bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of Adipokine Levels with Levels of Remnant Cholesterol: the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Quispe Renato , Sweeney Ty , Martin Seth S. , Jones Steven R. , Allison Matthew A. , Budoff Matthew J. , Ndumele Chiadi E. , Elshazly Mohamed B. , Michos Erin D. 
Published: April 2023

ABSTRACTBackgroundThe metabolic syndrome phenotype of individuals with obesity is characterized by elevated levels of triglyceride (TG)-rich lipoproteins and remnant particles, which have been shown to be significantly atherogenic. Understanding the association between adipokines, endogenous hormones produced by adipose tissue, and remnant cholesterol (RC) would give insight into the link between obesity and atherosclerotic cardiovascular disease.MethodsWe studied 1,791 MESA participants of an ancillary study on body composition who had adipokine levels measured (leptin, adiponectin, resistin) at either visit 2 or 3. RC was calculated as non-high density lipoprotein cholesterol minus low-density lipoprotein cholesterol (LDL-C), measured at the same visit as the adipokines, as well as subsequent visits 4 through 6. Multivariable-adjusted linear mixed effects models were used to assess the cross-sectional and longitudinal associations between adipokines and levels of RC.ResultsMean (SD) age was 64.5±9.6 years and for body mass index (BMI) was 29.9±5.0 kg/m2; 52.0% were women. In fully adjusted models that included BMI, LDL-C and lipid-lowering therapy, for each 1-unit increment in adiponectin, there was 14.4% (12.0, 16.8) lower RC. With each 1-unit increment in leptin and resistin, there was 4.5% (2.3, 6.6) and 5.1% (1.2, 9.2) higher RC, respectively. Lower adiponectin and higher leptin were also associated with longitudinal increases in RC levels over median follow-up of 5(4-8) years.ConclusionsLower adiponectin and higher leptin levels were independently associated with higher levels of RC at baseline and longitudinal RC increase, even after accounting for BMI and LDL-C.CLINICAL PERSPECTIVEWhat is new?- Among individuals without history of cardiovascular disease, adiponectin is inversely associated with cross-sectional levels of remnant cholesterol, whereas leptin and resistin are directly associated.- Adiponectin had an inverse association with progression of remnant cholesterol levels over time.What are the clinical implications?- Adiponectin levels were not associated with LDL-C levels but with levels of triglyceride-rich lipoproteins, particularly remnant cholesterol.-Incrementing adiponectin via lifestyle modification and/or pharmacological therapies (i.e. GLP-1 agonists) could be a mechanism to reduce remnant cholesterol levels and ultimately cardiovascular risk.
Transcriptome Analysis Reveals Organ-Specific Effects of 2-Deoxyglucose Treatment in Healthy Mice
Authors: Wells Ann E. , Wilson John J. , Heuer Sarah E. , Sears John D. , Wei Jian , Pandey Raghav , Costa Mauro W. , Kaczorowski Catherine C. , Roopenian Derry C. , Chang Chih-Hao , Carter Gregory W. 
Published: April 2023

AbstractObjectiveGlycolytic inhibition via 2-deoxy-D-glucose (2DG) has potential therapeutic benefits for a range of diseases, including cancer, epilepsy, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and COVID-19, but the systemic effects of 2DG on gene function across different tissues are unclear.MethodsThis study analyzed the transcriptional profiles of nine tissues from C57BL/6J mice treated with 2DG to understand how it modulates pathways systemically. Principal component analysis (PCA), weighted gene co-network analysis (WGCNA), analysis of variance, and pathway analysis were all performed to identify modules altered by 2DG treatment.ResultsPCA revealed that samples clustered predominantly by tissue, suggesting that 2DG affects each tissue uniquely. Unsupervised clustering and WGCNA revealed six distinct tissue-specific modules significantly affected by 2DG, each with unique key pathways and genes. 2DG predominantly affected mitochondrial metabolism in the heart, while in the small intestine, it affected immunological pathways.ConclusionsThese findings suggest that 2DG has a systemic impact that varies across organs, potentially affecting multiple pathways and functions. The study provides insights into the potential therapeutic benefits of 2DG across different diseases and highlights the importance of understanding its systemic effects for future research and clinical applications.
Regulation of adaptive growth decisions via phosphorylation of the TRAPPII complex in Arabidopsis
Authors: Wiese Christian , Abele Miriam , Al Benjamin , Altmann Melina , Steiner Alexander , Kalbfuß Nils , Strohmayr Alexander , Ravikumar Raksha , Park Chan Ho , Brunschweiger Barbara , Meng Chen , Facher Eva , Ehrhardt David W. , Falter-Braun Pascal , Wang Zhi-Yong , Ludwig Christina , Assaad Farhah F. 
Published: April 2023

