bluuebunny/crossref_metadata_2025_split huggingface dataset:
How do socioeconomic trajectories experienced during early adulthood contribute to the development of cardiometabolic health in young adults?
Authors: Winpenny Eleanor , Stochl Jan , Hughes Alun , Tilling Kate , Howe Laura D 
Published: September 2024

AbstractIntroductionSocioeconomic position has been strongly associated with cardiovascular health. However, little is known about the short-term health impacts of socioeconomic exposures during early adulthood. In this study we describe distinct socioeconomic trajectories of early adulthood (age 16-24y), and assess associations of these trajectories with measures of cardiometabolic health at age 24y.MethodsParticipants of the Avon Longitudinal Study of Parents and Children (ALSPAC), with data across age 16y to 24y (2007-2017) were included (n=7,568). Longitudinal latent class analysis identified socioeconomic trajectories, based on education and employment data across ages 16–24y. Cardiometabolic outcomes at age 24y comprised anthropometric, vascular, metabolic and cardiovascular structure and function measures. We modelled differences in cardiometabolic outcomes at age 24y across the socioeconomic trajectory classes, adjusting for childhood socioeconomic position, adolescent health behaviours and adolescent health.ResultsFour early adulthood socioeconomic trajectories were identified: (1) Higher Education (41% of the population), (2) Extended Education (9%), (3) Part-Time Employment (21%), and (4) Early Employment (29%). Associations between socioeconomic trajectory and cardiometabolic outcomes differed by sex. Among males, the Higher Education and Extended Education classes showed a healthier cardiometabolic profile, and the Part-time Employment class the least healthy. Among females there was less clear distinction between the classes, and the pattern across different outcomes was not consistent.ConclusionThe newly identified ‘Part-time Employment’ class showed the least healthy cardiometabolic profile, and further research should focus on this group to understand the exposures contributing to poor cardiometabolic health in this sector of the population.
Understanding Tooth Agenesis: A Multi-omics Insight into MicroRNA Regulation
Authors: Ranjan Prashant , Devi Chandra , Verma Neha , Bansal Rajesh , Srivastava Vinay Kumar , Das Parimal 
Published: September 2024

AbstractThis study reveals novel microRNAs (miRNAs) implicated in congenital tooth agenesis (CTA), a common dental anomaly with a complex genetic basis. Through a multi-omics approach combining bioinformatics, whole exome sequencing, metabolite analysis, and gene expression profiling, we identified eight key miRNAs potentially involved in tooth development. Among these, four miRNAs viz. miR-218-5p, miR-15b-5p, miR-200b-3p, and let-7a-3p were validated as significant regulators in CTA, marking their first investigation in blood samples from CTA patients. Our analysis revealed that these miRNAs play critical roles in odontogenesis, influencing essential signaling pathways, includingWnt, FGF, andPI3kinase pathways. Among these four, miR-218-5p and let-7a-3p emerged as key players in dental tissue morphogenesis, each contributing to previously unidentified networks crucial for tooth development.This study highlights the potential of these miRNAs as non-invasive biomarkers for early CTA diagnosis and therapeutic targets. This is the first comprehensive investigation of these specific miRNAs in CTA, utilizing a multi-omics approach to offer fresh insights into miRNA-mediated mechanisms and their role in regulating dental anomalies. Our findings not only advance the understanding of the genetic regulation of tooth development but also pave the way for personalized approaches in managing dental anomalies. Further research is needed to validate these results and explore their clinical applications.Graphical Abstract
Generation of motor program diversity and variability through inhibitory circuit motifs in theDrosophilalarval locomotor system
Authors: Francis Jacob , Gibeily Caius R. , Smith William V. , Petropoulos Isabel S. , Anderson Michael , Heitler William J. , Prinz Astrid A. , Pulver Stefan R. 
Published: September 2024

