bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular programming in utero modulates hepatic lipid metabolism and adult metabolic risk in obese mother offspring in a sex-specific manner
Authors: Savva Christina , Helguero Luisa A. , González-Granillo Marcela , Melo Tânia , Couto Daniela , Angelin Bo , Rosário Domingues Maria , Li Xidan , Kutter Claudia , Korach-André Marion 
Published: May 2021

AbstractMale and female offspring of obese mothers are known to differ significantly in their metabolic adaptation and later development of complications. We investigated the sex-dependent responses in obese offspring of mice with maternal obesity, focusing on changes in liver glucose and lipid metabolism. Maternal obesity prior to and during gestation led to hepatic insulin resistance and inflammation in male offspring, while female offspring were protected. These sex differences were explained by more efficient transcriptional and posttranscriptional reprogramming of metabolic pathways to prevent the damaging effects of maternal obesity in females compared to males. These differences were sustained later in life, resulting in a better metabolic balance in female offspring. In conclusion, sex and maternal obesity drive transcriptional and posttranscriptional regulation of major metabolic processes in offspring liver differently, explaining the sexual dimorphism in obesity-associated metabolic risk.
Genome-wide screening in human kidney organoids identifies novel aspects of nephrogenesis
Authors: Ungricht Rosemarie , Guibbal Laure , Lasbennes Marie-Christine , Orsini Vanessa , Beibel Martin , Waldt Annick , Cuttat Rachel , Carbone Walter , Basler Anne , Roma Guglielmo , Nigsch Florian , Tchorz Jan , Hoepfner Dominic , Hoppe Philipp S. 
Published: May 2021

AbstractHuman organoids allow studying proliferation, lineage specification, and three-dimensional tissue development. Due to the inherent multicellular complexity, interrogation by systematic genetic methodologies is challenging. Here, we present the first genome-wide CRISPR screen in iPSC-derived kidney organoids. The combination of genome editing, longitudinal sampling and sorting of specific cell populations enabled us to uncover novel biology from development to tubular morphogenesis. We validated the high quality of our screen by individual hit follow up and comparisons to kidney disease datasets. The discovery of a novel regulatory mechanism which controls epithelial proliferation via a trans-activating but cis-inhibitory effect of the Notch ligand Jagged1 proves how mosaic knockouts generated by pooled CRISPR screening in organoids can identify novel ways of communication between heterogeneous cell populations in complex tissues. Collectively, these data demonstrate the feasibility of using complex iPSC- derived organoids for genome-scale screening and serves as a benchmark for future organoid CRISPR screens.
SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation
Authors: Li Taiwei , Kenney Adam D. , Liu Helu , Fiches Guillaume N. , Zhou Dawei , Biswas Ayan , Que Jianwen , Santoso Netty , Yount Jacob S. , Zhu Jian 
Published: May 2021

SummarySevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to NF-κB activation and induction of pro-inflammatory cytokines, though the underlying mechanism for this activation is not fully understood. Our results reveal that the SARS-CoV-2 Nsp14 protein contributes to the viral activation of NF-κB signaling. Nsp14 caused the nuclear translocation of NF-κB p65. Nsp14 induced the upregulation of IL-6 and IL-8, which also occurred in SARS-CoV-2 infected cells. IL-8 upregulation was further confirmed in lung tissue samples from COVID-19 patients. A previous proteomic screen identified the putative interaction of Nsp14 with host Inosine-5’-monophosphate dehydrogenase 2 (IMPDH2) protein, which is known to regulate NF-κB signaling. We confirmed the Nsp14-IMPDH2 protein interaction and found that IMPDH2 knockdown or chemical inhibition using ribavirin (RIB) and mycophenolic acid (MPA) abolishes Nsp14-mediated NF-κB activation and cytokine induction. Furthermore, IMDPH2 inhibitors (RIB, MPA) efficiently blocked SARS-CoV-2 infection, indicating that IMDPH2, and possibly NF-κB signaling, is beneficial to viral replication. Overall, our results identify a novel role of SARS-CoV-2 Nsp14 in causing the activation of NF-κB.
The complete sequence of a human genome
Authors: Nurk Sergey , Koren Sergey , Rhie Arang , Rautiainen Mikko , Bzikadze Andrey V. , Mikheenko Alla , Vollger Mitchell R. , Altemose Nicolas , Uralsky Lev , Gershman Ariel , Aganezov Sergey , Hoyt Savannah J. , Diekhans Mark , Logsdon Glennis A. , Alonge Michael , Antonarakis Stylianos E. , Borchers Matthew , Bouffard Gerard G. , Brooks Shelise Y. , Caldas Gina V. , Cheng Haoyu , Chin Chen-Shan , Chow William , de Lima Leonardo G. , Dishuck Philip C. , Durbin Richard , Dvorkina Tatiana , Fiddes Ian T. , Formenti Giulio , Fulton Robert S. , Fungtammasan Arkarachai , Garrison Erik , Grady Patrick G.S. , Graves-Lindsay Tina A. , Hall Ira M. , Hansen Nancy F. , Hartley Gabrielle A. , Haukness Marina , Howe Kerstin , Hunkapiller Michael W. , Jain Chirag , Jain Miten , Jarvis Erich D. , Kerpedjiev Peter , Kirsche Melanie , Kolmogorov Mikhail , Korlach Jonas , Kremitzki Milinn , Li Heng , Maduro Valerie V. , Marschall Tobias , McCartney Ann M. , McDaniel Jennifer , Miller Danny E. , Mullikin James C. , Myers Eugene W. , Olson Nathan D. , Paten Benedict , Peluso Paul , Pevzner Pavel A. , Porubsky David , Potapova Tamara , Rogaev Evgeny I. , Rosenfeld Jeffrey A. , Salzberg Steven L. , Schneider Valerie A. , Sedlazeck Fritz J. , Shafin Kishwar , Shew Colin J. , Shumate Alaina , Sims Yumi , Smit Arian F. A. , Soto Daniela C. , Sović Ivan , Storer Jessica M. , Streets Aaron , Sullivan Beth A. , Thibaud-Nissen Françoise , Torrance James , Wagner Justin , Walenz Brian P. , Wenger Aaron , Wood Jonathan M. D. , Xiao Chunlin , Yan Stephanie M. , Young Alice C. , Zarate Samantha , Surti Urvashi , McCoy Rajiv C. , Dennis Megan Y. , Alexandrov Ivan A. , Gerton Jennifer L. , O’Neill Rachel J. , Timp Winston , Zook Justin M. , Schatz Michael C. , Eichler Evan E. , Miga Karen H. , Phillippy Adam M. 
Published: May 2021

AbstractIn 2001, Celera Genomics and the International Human Genome Sequencing Consortium published their initial drafts of the human genome, which revolutionized the field of genomics. While these drafts and the updates that followed effectively covered the euchromatic fraction of the genome, the heterochromatin and many other complex regions were left unfinished or erroneous. Addressing this remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium has finished the first truly complete 3.055 billion base pair (bp) sequence of a human genome, representing the largest improvement to the human reference genome since its initial release. The new T2T-CHM13 reference includes gapless assemblies for all 22 autosomes plus Chromosome X, corrects numerous errors, and introduces nearly 200 million bp of novel sequence containing 2,226 paralogous gene copies, 115 of which are predicted to be protein coding. The newly completed regions include all centromeric satellite arrays and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies for the first time.
Impaired function and delayed regeneration of dendritic cells in COVID-19
Authors: Winheim Elena , Rinke Linus , Lutz Konstantin , Reischer Anna , Leutbecher Alexandra , Wolfram Lina , Rausch Lisa , Kranich Jan , Wratil Paul R. , Huber Johanna E. , Baumjohann Dirk , Rothenfußer Simon , Hellmuth Johannes C. , Scherer Clemens , Muenchhoff Maximilian , Bergwelt-Baildon Michael von , Stark Konstantin , Straub Tobias , Brocker Thomas , Keppler Oliver T. , Subklewe Marion , Krug Anne B. 
Published: May 2021

AbstractDisease manifestations in COVID-19 range from mild to severe illness associated with a dysregulated innate immune response. Alterations in function and regeneration of dendritic cells (DC) and monocytes may contribute to immunopathology and influence adaptive immune responses in COVID-19 patients. We analyzed circulating DC and monocyte subsets in 65 hospitalized COVID-19 patients with mild/moderate or severe disease from acute disease to recovery and in healthy controls. Persisting reduction of all DC subpopulations was accompanied by an expansion of proliferating Lineage- HLADR+ cells lacking DC markers. Increased frequency of the recently discovered CD163+ CD14+ DC3 subpopulation in patients with more severe disease was associated with systemic inflammation, activated T follicular helper cells, and antibody-secreting cells. Persistent downregulation of CD86 and upregulation of PD-L1 in conventional DC (cDC2 and DC3) and classical monocytes associated with a reduced capacity to stimulate naïve CD4+ T cells correlated with disease severity. Long-lasting depletion and functional impairment of DCs and monocytes may have consequences for susceptibility to secondary infections and therapy of COVID-19 patients.
Comparison of linear combination modeling strategies for GABA-edited MRS at 3T
Authors: Zöllner Helge J. , Tapper Sofie , Hui Steve C. N. , Barker Peter B. , Edden Richard A. E. , Oeltzschner Georg 
Published: May 2021

