bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mid-Life Plasmalogens and Other Metabolites with Anti-Inflammatory Properties are Inversely Associated with Long term Cardiovascular Disease Events: Heart SCORE Study
Authors: Saeed Anum , McKennan Chris , Duan Jiaxuan , Kip Kevin E. , Finegold David , Vu Michael , Swanson Justin , Lopez Oscar , Cohen Ann , Mapstone Mark , Reis Steven E. 
Published: March 2023

BackgroundPreclinical data have shown that low levels of plasmalogens and other metabolites with anti-inflammatory properties may impact metabolic disease processes. However, the association between mid-life levels of such metabolites and late-life atherosclerotic cardiovascular disease (ASCVD) is not known.MethodsWe characterized the midlife plasma metabolomic profile (1,228 metabolites) of 1,852 participants (age 58.1±7.5 years, 69.6% female, 43.6% self-identified as Black) enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study. Participants were followed for ∼16 years for incident ASCVD events (nonfatal MI, acute ischemic syndrome, coronary revascularization and ASCVD mortality). We used regression model to assess associations of metabolites with ASCVD events. We assessed the impact of genetic variants using whole-exome sequencing with single-variant analysis for common variants and gene-based burden tests for rare variants. We used unbiased and candidate gene approaches to explore genetic associations with metabolites found to be associated with ASCVD events.ResultsA total of twelve metabolites were independently associated with incident ASCVD in fully adjusted models over a median of 12.1 years. A subset of plasmalogens showed an independent inverse association with incident ASCVD events [1-(1-enyl-palmitoyl)-2-arachidonoyl-GPC (OR, 0.54; 95% CI, 0.40-0.74); 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPE (OR, 0.57; 95% CI, 0.42-0.78), 1-methylnicotinamide1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (OR, 0.76; 95% CI, 0.65-0.89)]. Metabolome-wide genetic analysis revealed that two of these plasmalogen metabolites were strongly influenced by polymorphisms of the rs174535, an eQTL for FADS1 and FADS2 genotype. Two amino acid metabolites (2-oxoarginine [OR, 0.42; 95% CI, 0.25-0.69], alpha-ketobutyrate [OR, 0.62; 95% CI, 0.49-0.80]) and a bilirubin degradation product (C16H18N2O5[OR, 0.50; 95% CI, 0.38-0.66) were inversely associated with ASCVD events.ConclusionsHigher mid-life levels of three plasmalogens, two amino acid metabolites, and a bilirubin degradation product, all of which have anti-inflammatory properties, are associated with lower risk of late-life ASCVD events. Further research is needed to determine whether these metabolites play a causal role in ASCVD and may be a target for future therapies.
Integrating extracellular vesicle and circulating cell-free DNA analysis on a single plasma aliquot from breast cancer patients improves the detection of HER2 positivity
Authors: Mugoni Vera , Ciani Yari , Quaini Orsetta , Tomasini Simone , Notarangelo Michela , Vannuccini Federico , Marinelli Alessia , Leonardi Elena , Pontalti Stefano , Martinelli Angela , Rossetto Daniele , Pesce Isabella , Mansy Sheref S. , Barbareschi Mattia , Ferro Antonella , Caffo Orazio , Attard Gerhardt , Di Vizio Dolores , D’Agostino Vito Giuseppe , Nardella Caterina , Demichelis Francesca 
Published: March 2023

AbstractBackgroundMulti-analyte liquid biopsies represents an emerging opportunity for non-invasive cancer assessment. We developed ONCE (ONe Aliquot for Circulating Elements), a novel multi-analytes liquid biopsy approach for the isolation of extracellular vesicles (EVs) and cell-free DNA (cfDNA) from a single aliquot of blood.MethodsWe assessed ONCE performance to classify HER2-positive early-stage breast cancer (BrCa) patients by combining RNA and DNA signals on n=64 healthy donors (HD) and non–metastatic BrCa patients. Specifically, we investigated EVs-derived RNA (EV-RNA) and cfDNA by next-generation sequencing (NGS) and by digital droplet PCR (ddPCR). Additionally, we utilized imaging flow cytometry to evaluate EVs as potential carriers of the HER2 protein.ResultsWestern blot analysis and immunocapture assay revealed that EVs-enriched proteins were detected at similar levels among the HER2+ and HER2- subtypes. Sequencing of cfDNA and EV-RNA from HER2- and HER2+ patients demonstrated concordance within situmolecular analyses of matched tissues. Combined analysis of the two circulating analytes by ddPCR showed increased sensitivity inERBB2/HER2 detection compared to single nucleic acid components. Multi-analyte liquid biopsy prediction performance was comparable to tissue-based sequencing results from TCGA. Also, we observed HER2 protein on the surface of EVs isolated from the HER2+ BrCa plasma, thus corroborating the potential relevance of studying EVs as companion analyte to cfDNA.ConclusionsThis data confirms the relevance of combining cfDNA and EV-RNA analytes for cancer assessment and supports the ONCE approach as a valuable tool for multi-analytes liquid biopsies’ clinical implementation.
Persistent DNA methylation changes associated with prenatal NO2exposure in a Canadian prospective birth study
Authors: Lee Samantha , Sbihi Hind , MacIsaac Julia L. , Subbarao Padmaja , Mandhane Piushkumar J. , Moraes Theo J. , Turvey Stuart E. , Duan Qingling , Ambalavanan Amirthagowri , Brauer Michael , Brook Jeffrey , Kobor Michael S. , Jones Meaghan J. 
Published: March 2023

