below Jennifer E. 
Published: December 2021

AbstractLate-onset Alzheimer disease (LOAD) is highly polygenic, with a heritability estimated between 40 and 80%, yet risk variants identified in genome-wide studies explain only ~8% of phenotypic variance. Due to its increased power and interpretability, genetically regulated expression (GReX) analysis is an emerging approach to investigate the genetic mechanisms of complex diseases. Here, we conducted GReX analysis within and across 51 tissues on 39 LOAD GWAS data sets comprising 58,713 cases and controls from the Alzheimer’s Disease Genetics Consortium (ADGC) and the International Genomics of Alzheimer’s Project (IGAP). Meta-analysis across studies identified 216 unique significant genes, including 72 with no previously reported LOAD GWAS associations. Cross-brain-tissue and cross-GTEx models revealed eight additional genes significantly associated with LOAD. Conditional analysis of previously reported loci using established LOAD-risk variants identified eight genes reaching genome-wide significance independent of known signals. Moreover, the proportion of SNP-based heritability is highly enriched in genes identified by GReX analysis. In summary, GReX-based meta-analysis in LOAD identifies 216 genes (including 72 novel genes), illuminating the role of gene regulatory models in LOAD.
Low NCOR2 levels in multiple myeloma patients drive multidrug resistance via MYC upregulation
Authors: Mori Tomoaki , Verma Rakesh , Nakamoto-Matsubara Rie , Siu Ka Tat , Panaroni Cristina , Fulzele Keertik S. , Mukaihara Kenta , Onyewadume Chukwuamaka , Maebius Allison , Kato Hiroki , Wong Lai Ping , Sadreyev Ruslan I. , Scadden David T. , Raje Noopur S. 
Published: December 2021

AbstractMYC upregulation is associated with multidrug refractory disease in patients with multiple myeloma (MM). We, isolated patient-derived MM cells with high MYC expression and discovered that NCOR2 was down-regulated in these cells. NCOR2 is a transcriptional coregulatory protein and its role in MM remains unknown. To define the role of NCOR2 in MM, we created NCOR2 knockout human myeloma cell lines and demonstrated that NCOR2 knockout led to high MYC expression. Furthermore, NCOR2 knockout conferred resistance to pomalidomide, BET and HDAC inhibitors, independent of Cereblon (CRBN), indicating high MYC expression as a cause of multidrug resistance. Moreover, NCOR2 interacted with the nucleosome remodeling and deacetylase (NuRD) complex and repressed the expression of CD180 by directly binding to its promoter and inducing MYC expression. Next, we generated lenalidomide-resistant and pomalidomide-resistant human myeloma cell lines. Whole-exome sequencing revealed that these cell lines acquired the same exonic mutations of NCOR2. These cell lines showed NCOR2 downregulation and MYC upregulation independent of CRBN and demonstrated resistance to BET and HDAC inhibitors. Our findings reveal a novel CRBN independent molecular mechanism associated with drug resistance. Low NCOR2 expression can serve as a potential biomarker for drug resistance and needs further validation in larger prospective studies.
HP1a-mediated heterochromatin formation inhibits high dietary sugar-induced tumor progression
Authors: Chang Che-Wei , Shen Yu-Chia , Yan Shian-Jang 
Published: December 2021

AbstractHigh dietary sugar (HDS) is a modern dietary concern that involves excessive consumption of carbohydrates and added sugars, and increases the risk of metabolic disorders and associated cancers. However, epigenetic mechanisms by which HDS induces tumor progression remain unclear. Here, we investigate the role of heterochromatin, an important yet poorly understood part of the epigenome, in HDS-induced tumor progression of Drosophila Ras/Src and Ras/scrib tumor systems. We found that increased heterochromatin formation with overexpression of heterochromatin protein 1a (HP1a), specifically in tumor cells, not only decreases HDS-induced tumor growth/burden but also drastically improves survival of Drosophila with HDS and Ras/Src or Ras/scrib tumors. Moreover, HDS reduces heterochromatin levels in tumor cells. Mechanistically, we demonstrated that increased heterochromatin formation decreases wingless (wg) and Hippo (Hpo) signaling, thereby promoting apoptosis, via inhibition of Yorkie (Yki) nuclear accumulation and upregulation of apoptotic genes, and reduces DNA damage in tumor cells under HDS. Taken together, our work identified a novel epigenetic mechanism by which HP1a-mediated heterochromatin formation suppresses HDS-induced tumor progression likely by decreasing wingless and Hippo signaling, increasing apoptosis, and maintaining genome stability. Our model explains that the molecular, cellular, and organismal aspects of HDS-aggravated tumor progression are dependent on heterochromatin formation, and highlights heterochromatin as a therapeutic target for cancers associated with HDS-induced metabolic disorders.
Matrix stiffness modulates hepatic stellate cell activation into tumor-promoting myofibroblasts via E2F3-dependent signaling and regulates malignant progression
Authors: Liu Zhikui , Mo Huanye , Liu Runkun , Niu Yongshen , Chen Tianxiang , Xu Qiuran , Tu Kangsheng , Yang Nan 
Published: December 2021