AbstractHow do neural networks generate and regulate diversity and variability in motor outputs with finite cellular components? Here we examine this problem by exploring the role that inhibitory neuron motifs play in generating mixtures of motor programs in the segmentally organisedDrosophilalarval locomotor system. We developed a computational model that is constrained by experimental calcium imaging data. The model comprises single-compartment cells with a single voltage-gated calcium current, which are interconnected by graded excitatory and inhibitory synapses. Local excitatory and inhibitory neurons form conditional oscillators in each hemisegment. Surrounding architecture reflects key aspects of inter- and intrasegmental connectivity motifs identified in the literature. The model generates metachronal waves of activity that recapitulate key features of fictive forwards and backwards locomotion, as well as bilaterally asymmetric activity in anterior regions that represents fictive head sweeps. The statistics of inputs to competing command-like motifs, coupled with inhibitory motifs that detect activity across multiple segments generate network states that promote diversity in motor outputs, while at the same time preventing maladaptive overlap in motor programs. Overall, the model generates testable predictions for connectomics and physiological studies while providing a platform for uncovering how inhibitory circuit motifs underpin generation of diversity and variability in motor systems.
PPARγ, a key modulator of metabolic reprogramming, stemness and chemoresistance associated with retrodifferentiation in human hepatocellular carcinomas
Authors: Daniel Yoann , Rauch Claudine , Moutaux Lucille , Fekir Karim , Desquilles Lise , Cano Luis , Catheline Daniel , Pierre Servane , Burel Agnès , Savary Camille , Ribault Catherine , Bendavid Claude , Clément Bruno , Aninat Caroline , Rioux Vincent , Musso Orlando , Fromenty Bernard , Cabillic Florian , Corlu Anne 
Published: September 2024

AbstractHuman hepatocellular carcinomas (HCCs) with cancer stem cell (CSC) features are a subclass of therapeutically challenging cancers. We recently showed that retrodifferentiation of hepatic cancer cells into CSC-like cells leads to metabolic reprogramming and chemoresistance. The molecular mechanisms whereby differentiated cancer cells switch towards a CSC phenotype are poorly understood. By studying metabolic reprogramming associated with HCC cell plasticity, we identified an unsuspected role of peroxisome proliferator-activated receptor (PPAR)γ in hepatic CSC phenotype acquisition.Gene expression and metabolic analyses performed throughout cell differentiation/retrodifferentiation process of human HepaRG and HBG-BC2 HCC cells show that metabolic reprogramming in hepatic CSCs is associated with fragmented mitochondrial network, decreased respiration,de novolipogenesis, fatty acid oxidation, but increased glycolysis and lipid storage. Mitochondrial genes downregulated in HepaRG-CSCs are also downregulated in the STEM HCC subclass. While PPARα is the main isoform in differentiated hepatic cells, we find high PPARγ expression in hepatic CSCs. Accordingly, nuclear localization of PPARγ is detected in human HCC tumors and PPARγhigh/PPARαlowexpression is associated with the STEM HCC subclass and a poor outcome in human HCC cohorts. PPARγ silencing or/and inhibition of its target gene pyruvate dehydrogenase kinase 4 reactivates cell respiration, increases reactive oxygen species production and sensitizes hepatic CSCs to chemotherapy. Conversely, PPARα activation synergizes with chemotherapy to induce cell death.Targeting PPARγ, a key regulator of metabolic reprogramming and stemness in hepatic CSCs, or modulating the PPARγ/PPARα balance that finely tunes the differentiation/retrodifferentiation process in HCC deserves further investigation for antitumor therapy.Implications heading and statementPPARγ, a key regulator of metabolic reprogramming and stemness in hepatic CSC, reduces oxidative phosphorylation and reactive oxygen species production, therefore contributing to HCC chemoresistance.
Molecular insights into dynamic protein structures by high-contrast crosslinking mass spectrometry
Authors: Chen Zhuo Angel , Absmeier Eva , Stowell James , Sinn Ludwig Roman , Shakeel Shabih , Sijacki Tamara , Njo Kendra , Stahl Kolja , Rullmann Edward , O’Reilly Francis J. , Passmore Lori A. , Rappsilber Juri 
Published: September 2024

AbstractProteins are comprised of structured domains and dynamic regions, and both are essential for biological function. However, studying dynamic regions is challenging using most structural biology methods, including crosslinking mass spectrometry. Here, we dramatically improve the usefulness of distance restraints from crosslinking MS by taking advantage of short-lived reactive species generated from diazirine-based photo-crosslinking. This leads to a clear view of complex topologies and conformational changes, including in dynamic regions. We demonstrate that photo-crosslinking MS data can be used to model flexible regions and conformational changes in the DNA repair complexes; Fanconi Anemia core complex and FANCD2-FANCI. In addition, we obtain new insights into the architecture and arrangement of the highly flexible CCR4-NOT mRNA deadenylation complex. The improved contrast of photo-crosslinking empowers structural biology by providing clearer structural insights into dynamic biological systems that have eluded other structural biology approaches.
Yeast-MetaTwin for Systematically Exploring Yeast Metabolism through Retrobiosynthesis and Deep Learning
Authors: Wu Ke , Liu Haohao , Sun Manda , Mao Runze , Jiang Yindi , Kerkhoven Eduard J. , Chen Yu , Nielsen Jens , Li Feiran 
Published: September 2024