AbstractBackgroundAccumulating evidence suggests prenatal air pollution exposure alters DNA methylation (DNAm), which could go on to affect long-term health. However, it remains unclear whether prenatal DNAm alterations persist through early life. Identifying DNAm changes that persist from birth into childhood would provide greater insight into the molecular mechanisms that most likely contribute to the association of prenatal air pollution exposure with health outcomes such as atopic disease.ObjectivesThis study investigated the persistence of DNAm changes associated with prenatal NO2exposure (a surrogate measure of traffic-related air pollution) at age one to begin characterizing which DNAm changes most likely to contribute to atopic disease.MethodsWe used an atopy-enriched subset of CHILD study participants (N=145) to identify individual and regional cord blood DNAm differences associated with prenatal NO2, followed by an investigation of persistence in age one peripheral blood. As we had repeated DNAm measures, we also isolated postnatal-specific DNAm changes and examined their association with NO2exposure in the first year of life. MANOVA tests were used to examine the association between DNAm changes associated with NO2and child wheeze and atopy.ResultsWe identified 24 regions of altered cord blood DNAm, with several annotated toHOXgenes. Two regions annotated toMPDU1andC5orf63were significantly associated with age one wheeze. Further, we found the effect of prenatal NO2exposure across CpGs within all altered regions remained similar at age one. A single region of postnatal-specific DNAm annotated toHOXB6was associated with year one NO2and age one atopy.DiscussionRegional cord blood DNAm changes associated with prenatal NO2exposure persist through at least the first year of life, and some of these changes are associated with age one wheeze. The early-postnatal period remains a sensitive window to DNAm perturbations that may also influence child health.
Delineating memory reactivation in sleep with verbal and non-verbal retrieval cues
Authors: Guttesen Anna á V. , Gaskell M. Gareth , Cairney Scott A. 
Published: March 2023

AbstractSleep supports memory consolidation via the reactivation of newly formed memory traces. One way to investigate memory reactivation in sleep is by exposing the sleeping brain to auditory retrieval cues; a paradigm known as targeted memory reactivation (TMR). To what extent to acoustic properties of memory cues influence the effectiveness of TMR, however, has received limited attention. We addressed this question by exploring how verbal and non-verbal memory cues affect oscillatory activity linked to memory reactivation in slow-wave sleep. Fifty-one healthy adult males learned to associate visual stimuli with spoken words (verbal cues) and environmental sounds (non-verbal cues). Subsets of the verbal and non-verbal cues were then replayed during sleep, alongside previously unheard control cues. For a subset of the participants, the voice of the verbal cues was mismatched between sleep and learning. Memory cues (relative to control cues) prompted an increase in theta/alpha and spindle power, which have been heavily implicated in sleep-associated memory processing. Moreover, verbal memory cues were associated with a stronger increase in spindle power than non-verbal memory cues. There were no significant differences between the matched and mismatched conditions when analysing verbal memory cues in isolation. Our findings suggest that verbal memory cues may be more effective than non-verbal memory cues for triggering memory reactivation in sleep, as indicated by an amplified spindle response.
SifA SUMOylation governsSalmonellaTyphimurium intracellular survival via modulation of lysosomal function
Authors: Chandrasekhar Hridya , Mohapatra Gayatree , Singh Mukesh , Rana Sarika , Kaur Navneet , Sharma Sheetal , Tuli Amit , Das Prasenjit , Srikanth C. V. 
Published: March 2023