AbstractPurposeJ-difference-edited spectroscopy is a valuable approach for the in vivo detection of γ-aminobutyric-acid (GABA) with MRS. A recent expert consensus article recommends linear combination modeling (LCM) of edited MRS but does not give specific details of implementation. This study explores different modeling strategies to adapt LCM for GABA-edited MRS.Methods61 medial parietal lobe GABA-edited MEGA-PRESS spectra from a recent 3T multi-site study were modeled using 102 different strategies combining six different approaches to account for co-edited macromolecules, three modeling ranges, three baseline knot spacings, and the use of basis sets with or without homocarnosine. The resulting GABA and GABA+ estimates (quantified relative to total creatine), the residuals at different ranges, SDs and CVs, and Akaike information criteria, were used to evaluate the models’ performance.ResultsSignificantly different GABA+ and GABA estimates were found when a well-parameterized MM3cobasis function was included in the model. The mean GABA estimates were significantly lower when modeling MM, while the CVs were similar. A sparser spline knot spacing led to lower variation in the GABA and GABA+ estimates, and a narrower modeling range – only including the signals of interest – did not substantially improve or degrade modeling performance. Additionally, results suggest that LCM can separate GABA and the underlying co-edited MM3co. Incorporating homocarnosine into the modeling did not significantly improve variance in GABA+ estimates.ConclusionGABA-edited MRS is most appropriately quantified by LCM with a well-parameterized co-edited MM3cobasis function with a constraint to the non-overlapped MM0.93, in combination with a sparse spline knot spacing (0.55 ppm) and a modeling range between 0.5 and 4 ppm.Graphical Abstract102 strategies to model GABA-edited MRS with linear combination modeling were evaluated to quantify GABA and GABA+ in Osprey. Significantly different GABA and GABA+ estimates were found when a well-parameterized macro-molecule at 3 ppm was included. The findings suggest that linear combination modeling needs to be adapted for quantification of GABA-edited MRS.
PGC1α Regulates the Endothelial Response to Fluid Shear Stress via Telomerase Reverse Transcriptase Control of Heme Oxygenase-1
Authors: Kant Shashi , Tran Khanh-Van , Kvandova Miroslava , Caliz Amada D. , Yoo Hyung-Jin , Learnard Heather , Craige Siobhan M. , Hall Joshua D. , Jiménez Juan M. , Hilaire Cynthia St. , Schulz Eberhard , Kröller-Schön Swenja , Keaney John F. 
Published: May 2021

AbstractFluid shear stress (FSS) is known to mediate multiple phenotypic changes in the endothelium. Laminar FSS (undisturbed flow) is known to promote endothelial alignment to flow that is key to stabilizing the endothelium and rendering it resistant to atherosclerosis and thrombosis. The molecular pathways responsible for endothelial responses to FSS are only partially understood. Here we have identified peroxisome proliferator gamma coactivator-1α (PGC-1α) as a flow-responsive gene required for endothelial flow alignment in vitro and in vivo. Compared to oscillatory FSS (disturbed flow) or static conditions, laminar FSS (undisturbed flow) increased PGC-1α expression and its transcriptional co-activation. PGC-1α was required for laminar FSS-induced expression of telomerase reverse transcriptase (TERT) in vitro and in vivo via its association with ERRα and KLF4 on the TERT promoter. We found that TERT inhibition attenuated endothelial flow alignment, elongation, and nuclear polarization in response to laminar FSS in vitro and in vivo. Among the flow-responsive genes sensitive to TERT status was heme oxygenase-1 (HMOX1), a gene required for endothelial alignment to laminar FSS. Thus, these data suggest an important role for a PGC-1α-TERT-HMOX1 axis in the endothelial stabilization response to laminar FSS.
Hydrophobic mismatch is a key factor in protein transport on the Tat pathway
Authors: Hao Binhan , Zhou Wenjie , Theg Steven M. 
Published: May 2021