AbstractThe hepatic stellate cells (HSCs) activation by myofibroblastic differentiation is critical for liver fibrosis. Crosstalk between stromal cells and tumor cells in the microenvironment alters the properties and facilitates the growth and metastasis of tumor cells. How mechanical stimuli originally stiffness of extracellular matrix (ECM) contribute to tumor development remains poorly understood. Here, we demonstrated that stiffness contributes to mechanosignal transduction in HSCs, which promotes hepatocellular carcinoma (HCC) cells growth and metastasis through secretion of FGF2. On stiffness matrix, HSCs activation was confirmed by immunofluorescence (IF) and Western blot (WB) for α-smooth muscle actin (SMA). Increasing matrix stiffness promoted HSCs activation by CD36-AKT-E2F3 mechanosignaling through shRNA-mediated E2F3 knockdown, AKT inhibitors, and CD36 shRNA. Moreover, ChIP-qPCR. Confirmed that E2F3 combined the promoter of FGF2, and stiffness promoted FGF2 expression. On a stiff matrix, HCC cells cultured with conditioned media (CM) from HSCs increased HCC cells growth and metastasis by binding FGFR1 to activate PI3K/AKT and MEK/ERK signaling pathways. Moreover, conditional E2F3 knockout mice were subjected to CCl4 treatment to assess the role of E2F3 in HSC activation. Additionally, the DEN-induced HCC model was also used to evaluate the role of E2F3 in liver fibrosis and HCC growth. In conclusion, we demonstrated that stiffness-induced HSC activation by E2F3 dependent. Stiffness activated CD36-AKT-E2F3 signaling and targeted FGF2 transcription, subsequently, activated HCC growth and metastasis by FGFR1-mediated PI3K/AKT and MEK/ERK signaling.
Oligodendrocytes depend on MCL-1 to prevent spontaneous apoptosis and white matter degeneration
Authors: Cleveland Abigail H. , Romero-Morales Alejandra , Azcona Laurent Alfonso , Herrero Melisa , Nikolova Viktoriya D. , Moy Sheryl , Elroy-Stein Orna , Gama Vivian , Gershon Timothy R. 
Published: December 2021

AbstractNeurologic disorders often disproportionately affect specific brain regions, and different apoptotic mechanisms may contribute to white matter pathology in leukodystrophies or gray matter pathology in poliodystrophies. We previously showed that neural progenitors that generate cerebellar gray matter depend on the anti-apoptotic protein BCL-xL. Conditional deletion of Bcl-xL in these progenitors produces spontaneous apoptosis and cerebellar hypoplasia, while similar conditional deletion of Mcl-1 produces no phenotype. Here we show that, in contrast, postnatal oligodendrocytes depend on MCL-1. We found that brain-wide Mcl-1 deletion caused apoptosis specifically in mature oligodendrocytes while sparing astrocytes and oligodendrocyte precursors, resulting in impaired myelination and progressive white matter degeneration. Disabling apoptosis through co-deletion of Bax or Bak rescued white matter degeneration, implicating the intrinsic apoptotic pathway in Mcl-1-dependence. Bax and Bak co-deletions rescued different aspects of the Mcl-1-deleted phenotype, demonstrating their discrete roles in white matter stability. MCL-1 protein abundance was reduced in eif2b5-mutant mouse model of the leukodystrophy vanishing white matter disease (VWMD), suggesting the potential for MCL-1 deficiency to contribute to clinical neurologic disease. Our data show that oligodendrocytes require MCL-1 to suppress apoptosis, implicate MCL-1 deficiency in white matter pathology, and suggest apoptosis inhibition as a leukodystrophy therapy.
2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA
Authors: Pantic Boris , Ives Daniel , Mennuni Mara , Perez-Rodriguez Diego , Fernandez-Pelayo Uxoa , Lopez de Arbina Amaia , Muñoz-Oreja Mikel , Villar-Fernandez Marina , Dang Thanh-mai Julie , Vergani Lodovica , Johnston Iain G. , Pitceathly Robert D. S. , McFarland Robert , Hanna Michael G. , Taylor Robert W. , Holt Ian J. , Spinazzola Antonella 
Published: December 2021