AbstractUnderground metabolism plays a crucial role in understanding enzyme promiscuity, cellular metabolism, and biological evolution, yet experimental exploration of underground metabolism is often sparse. Even though yeast genome-scale metabolic models have been reconstructed and curated for over 20 years, more than 90% of the yeast metabolome is still not covered by these models. To address this gap, we have developed a workflow based on retrobiosynthesis and deep learning methods to comprehensively explore yeast underground metabolism. We integrated the predicted underground network into the yeast consensus genome-scale model, Yeast8, to reconstruct the yeast metabolic twin model, Yeast-MetaTwin, covering 16,244 metabolites (92% of the total yeast metabolome), 2,057 metabolic genes and 59,914 reactions. We revealed thatKmparameters differ between the known and underground network, identified hub molecules connecting the underground network and pinpointed the underground percentages for yeast metabolic pathways. Moreover, the Yeast-MetaTwin can predict the by-products of chemicals produced in yeast, offering valuable insights to guide metabolic engineering designs.
Nanoscale visualization ofDrosophilaE-cadherin ectodomain fragments and their interactions using DNA origami nanoblocks
Authors: Oda Hiroki , Nishiguchi Shigetaka , Song Chihong , Murata Kazuyoshi , Uchihashi Takayuki , Suzuki Yuki 
Published: September 2024

AbstractThe adhesive function of cell surface proteins can be visually assessed through direct observation; however, the underlying structures that mediate adhesion typically remain invisible at the nanoscale level. This hinders knowledge on the diversity of molecular architectures responsible for cell-cell adhesion.DrosophilaE-cadherin (DE-cadherin), a classical cadherin with a unique domain structure, demonstrates adhesive function; however, it lacks a structural model that explains its adhesion mechanism. In this study, we present a novel application of DNA origami technology to create a cell-free, flat environment in which full DE-cadherin ectodomains are anchored using SNAP-tags and biotin-streptavidin interactions. DNA origami was assembled into a 120 nm long block, bearing 5 or 14 biotin:streptavidin sites that were evenly spaced on one lateral face. DE-cadherin ectodomain fragments were attached via biotinylated SNAP-tags. These decorated DNA origami nanoblocks were subjected to transmission electron and high-speed atomic force microscopy, which revealed a hinge-like site that separated the membrane-distal and -proximal portions of the DE-cadherin ectodomain, suggesting a role in mechanical flexibility. We also observed interactions between DE-cadherin ectodomains via their membrane-distal portions on single DNA origami nanoblocks. We reconstituted an adhesion-like process via pairing DNA origami nanoblocks using DE-cadherin ectodomain interactions. Homophilic associations of functional DE-cadherin ectodomains between the paired DNA origami nanoblocks were visualized at the nanoscale, displaying strand-like molecular configurations, likely representing the extracellular cadherin repeats without regular arrays of structural elements. This study introduces a DNA origami-based platform for reconstituting and visualizing cadherin ectodomain interactions, with potential applications for a broader range of adhesion molecules.HighlightsDNA origami technology was applied to perform a structure-function study of cadherin.DNA origami nanoblocks decorated with DE-cadherin ectodomains were observed by TEM/HS-AFM.A hinge-like site that separated the membrane-distal and -proximal portions of the DE-cadherin ectodomain was revealed.An adhesion-like process was mimicked via pairing two nanoblocks using DE-cadherin ectodomain interactions.Homophilic associations of DE-cadherin ectodomains between the nanoblocks were visualized at the nanoscale level.
eProbe: a capture probe design toolkit for genetic diversity reconstructions from ancient environmental DNA
Authors: Huang Zihao , Gu Zhengquan , Cai Yuanyang , Macleod Ruairidh , Xue Zhe , Dong Haoran , Overballe-Petersen Søren , Liu Shanlin , Gao Yu , Li Hao , Tang Sha , Diao Xianmin , Joergensen Morten Egevang , Dockter Christoph , Vinner Lasse , Willerslev Eske , Chen Fahu , Wang Hongru , Wang Yucheng 
Published: September 2024