AbstractThe twin-arginine translocation (Tat) pathway transports folded proteins across membranes in bacteria, thylakoid, plant mitochondria, and archaea. In most species, the active Tat machinery consists of three independent subunits, TatA, TatB and TatC. TatA and TatB from all bacterial species possess short transmembrane alpha-helices (TMHs), both of which are only fifteen residues long in E. coli. Such short TMHs cause a hydrophobic mismatch between Tat subunits and the membrane bilayer. Here, by modifying the length of the TMHs of E. coli TatA and TatB, we assess the functional importance of the hydrophobic mismatch in the Tat transport mechanism. Surprisingly, both TatA and TatB with as few as 11 residues in their respective TMHs are still able to insert into the membrane bilayer, albeit with a decline in membrane integrity. Three different assays, both qualitative and quantitative, were conducted to evaluate the Tat activity of the TMH length mutants. Our experiments indicate that the TMHs of TatA and TatB appear to be evolutionarily tuned to 15 amino acids, with activity dropping off with any modification of this length. We believe our study supports a model of Tat transport utilizing localized toroidal pores that form when the membrane bilayer is thinned to a critical threshold. In this context, the 15-residue length of the TatA and TatB TMHs can be seen as a compromise between the need for some hydrophobic mismatch to allow the membrane to reversibly reach the threshold thinness required for toroidal pore formation, and the permanently destabilizing effect of placing even shorter helices into these energy-transducing membranes.
Microtubules Promote the Non-cell Autonomy of MicroRNAs by Inhibiting their Cytoplasmic Loading into ARGONAUTE1 inArabidopsis
Authors: Fan Lusheng , Zhang Cui , Zhang Yong , Stewart Ethan , Jez Jakub , Nakajima Keiji , Chen Xuemei 
Published: May 2021

ABSTRACTMobile microRNAs (miRNAs) serve as local and long-distance signals in developmental patterning and stress responses in plants. However, mechanisms governing the non-cell autonomous activities of miRNAs remain elusive. Here, we show that mutations that disrupt microtubule dynamics are specifically defective for the non-cell autonomous actions of mobile miRNAs, including miR165/6 that is produced in the endodermis and moves to the vasculature to pattern xylem cell fates inArabidopsisroots. We show that KTN1, a subunit of a microtubule-severing enzyme, is required in source and intermediary cells to inhibit the loading of miR165/6 into ARGONUATE1 (AGO1), which is cell-autonomous, to enable the miRNA‟s cell exit. Microtubule disruption enhances the association of miR165/6 with AGO1 in the cytosol. These findings suggest that, while cell-autonomous miRNAs load into AGO1 in the nucleus, cytoplasmic AGO1 loading of mobile miRNAs is a key step regulated by microtubules to promote the range of miRNA‟s cell-to-cell movement.
Histone acetyltransferase activity of CREB-binding protein is essential for synaptic plasticity in Lymnaea
Authors: Hatakeyama Dai , Sunada Hiroshi , Totani Yuki , Watanabe Takayuki , Felletár Ildikó , Fitchett Adam , Eravci Murat , Anagnostopoulou Aikaterini , Miki Ryosuke , Kuzuhara Takashi , Kemenes Ildikó , Ito Etsuro , Kemenes György 
Published: May 2021

AbstractIn eukaryotes, CREB-binding protein (CBP), a coactivator of CREB, functions both as a platform for recruiting other components of the transcriptional machinery and as a histone acetyltransferase (HAT) that alters chromatin structure. We previously showed that the transcriptional activity of cAMP-responsive element binding protein (CREB) plays a crucial role in neuronal plasticity in the pond snail Lymnaea stagnalis. However, there is no information on the role CBP plays in CREB-initiated plastic changes in Lymnaea. In this study, we characterized the Lymnaea CBP (LymCBP) gene and investigated the roles it plays in synaptic plasticity involved in regulating feeding behaviors. Similar to CBPs of other species, LymCBP possesses functional domains, such as KIX domain, which is essential for interaction with CREB and was shown to regulate long-term memory (LTM). In situ hybridization showed that the staining patterns of LymCBP mRNA in the central nervous system were very similar to those of Lymnaea CREB1 (LymCREB1). A particularly strong LymCBP mRNA signal was observed in the Cerebral Giant Cell (CGC), an identified extrinsic modulatory interneuron of the feeding circuit, key to both appetitive and aversive LTM for taste. Biochemical experiments using the recombinant protein of LymCBP HAT domain showed that its enzymatic activity was blocked by classical HAT inhibitors such as curcumin, anacardic acid and garcinol. Preincubation of Lymnaea CNSs with these HAT inhibitors blocked cAMP-induced long-term potentiation between the CGC and the follower B1 motoneuron. We therefore suggest that HAT activity of LymCBP in the CGCs is a key factor in synaptic plasticity contributing to LTM after classical conditioning.
An altered metabolism in leukocytes showing in vitro igG memory from SARS-CoV-2-infected patients
Authors: Fanelli G. , Gevi F. , Zarletti G. , Tiberi M. , De Molfetta V. , Scapigliati G. , Timperio A.M. 
Published: May 2021