AbstractGastroenteritis causing pathogenSalmonellaTyphimurium (S.Tm) during its infection in host cells thrives in a vacuolated compartment,SalmonellaContaining Vacuole (SCV), which sequentially acquires host endosomal and lysosomal markers. Long tubular structures, called asSalmonellainduced filaments (SIFs), are known to be required for SCV’s nutrient acquisition, membrane maintenance and stability. A tightly coordinated interactions involving prominent effector SifA and various host adapters PLEKHM1, PLEKHM2 and Rab GTPases govern SCV integrity and SIF formation. Here, we report for the first time, the functional regulation of SifA is modulated by its SUMOylation at lysine 11.S.Tm expressing lysine 11 mutant SifA (SifAK11R) is defective in intracellular proliferation due to compromised SIF formation and enhanced lysosomal acidification. Furthermore, murine competitive index experiments reveal defective in vivo proliferation and weakened virulence of SifAK11Rmutant. Concisely, our results demonstrate that SUMO deficient SifA mutant nearly behaves like a SifA knockout strain which impacts PLEKHM2-M6PR mediated lysosomal acidification pathway. Thus, our results bring forth a novelS.Tm-host crosstalk mechanism involving host mediated effector SUMOylation critical for pathogenicity.
Vascular adaptation model from force balance:Physarum polycephalumas a case study
Authors: Marbach Sophie , Ziethen Noah , Alim Karen 
Published: March 2023

AbstractUnderstanding vascular adaptation, namely what drives veins to shrink or grow, is key for the self-organization of flow networks and their optimization. From the top-down principle of minimizing flow dissipation at a fixed metabolic cost within flow networks, flow shear rate resulting from the flows pervading veins is hypothesized to drive vein adaptation. Yet, there is no bottom-up derivation of how flow forces impact vein dynamics. From the physical principle of force balance, shear rate acts parallel to vein walls, and hence, naively shear rate could only stretch veins and not dilate or shrink them. We, here, resolve this paradox by theoretically investigating force balance on a vein wall in the context of the vascular network of the model organismP. polycephalum. We propose, based on previous mechanical studies of cross-linked gels, that shear induces a nonlinear, anisotropic response of the actomyosin gel, making up vein walls that can indeed drive vein dilatation. Furthermore, our force balance approach allows us to identify that shear feedback occurs with a typical timescale and with a typical target shear rate that are not universal properties of the material but instead depend smoothly on the location of the vein within the network. In particular, the target shear rate is related to the vein’s hydrostatic pressure, which highlights the role of pressure in vascular adaptation. Finally, since our derivation is based on force balance and fluid mechanics, we believe our approach can be extended to vascular adaptation in other organisms.
Triploid Pacific oysters exhibit stress response dysregulation and elevated mortality following marine heatwaves
Authors: George Matthew N. , Cattau Olivia , Middleton Mollie , Lawson Delaney , Vadopalas Brent , Gavery Mackenzie , Roberts Steven 
Published: March 2023

AbstractPolyploidy has been shown to negatively impact environmental stress tolerance, resulting in increased susceptibility to extreme climate events such as marine heatwaves (MHWs). In this study, we used the response of the Pacific oysterCrassostrea gigasto MHWs as a model system to identify key ploidy-specific differences in the physiological and transcriptomic response of oysters to environmental stress. In this study, adult diploid (2n) and triploid (3n) oysters were exposed to elevated seawater temperature (single stressor; 30°C), elevated temperature followed by acute desiccation stress (multiple stressor; 30°C + emersion at an aerial temperature of 44°C for 4h), or a control (17°C) within a hatchery setting. Oyster mortality rate was elevated within stress treatments with respect to the control and was significantly higher in triploids than diploids following multiple stress exposure (36.4% vs. 14.8%). Triploids within the multiple stressor treatment exhibited signs of energetic limitation, including metabolic depression, a significant reduction in ctenidium Na+/K+ATPase activity, and the dysregulated expression of key genes associated with heat tolerance, the inhibition of apoptosis, and mitochondrial function. Functional enrichment analysis of ploidy-specific gene sets identified that biological processes associated with metabolism, stress tolerance, and immune function were overrepresented within triploids across stress treatments. Our results demonstrate that triploidy impacts the transcriptional regulation of key metabolic processes that underly the environmental stress response of Pacific oysters, resulting in downstream shifts in physiological tolerance limits that may be detrimental to survival. The impact of chromosome set manipulation on the climate resilience of marine populations has important implications for the adaptability of marine populations and domestic food security within future climate scenarios, especially as triploidy induction becomes an increasingly popular tool to elicit reproductive control across a wide range of marine organisms used within marine aquaculture.
Human Vascularized Bile Duct-on-a Chip: A multi-cellular micro-physiological system for studying Primary Sclerosing Cholangitis
Authors: Du Yu , Gupta Kapish , Waisbourd-Zinman Orith , Har-Zahav Adi , Soroka Carol J. , Boyer James L. , Llewellyn Jessica , Liu Chengyang , Naji Ali , Polacheck William J. , Wells Rebecca G. 
Published: March 2023

AbstractPrimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease in which the bile ducts of the liver become inflamed and scarred. Scarred bile ducts eventually narrow and obstruct and can cause additional liver pathology including liver failure, repeated infections, and tumors. The pathogenesis of PSC remains largely unknown, partly due to difficulty in obtaining cholangiocytes and partly due to a paucity ofin vitromodels that capture the various factors contributing to disease progression. Here we report the development of a human vascularized bile duct-on-a-chip that models blood vessels and bile ducts structurally and functionally in three dimensions and includes cholangiocytes derived from control and PSC patient tissue and bile. The flow of blood and bile was modeled by perfusion of cell-lined channels, and cholangiocytes and endothelial cells displayed differential responses to perfusion. Normal and PSC cholangiocytes polarized normally, formed mature tight junctions and displayed similar permeability, comparable toex vivomeasurements. The model with PSC cholangiocytes, however, became more inflammatory than the normal under the stimulation of IL-17A, which induced PBMC and differentiated Th17 cells in the vascular channel to transmigrate more through the endothelial layer of the vascular compartment. In sum, this human vascularized bile duct-on-a-chip recapitulated the vascular-biliary interface structurally and functionally and represents a novel multicellular platform to study inflammatory and fibrotic cholangiopathies such as PSC.
Oligodendrocyte Development and Myelin Sheath Formation are Regulated by the Antagonistic Interaction between the Rag-Ragulator Complex and TFEB
Authors: Bouchard Ellen L. , Meireles Ana M. , Talbot William S. 
Published: March 2023

AbstractMyelination by oligodendrocytes is critical for fast axonal conduction and for the support and survival of neurons in the central nervous system. Recent studies have emphasized that myelination is plastic and that new myelin is formed throughout life. Nonetheless, the mechanisms that regulate the number, length, and location of myelin sheaths formed by individual oligodendrocytes are incompletely understood. Previous work showed that lysosomal transcription factor TFEB represses myelination by oligodendrocytes and that the RagA GTPase inhibits TFEB, but the step or steps of myelination in which TFEB plays a role have remained unclear. Here, we show that TFEB regulates oligodendrocyte differentiation and also controls the number and length of myelin sheaths formed by individual oligodendrocytes. In the dorsal spinal cord oftfebmutants, individual oligodendrocytes produce fewer myelin sheaths, and these sheaths are longer than those produced by wildtype cells. Transmission electron microscopy shows that there are more myelinated axons in the dorsal spinal cord oftfebmutants than in wildtype animals, but no significant change in axon diameter. In contrast totfebmutants, oligodendrocytes inrragamutants produce shorter myelin sheaths. The sheath length inrraga; tfebdouble mutants is not significantly different from wildtype, consistent with the antagonistic interaction between RagA and TFEB. Finally, we find that the GTPase activating protein Flcn and the RagCa and RagCb GTPases are also necessary for myelination by oligodendrocytes. These findings demonstrate that TFEB coordinates myelin sheath length and number during myelin formation in the central nervous system.Graphical Abstract
CD4+T cells display a spectrum of recall dynamics during re-infection with malaria parasites
Authors: Lee Hyun Jae , Moreira Marcela L. , Li Shihan , Williams Cameron G. , Skinner Oliver P. , Asad Saba , Asatsuma Takahiro , Bramhall Michael , Jiang Zhe , Engel Jessica A. , Soon Megan S. F. , Straube Jasmin , Barrera Irving , Murray Evan , Chen Fei , Nideffer Jason , Jagannathan Prasanna , Haque Ashraful 
Published: March 2023