ABSTRACTPlants often adapt to adverse or stress conditions via differential growth. The trans-Golgi Network (TGN) has been implicated in stress responses, but it is not clear in what capacity it mediates adaptive growth decisions. In this study, we assess the role of the TGN in stress responses by exploring the interactome of the Transport Protein Particle II (TRAPPII) complex, required for TGN structure and function. We identified physical and genetic interactions between TRAPPII and shaggy-like kinases (GSK3/AtSKs). Kinase assays and pharmacological inhibition providedin vitroandin vivoevidence that AtSKs target the TRAPPII-specific subunit AtTRS120/TRAPPC9. GSK3/AtSK phosphorylation sites in AtTRS120/TRAPPC9 were mutated, and the resulting AtTRS120 phosphovariants subjected to a variety of single and multiple stress conditionsin planta. The non-phosphorylatable TRS120 mutant exhibited enhanced adaptation to multiple stress conditions and to osmotic stress whereas the phosphomimetic version was less resilient. Higher order inducibletrappii atskmutants had a synthetically enhanced defect in root gravitropism. Our results suggest that the TRAPPII phosphostatus mediates adaptive responses to abiotic cues. AtSKs are multifunctional kinases that integrate a broad range of signals. Similarly, the TRAPPII interactome is vast and considerably enriched in signaling components. An AtSK-TRAPPII interaction would integrate all levels of cellular organization and instruct the TGN, a central and highly discriminate cellular hub, as to how to mobilize and allocate resources to optimize growth and survival under limiting or adverse conditions.
Genomes from 25 historicalDrosophila melanogasterspecimens illuminate adaptive and demographic changes across more than 200 years of evolution
Authors: Shpak Max , Ghanavi Hamid R. , Lange Jeremy D. , Pool John E. , Stensmyr Marcus C. 
Published: April 2023

ABSTRACTThe ability to perform genomic sequencing on long-dead organisms is opening new frontiers in evolutionary research. These opportunities are especially profound in the case of museum collections, from which countless documented specimens may now be suitable for genomic analysis. Here, we report 25 newly sequenced genomes from museum specimens of the model organismDrosophila melanogaster, including the oldest extant specimens of this species. By comparing historical samples ranging from the early 1800s to 1933 against modern day genomes, we document evolution across thousands of generations, including time periods that encompass the species’ initial occupation of northern Europe and an era of rapidly increasing human activity. At the genome-wide level, we find that historical flies from the same time and place show much greater evidence for relatedness than flies from modern collections, and some show evidence of inbreeding as well, potentially reflecting either much smaller local population sizes in the past or else the specific circumstances of the collections. We also find that the Lund, Sweden population underwent local genetic differentiation during the early 1800s to 1933 interval (potentially due to accelerated drift) but then became more similar to other European populations thereafter (potentially due to increased migration). Within each time period, our temporal sampling allows us to document compelling candidates for recent natural selection. In some cases, we gain insights regarding previously implicated selection candidates, such asChKov1, for which our inferred timing of selection favors the hypothesis of antiviral resistance over insecticide resistance. Other candidates are novel, such as the circadian-related geneAhcy, which yields a selection signal that rivals that of the DDT resistance geneCyp6g1. These insights deepen our understanding of recent evolution in a model system, and highlight the potential of future museomic studies.
Monoterpene glucosides accumulated inEustoma grandiflorumroots promote hyphal branching in arbuscular mycorrhizal fungi
Authors: Tominaga Takaya , Ueno Kotomi , Saito Hikaru , Egusa Mayumi , Yamaguchi Katsushi , Shigenobu Shuji , Kaminaka Hironori 
Published: April 2023