AbstractCoronavirus disease 2019 (COVID 19) is a systemic infection that exerts a significant impact on cell metabolism. In this study we performed metabolomic profiling coupled with multivariate statistics analysis obtained from 43 in vitro cultures of peripheral blood mononuclear cells (PBMC), 19 of which displaying IgG memory for spike-S1 antigen 60-90 days after infection. By using mass spectrometry analysis, a significant up regulation of S-adenosyl-Homocysteine, Sarcosine and Arginine was found in leukocytes showing IgG memory. These metabolites are known to be involved in physiological recovering from viral infections and immune activities, and our findings might represent a novel and easy measure that could be of help in understanding SARS-Cov-2 effects on leukocytes.
Transcriptional milestones in Dictyostelium development
Authors: Katoh-Kurasawa Mariko , Hrovatin Karin , Hirose Shigenori , Webb Amanda , Ho Hsing-I , Zupan Blaž , Shaulsky Gad 
Published: May 2021

AbstractDevelopment of the social amoeba Dictyostelium discoideum begins by starvation of single cells and ends in multicellular fruiting bodies 24 hours later. These major morphological changes are accompanied by sweeping gene expression changes, encompassing nearly half of the 13,000 genes in the genome. To explore the relationships between the transcriptome and developmental morphogenesis, we performed time-series RNA-sequencing analysis of the wild type and 20 mutant strains with altered morphogenesis. These strains exhibit arrest at different developmental stages, accelerated development, or terminal morphologies that are not typically seen in the wild type. Considering eight major morphological transitions, we identified 1,371 milestone genes whose expression changes sharply between two consecutive transitions. We also identified 1,099 genes as members of 21 regulons, which are groups of genes that remain coordinately regulated despite the genetic, temporal, and developmental perturbations in the dataset. The gene annotations in these milestones and regulons validate known transitions and reveal several new physiological and functional transitions during development. For example, we found that DNA replication genes are co-regulated with cell division genes, so they are co-expressed in mid-development even though chromosomal DNA is not replicated at that time. Altogether, the dataset includes 486 transcriptional profiles, across developmental and genetic conditions, that can be used to identify new relationships between gene expression and developmental processes and to improve gene annotations. We demonstrate the utility of this resource by showing that the cycles of aggregation and disaggregation observed in allorecognition-defective mutants involve a dedifferentiation process. We also show unexpected variability and sensitivity to genetic background and developmental conditions in two commonly used genes, act6 and act15, and robustness of the coaA gene. Finally, we propose that gpdA should be used as a standard for mRNA quantitation because it is less sensitive to genetic background and developmental conditions than commonly used standards. The dataset is available for democratized exploration without the need for programming skills through the web application dictyExpress and the data mining environment Orange.
Local atomic structure analysis around Mg atom doped in GaN by X-ray absorption spectroscopy and spectrum simulations
Authors: Isomura Noritake , Kimoto Yasuji 
Published: May 2021

The identification of the incorporated site of magnesium (Mg) and hydrogen (H) required for p-type formation in gallium nitride (GaN) power devices has been demonstrated by X-ray absorption spectroscopy (XAS). In this study, the fluorescence line of Mg with 3 × 1019 atoms cm−3 was successfully separated from that of Ga using a superconducting tunnel junction array detector with high sensitivity and high energy resolution, and consequently the Mg K-edge XAS spectra of such dilute samples were obtained. The site of Mg atoms incorporated into the GaN lattice was identified as the Ga substitutional site by comparing the experimental XAS spectrum with the simulated spectra calculated by density functional theory. In addition, the presence or absence of H around Mg can be determined through distinctive characteristics expected from the spectrum simulations.