AbstractPathological variants of human mitochondrial DNA (mtDNA) typically co-exist with wild-type molecules, but the factors driving the selection of each are not understood. Because mitochondrial fitness does not favour the propagation of functional mtDNAs in disease states, we sought to create conditions where it would be advantageous. Glucose and glutamine consumption are increased in mtDNA dysfunction, and so we targeted the use of both in cells carrying the pathogenic m.3243A>G variant with 2-Deoxy-D-glucose (2DG), or the related 5-thioglucose. Here, we show that both compounds selected wild-type over mutant mtDNA, restoring mtDNA expression and respiration. Mechanistically, 2DG selectively inhibits the replication of mutant mtDNA; and glutamine is the key target metabolite, as its withdrawal, too, suppresses mtDNA synthesis in mutant cells. Additionally, by restricting glucose utilization, 2DG supports functional mtDNAs, as glucose-fuelled respiration is critical for mtDNA replication in control cells, when glucose and glutamine are scarce. Hence, we demonstrate that mitochondrial fitness dictates metabolite preference for mtDNA replication; consequently, interventions that restrict metabolite availability can suppress pathological mtDNAs, by coupling mitochondrial fitness and replication.
Sexual dimorphism in glucose metabolism is shaped by androgen-driven gut microbiome
Authors: Gao Aibo , Su Junlei , Liu Ruixin , Zhao Shaoqian , Li Wen , Xu Xiaoqiang , Li Danjie , Shi Juan , Gu Bin , Zhang Juan , Li Qi , Wang Xiaolin , Zhang Yifei , Xu Yu , Lu Jieli , Ning Guang , Hong Jie , Bi Yufang , Gu Weiqiong , Wang Jiqiu , Wang Weiqing 
Published: December 2021

AbstractMales are generally more susceptible to impaired glucose metabolism and type 2 diabetes (T2D) than females. However, the underlying mechanisms remain to be determined. Here, we revealed that gut microbiome depletion abolished sexual dimorphism in glucose metabolism. The transfer of male donor microbiota into antibiotics-treated female mice led the recipients to be more insulin resistant. Depleting androgen via castration changed the gut microbiome of male mice to be more similar to that of females and improved glucose metabolism, while reintroducing dihydrotestosterone (DHT) reversed these alterations. More importantly, the effects of androgen on glucose metabolism were largely abolished when the gut microbiome was depleted. Next, we demonstrated that androgen modulated circulating glutamine and glutamine/glutamate (Gln/Glu) ratio partially depending on the gut microbiome, and glutamine supplementation increases insulin sensitivity in vitro. Our study identifies the effects of androgen in deteriorating glucose homeostasis partially by modulating the gut microbiome and circulating glutamine and Gln/Glu ratio, thereby contributing to the difference in glucose metabolism between the two sexes.
Monitoring the binding and insertion of a single transmembrane protein by an insertase
Authors: Laskowski Pawel R. , Pluhackova Kristyna , Haase Maximilian , Lang Brian M. , Nagler Gisela , Kuhn Andreas , Müller Daniel J. 
Published: December 2021