AbstractHost plant-derived strigolactones trigger hyphal branching in arbuscular mycorrhizal (AM) fungi, initiating a symbiotic interaction between land plants and AM fungi. However, our previous studies revealed that gibberellin-treatedEustoma grandiflorum(Gentianaceae) activates rhizospheric hyphal branching in AM fungi using unidentified molecules other than strigolactones. In this study, we analyzed independent transcriptomic data ofE. grandiflorumand found that the gentiopicroside (GPS) and swertiamarin (SWM), which are characteristic monoterpene glucosides in Gentianaceae, were highly biosynthesized in gibberellin-treatedE. grandiflorumroots. Moreover, these metabolites considerably promoted hyphal branching in the Glomeraceae AM fungiRhizophagus irregularisandR. clarus. GPS treatment also enhancedR. irregulariscolonization of the monocotyledonous cropAllium schoenoprasum. Interestingly, these metabolites did not provoke the germination of the root parasitic plantOrobanche minor. Altogether, our study unveiled the crucial role of GPS and SWM in activating the symbiotic relationship between AM fungi andE. grandiflorum.
Aggregated gene co-expression networks for predicting transcription factor regulatory landscapes in a non-model plant species
Authors: Orduña-Rubio Luis , Santiago Antonio , Navarro-Payá David , Zhang Chen , Wong Darren C. J. , Matus J. Tomás 
Published: April 2023

ABSTRACTGene co-expression networks (GCNs) have not been extensively studied in non-model plants. However, the rapid accumulation of transcriptome datasets in these species represents an opportunity to explore underutilized network aggregation approaches that highlight robust co-expression interactions and improve functional connectivity. We applied and evaluated two different aggregation methods on public grapevine RNA- Seq datasets belonging to three different tissue conditions (leaf, berry and ‘all organs’). Our results show that co-occurrence-based aggregation generally yielded the best-performing networks. We applied GCNs to study several TF gene families, showing its capacity of detecting both already-described and novel regulatory relationships between R2R3-MYBs, bHLH/MYC and multiple secondary metabolism pathway reactions. Specifically, TF gene-and pathway-centered network analyses successfully ascertained the previously established role ofVviMYBPA1in controlling the accumulation of proanthocyanidins while providing insights into its novel role as a regulator ofp-coumaroyl-CoA biosynthesis as well as the shikimate and aromatic amino-acid pathways. This network was validated using DNA Affinity Purification Sequencing data, demonstrating that co-expression networks of transcriptional activators can serve as a proxy of gene regulatory networks. This study presents an open repository to reproduce networks and a GCN application within the Vitviz platform, a user-friendly tool for exploring co-expression relationships.
Legionella pneumophilamacrophage infectivity potentiator protein appendage domains modulate protein dynamics and inhibitor binding
Authors: Wiedemann C. , Whittaker J.J. , Pérez Carrillo V.H. , Goretzki B. , Dajka M. , Tebbe F. , Harder J.-M. , Krajczy P. , Joseph B. , Hausch F. , Guskov A. , Hellmich U.A. 
Published: April 2023

AbstractMacrophage infectivity potentiator (MIP) proteins are widespread in human pathogens includingLegionella pneumophila, the causative agent of Legionnaires’ disease and protozoans such asTrypanosoma cruzi. All MIP proteins contain a FKBP (FK506 binding protein)-like prolyl-cis/trans- isomerase domain that hence presents an attractive drug target. Some MIPs such as theLegionella pneumophilaprotein (LpMIP) have additional appendage domains of mostly unknown function. In full- length, homodimericLpMIP, the N-terminal dimerization domain is linked to the FKBP-like domain via a long, free-standing stalk helix. Combining X-ray crystallography, NMR and EPR spectroscopy and SAXS, we elucidated the importance of the stalk helix for protein dynamics and inhibitor binding to the FKBP-like domain and bidirectional crosstalk between the different protein regions. The first comparison of a microbial MIP and a human FKBP in complex with the same synthetic inhibitor was made possible by high-resolution structures ofLpMIP with a [4.3.1]-aza-bicyclic sulfonamide and provides a basis for designing pathogen-selective inhibitors. Through stereospecific methylation, the affinity of inhibitors toL. pneumophilaandT. cruziMIP was greatly improved. The resulting X-ray inhibitor-complex structures ofLpMIP andTcMIP at 1.49 and 1.34 Å, respectively, provide a starting point for developing potent inhibitors against MIPs from multiple pathogenic microorganisms.
Autophagic activity acts as a rheostat in the control of nitrogen transfer from Arabidopsis rosette leaves to the seeds according to a principle of communicating vessels
Authors: James Maxence , Trouverie Jacques , Marmagne Anne , Chardon Fabien , Etienne Philippe , Masclaux-Daubresse Céline 
Published: April 2023