AbstractChildren in malaria-endemic regions can experience multiplePlasmodiuminfections over a short period of time, within vitroCD4+T cell recall responses becoming more regulatory with increasing age and exposure. This suggests that repeated infection qualitatively changes CD4+T cells, although the heterogeneity and dynamics of these responses await systematic analysisin vivo. Here, we examined TCR transgenic PbTII and polyclonal CD4+T cells duringPlasmodiumre-infection in mice, in conjunction with scRNA-seq/TCR-seq and spatial transcriptomics at near single-cell resolution. PbTII cells gave rise to multiple antigen-experienced states in different areas of the spleen after primary infection and antimalarial treatment, including ongoing GC responses and T-cell zone memory. Upon re-infection, Th1-memory PbTII cells initiated a rapid effector response prior to proliferating, while GC Tfh cells of the same antigen specificity were entirely refractory within the same organ. Transcriptome dynamic modelling and network analysis of Th1 recall revealed a biphasic wave of RNA processing that firstly preceded immune effector transcription, and later accompanied cellular proliferation. Importantly, Th1 recall constituted a partial facsimile of primary Th1 responses, with no unique genes amongst the small subset of those upregulated upon re-infection. Finally, we noted a similar spectrum of antigen-experienced states and recall dynamics by polyclonal CD4+T cells with diverse TCRs. Therefore, during re-infection withPlasmodium, persisting GC Tfh cells remained unaltered transcriptionally, Tcm/Tfh-like cells exhibited minimal proliferation, and Th1-memory cells displayed a rapid, proliferating IL-10-producing Tr1 response consistent with a shift towards immune-regulation. These data highlight a broad spectrum of simultaneous CD4+T cell responses that occur in the spleen during re-infection with malaria parasites.HighlightsSplenic TCR transgenic CD4+T cells are highly heterogeneous prior to re-infection.Persisting GC Tfh cells are refractory to re-activation during re-infection.Th1-memory cells rapidly upregulate RNA processing prior to effector function and proliferation.Th1-recall is an imperfect but faithful facsimile of primary Th1 responses.A spectrum of recall states is observed in polyclonal CD4+T cells with diverse TCRs.
Mechanisms underpinning morphogenesis of symbiotic organ specialized for hosting indispensable microbial symbiont in stinkbug
Authors: Oishi Sayumi , Harumoto Toshiyuki , Okamoto-Furuta Keiko , Moriyama Minoru , Fukatsu Takema 
Published: March 2023

ABSTRACTMicrobial mutualists are pivotal for insect adaptation, which often entails the evolution of elaborate organs for symbiosis. Addressing what mechanisms underpin the development of such organs is of evolutionary interest. Here we investigated the stinkbugPlautia staliwhose posterior midgut is transformed into a specialized symbiotic organ. Despite being a simple tube in newborns, it developed numerous crypts in four rows, whose inner cavity hosts a specific bacterial symbiont, during 1stto 2ndnymphal instar. Visualization of dividing cells revealed that active cell proliferation was coincident with the crypt formation, although spatial patterns of the proliferating cells did not reflect the crypt arrangement. Visualization of visceral muscles in the midgut, consisting of circular muscles and longitudinal muscles, uncovered that, strikingly, circular muscles exhibited a characteristic arrangement running between the crypts specifically in the symbiotic organ. Even in early 1stinstar when no crypts were seen, two rows of epithelial areas delineated by bifurcated circular muscles were identified. In 2ndinstar, crossing muscle fibers newly appeared and connected the adjacent circular muscles, whereby the midgut epithelium was divided into four rows of crypt-to-be areas. The crypt formation proceeded even in aposymbiotic nymphs, uncovering autonomous nature of the crypt development. We propose a mechanistic model of crypt formation wherein the spatial arrangement of muscle fibers and the proliferation of epithelial cells underpin the formation of crypts as midgut evaginations.IMPORTANCEDiverse organisms are associated with microbial mutualists, in which specialized host organs often develop for retaining the microbial partners. In the light of the origin of evolutionary novelties, it is important to understand what mechanisms underpin the elaborate morphogenesis of such symbiotic organs, which must have been shaped through interactions with the microbial symbionts. Using the stinkbugPlautia stalias a model, we demonstrated that visceral muscular patterning and proliferation of intestinal epithelial cells during early nymphal stages are involved in the formation of numerous symbiont-harboring crypts arranged in four rows in the posterior midgut to constitute the symbiotic organ. Strikingly, the crypt formation occurred normally even in symbiont-free nymphs, uncovering that the crypt development proceeds autonomously. These findings suggest that the crypt formation is deeply implemented into the normal development ofP. stali, which must reflect the considerably ancient evolutionary origin of the midgut symbiotic organ in stinkbugs.