AbstractCells employ highly conserved families of insertases and translocases to insert and fold proteins into membranes. How insertases insert and fold membrane proteins is not fully known. To investigate how the bacterial insertase YidC facilitates this process, we here combine single-molecule force spectroscopy and fluorescence spectroscopy approaches, and molecular dynamics simulations. We observe that within 2 ms, the cytoplasmic α-helical hairpin of YidC binds the polypeptide of the membrane protein Pf3 at high conformational variability and kinetic stability. Within 52 ms, YidC strengthens its binding to the substrate and uses the cytoplasmic α-helical hairpin domain and hydrophilic groove to transfer Pf3 to the membrane-inserted, folded state. In this inserted state, Pf3 exposes low conformational variability such as typical for transmembrane α-helical proteins. The presence of YidC homologues in all domains of life gives our mechanistic insight into insertase-mediated membrane protein binding and insertion general relevance for membrane protein biogenesis.
A genetically encoded fluorescent biosensor for extracellular l-lactate
Authors: Nasu Yusuke , Murphy-Royal Ciaran , Wen Yurong , Haidey Jordan N. , Molina Rosana S. , Aggarwal Abhi , Zhang Shuce , Kamijo Yuki , Paquet Marie-Eve , Podgorski Kaspar , Drobizhev Mikhail , Bains Jaideep S. , Lemieux M. Joanne , Gordon Grant R. , Campbell Robert E. 
Published: December 2021

Abstractl-Lactate, traditionally considered a metabolic waste product, is increasingly recognized as an important intercellular energy currency in mammals. To enable investigations of the emerging roles of intercellular shuttling of l-lactate, we now report an intensiometric green fluorescent genetically encoded biosensor for extracellular l-lactate. This biosensor, designated eLACCO1.1, enables cellular resolution imaging of extracellular l-lactate in cultured mammalian cells and brain tissue.
Proximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome
Authors: Roostaei Tina , Klein Hans-Ulrich , Ma Yiyi , Felsky Daniel , Kivisäkk Pia , Connor Sarah M. , Kroshilina Alexandra , Yung Christina , Kaskow Belinda J. , Shao Xiaorong , Rhead Brooke , Ordovás José M. , Absher Devin M. , Arnett Donna K. , Liu Jia , Patsopoulos Nikolaos , Barcellos Lisa F. , Weiner Howard L. , De Jager Philip L. 
Published: December 2021

AbstractIdentifying the effects of genetic variation on the epigenome in disease-relevant cell types can help advance our understanding of the first molecular contributions of genetic susceptibility to disease onset. Here, we establish a genome-wide map of DNA methylation quantitative trait loci in CD4+ T-cells isolated from multiple sclerosis patients. Utilizing this map in a colocalization analysis, we identify 19 loci where the same haplotype drives both multiple sclerosis susceptibility and local DNA methylation. We also identify two distant methylation effects of multiple sclerosis susceptibility loci: a chromosome 16 locus affects PRDM8 methylation (a chromosome 4 region not previously associated with multiple sclerosis), and the aggregate effect of multiple sclerosis-associated variants in the major histocompatibility complex influences DNA methylation near PRKCA (chromosome 17). Overall, we present a new resource for a key cell type in inflammatory disease research and uncover new gene targets for the study of predisposition to multiple sclerosis.
Evaluation of fNIRS signal components elicited by cognitive and hypercapnic stimuli
Authors: Reddy Pratusha , Izzetoglu Meltem , Shewokis Patricia A. , Sangobowale Michael , Diaz-Arrastia Ramon , Izzetoglu Kurtulus 
Published: December 2021

AbstractFunctional near infrared spectroscopy (fNIRS) measurements are confounded by signal components originating from multiple physiological causes, whose activities may vary temporally and spatially (across tissue layers, and regions of the cortex). Furthermore, the stimuli can induce evoked effects, which may lead to over or underestimation of the actual effect of interest. Here, we conducted a temporal, spectral, and spatial analysis of fNIRS signals collected during cognitive and hypercapnic stimuli to characterize effects of functional versus systemic responses. We utilized wavelet analysis to discriminate physiological causes and employed long and short source-detector separation (SDS) channels to differentiate tissue layers. Multi-channel measures were analyzed further to distinguish hemispheric differences. The results highlight cardiac, respiratory, myogenic, and very low frequency (VLF) activities within fNIRS signals. Regardless of stimuli, activity within the VLF band had the largest contribution to the overall signal. The systemic activities dominated the measurements from the short SDS channels during cognitive stimulus, but not hypercapnic stimulus. Importantly, results indicate that characteristics of fNIRS signals vary with type of the stimuli administered as cognitive stimulus elicited variable responses between hemispheres in VLF band and task-evoked temporal effect in VLF, myogenic and respiratory bands, while hypercapnic stimulus induced a global response across both hemispheres.