ABSTRACTMacroautophagy is known for long as essential for the degradation and the recycling of different macromolecules in eukaryotes. However how important is autophagy for nitrogen management at the whole plant level and for plant biomass and yield productivity in unstressed and well feed plants needed further investigation. In this study, we used both autophagy knock-out mutants and autophagy over-expressors that constitutively produce numerous autophagosomes. These mutants and over-expressors were cultivated using hydroponic system to observe and compare their phenotypes under sufficient nitrate supply, and when submitted after a while to strict nitrate starvation. The shift from nitrate sufficient condition to nitrate starvation allowed us to determine how autophagy defective or stimulated lines can use their own nitrogen resources to complete their cycle. Unexpectedly we observed that irrespective of the nitrate conditions, both mutants and over-expressors exhibited early leaf senescence phenotypes relative to wild type. While autophagy mutants exhibited strong defect for N remobilisation and seed production irrespective of nitrate condition, the better performance of autophagy-over expressors for N remobilisation and seeds production was only significant under sufficient nitrate supply, i.e. when autophagy was not naturally stimulated by nitrate limitation. Interestingly, comparisons of genotypes showed that the nitrogen pool used for seed filling originated from rosette leaves, as if rosette and seeds were used as communicating vessels independently of the stem and pod connecting organs. Altogether, results show that autophagy is a master player in nitrogen management at the whole plant level that controls yield production and leaf senescence.
Exercise improved P2Y12-regulated microglial dynamics during stroke via endocannabinoid signaling
Authors: He Xiao-fei , Zhao Yun , Li Ge , Luo Jing , Xu Jing-hui , Zheng Hai-qing , Zhang Li-ying , Hu Xi-quan 
Published: April 2023

AbstractMicroglia are vigilant housekeepers in the adult brain, they continually extend and retract their processes to survey their microenvironment. In a dependent manner involving P2Y12 receptors, microglia undergo morphological and functional changes to form microglia-neuron contacts to protect neurons from damage. By usingin vivotwo-photon imaging, we found that physical exercise (PE) upregulated microglial P2Y12 expression, increased microglial dynamics, and promoted the microglia contacting with neurons in a mouse model of transit middle cerebral artery occlusion (tMCAO). As a result, microglial processes inhibited neuronal calcium overloads, protected against damage of the neuronal mitochondria and synaptic structure. Inhibition of P2Y12 by PSB0739 abolished the protection induced by PE. Mechanistically, we found PE increased the cannabinoid receptor 2 (CBR2) in microglia, and administration of AM630, a CBR2 antagonist, decreased P2Y12R expression and abolished PE-mediated effects. These findings identified endocannabinoid signaling may as the critical regulator of the PE-induced P2Y12-mediated effect whereby PE increased the endocannabinoid system to regulate purinergic signaling, further inducing microglial processes at microglia-neuron contacts to monitor and protect neuronal functioning.
Comparison of different genotyping techniques to distinguish recrudescence from new infection in studies assessing the efficacy of antimalarial drugs againstPlasmodium falciparum
Authors: Schnoz Annina , Beuret Carla , Concu Maura , Hosch Salome , Rutaihwa Liliana K. , Golumbeanu Monica , Nsanzabana Christian 
Published: April 2023

ABSTRACTDistinguishing recrudescence from new infections is crucial for the assessment of antimalarial drug efficacy againstPlasmodium falciparum (P. falciparum). Different genotyping methods are used and may impede the comparison of drug efficacy estimates in space and time, particularly in patients from high transmission settings with polyclonal infections.We compared five different genotyping methods currently used to assess their sensitivity in detecting minority clones in polyclonal infections, their robustness, and the genetic diversity of the markers used. Our study utilized four well-characterizedP. falciparumlaboratory strains mixed in varying ratios, and 20 paired patient samples collected from a clinical trial.We found that high-resolution capillary electrophoresis (H-CE) using length-polymorphic markers, as well as targeted amplicon deep sequencing (TADS) using single nucleotide polymorphism (SNP)-rich markers, revealed the highest sensitivity in detecting minority clones, while also exhibiting robustness, and high genetic diversity in the used markers. Moreover, markers used by TADS gave more consistent results. We observed that microsatellites had a lower genetic diversity compared to markers such as msp1,msp2, glurpand SNP-rich markers, with some genotypes having allelic frequencies of > 30 %.The replacement ofglurpby microsatellites did not result in a change in the genotyping outcome, probably due to the lower genetic diversity of microsatellites used in comparison toglurp. More studies with large sample sizes are necessary to identify the most suitable microsatellites that could replaceglurpas per the latest recommendations from the World Health Organization (WHO) on genotyping to distinguish recrudescence from new infections in high transmission settings. Our study indicates that TADS should be considered the gold standard for genotyping to differentiate recrudescence from new infection and should be used to validate other techniques.
Adipocyte PI3K Links Adipostasis with Basal Insulin Secretion Through an Adipoincretin Effect
Authors: Becattini Barbara , Molinaro Angela , Henricsson Marcus , Borén Jan , Solinas Giovanni 
Published: April 2023

SUMMARYInsulin secretion is governed by insulin-PI3K signaling. Resolving the mechanism of this feedback is necessary to understand how insulin operates. Mice lacking the insulin receptor, or AKT1 and AKT2 in adipocytes, are severely lipoatrophic. Thus, the role of adipocyte insulin-PI3K signaling in the control of insulin secretion remains unknown. Using adipocyte- specific PI3Kα knockout mice (PI3KαAdQ) and a panel of isoform-selective PI3K inhibitors, we have found that PI3Kα and PI3Kβ activities are functionally redundant in adipocyte insulin signaling. PI3Kβ-selective inhibitors had no effect on adipocyte AKT phosphorylation in control mice but blunted AKT phosphorylation specifically in adipocytes of PI3KαAdQmice, demonstrating adipocyte-selective inhibition of PI3K signaling. Adipocyte-selective PI3K inhibition increased serum FFA and potently induced insulin secretion. We name this phenomenon the adipoincretin effect. The adipoincretin effect was dissociated from blood glucose and blood glucose counterregulatory response. The contribution of lipolysis, lipid, and amino acid metabolism, and selected adipokines to the adipoincretin effect has been investigated. We conclude that basal insulin secretion is chiefly controlled by adipocyte PI3K signaling through the adipoincretin effect. This phenomenon reveals an essential role for adipocyte insulin-PI3K signaling in linking the rates of adipose tissue lipolysis with baseline insulin secretion during fasting.
PhIP-Seq uncovers novel autoantibodies and unique endotypes in interstitial lung disease
Authors: Upadhyay Vaibhav , Yoon Young me , Vazquez Sara E. , Velez Tania E. , Jones Kirk D. , Lee Cathryn T. , Law Christopher S. , Wolters Paul J. , Lee Seoyeon , Yang Monica M. , Farrand Erica , Noth Imre , Strek Mary E. , Anderson Mark , DeRisi Joseph , Sperling Anne I. , Shum Anthony K. 
Published: April 2023

ABSTRACTInterstitial lung diseases (ILDs) are a heterogeneous group of disorders that can develop in patients with connective tissue diseases (CTD). Establishing autoimmunity in ILD impacts prognosis and treatment. ILD patients are screened for autoimmunity by assaying for anti-nuclear autoantibodies, rheumatoid factors and other non-specific tests. However, this approach has not been rigorously validated and may miss autoimmunity that manifests as autoantibodies to tissue antigens not previously defined in ILD. Here, we use Phage Immunoprecipitation-Sequencing (PhIP-Seq) to conduct a large, multi-center unbiased autoantibody discovery screen of ILD patients and controls. PhIP-Seq identified 17 novel autoreactive targets, and machine learning classifiers derived from these targets discriminated ILD serum from controls. Among these 17 candidates, we validated Cadherin Related Family Member 5 (CDHR5) as an autoantigen and found CDHR5 autoantibodies in patients with rheumatologic disorders and importantly, subjects not previously diagnosed with autoimmunity. Lung tissue of CDHR5 autoreactive patients showed transcriptional profiles consistent with activation of NFκB signaling and upregulation of chitotriosidase (CHIT1), a molecular pathway linked to fibrosis. Our study shows PhIP-Seq uncovers novel autoantibodies in ILD patients not revealed by standard clinical tests. Furthermore, CDHR5 autoantibodies may define a novel molecular endotype of ILD characterized by inflammation and fibrosis.