AbstractAncient environmental DNA (aeDNA) is now commonly used in paleoecology and evolutionary ecology, yet due to difficulties in gaining sufficient genome coverage on individual species from metagenome data, its genetic perspectives remain largely uninvestigated. Hybridization capture has proven as an effective approach for enriching the DNA of target species, thus increasing the genome coverage of sequencing data and enabling population and evolutionary genetics analysis. However, to date there is no tool available for designing capture probe sets tailored for aeDNA based population genetics. Here we presenteProbe, an efficient, flexible and easy-to-use program toolkit that provides a complete workflow for capture probe design, assessment and validation. By benchmarking a probe set for foxtail millet, an annual grass, made by theeProbeworkflow, we demonstrate a remarkable increase of capturing efficiency, with the target taxa recovery rate improved by 577-fold, and the genome coverage achieved by soil capture-sequencing data even higher than data directly shotgun sequenced from the plant tissues. Probes that underwent our filtering panels show notably higher efficiency. The capture sequencing data enabled accurate population and evolutionary genetic analysis, by effectively inferring the fine-scale genetic structures and patterns, as well as the genotypes on functional genes.
Bacteriophages Phi 8 and Phi 12 host infection are inhibited by OMVs and LPS purified fromP. pseudoalcaligenesstrain: East River Isolate A
Authors: Robinson Charles F. , Khayat Reza 
Published: September 2024

AbstractCystoviridaeis a family of double stranded RNA (dsRNA) phage that infects various strains ofPseudomonas syringae, a Gram-negative soil bacteria known to infect various crops. Surrounding the icosahedral capsids of these phages is a bacterial derived phospholipid membrane. Embedded within this membrane is a multi-component protein complex, referred to as the spike complex. The spike complex is responsible for host recognition and membrane fusion. We studied the ability of two members of theCystivirdaefamily to infect cells in the presence of purified outer membrane vesicles (OMVs) and lipopolysaccharide (LPS) derived from distinct sources. In this study we determined that OMVs from the hostPseudomonas pseudoalcaligenesstrain: East River isolate A (ERA) inhibit Phi 8 and Phi 12 host infection. These OMVs range in size from 30 to 60 nm and bind to Phi 8 and Phi 12. However, OMV purified fromP. syringaepv. phaseolicola LM2691 andE. coliΔyciBΔdcrBdid not inhibit Phi 8 or Phi 12 host infection. However, LPS derived from ERA and LM2691 inhibited Phi 8 and Phi 12 infection, demonstrating that LPS is the receptor for these two viruses, and that OMV biogenesis is selective of LPS. LPS derived from other non-CystoviridaeGram-negative bacteria, did not inhibit infection. We confirmed that host proteins are not required for Phi 8 or Phi 12 host interaction. Our results also suggest that differences in lipid A and the core polysaccharide in LPS may influence Phi 8 and Phi 12 host binding.IMPORTANCEMost phage families studied to date use a tailed appendage, composed of a multitude of proteins, for cellular recognition, membrane penetration, and genome injection. This contrasts with members of theCystoviridaefamily which possess a phospholipid membrane bilayer with embedded proteins responsible for cellular recognition and membrane fusion. Thus, theCystoviridaeare akin to enveloped viruses which also use protein complexes embedded into their membrane for cellular recognition and membrane fusion. Examples of such viruses include theRetroviridae, Coronoviridae, Herpesviridae, andOrthomyxoviridaefamilies. The binding specifics ofCystoviridaeto the host outer membrane are unknown. UsingCystoviridae-OMV interaction we began to uncover the host requirements for bindingCystoviridae. The results presented determine that only lipid A and the core polysaccharide of LPS are required forCystoviridaeouter membrane binding.
Identification of nuclear pore proteins at plasmodesmata
Authors: Schladt T. Moritz , Miras Manuel , Ejike Jona Obinna , Pottier Mathieu , Xi Lin , Restrepo-Escobar Andrea , Nakamura Masayoshi , Pütz Niklas , Hänsch Sebastian , Gao Chen , Engelhorn Julia , Dickmanns Marcel , Davis Gwendolyn V. , Dalal Ahan , Gombos Sven , Lange Ronja , Simon Rüdiger , Schulze Waltraud X. , Frommer Wolf B. 
Published: September 2024

SummaryPlasmodesmata (PD) exchange small molecules, RNAs and proteins between plant cells with an exclusion limit for passive, non-specific transport. PD also facilitate the transport of specific cargo that may require chaperones or carriers for transport. The mechanisms underlying PD transport are not understood. PD and nuclear pore complexes (NPC), are nanometer size micropores with similar transport properties. The permeability barrier in NPCs is a phase separation domain formed by FG-nucleoporins (FG-NUP). Here we used bioinformatics, proteomics and fluorescence imaging to identify proteins with similarities to phase separating FG-NUPs at PD. We identified 20 NUPs in PD fractions, and validated dual localization to NPC and PD for 7 NUPs. Structured illumination microscopy detected the transmembrane anchor NUP CPR5 at both orifices of PD.cpr5mutants showed reduced intercellular transport of SHR from stele to endodermis. The identification of FG-NUPs at PD is consistent with the recruitment of NUPs in the green lineage to form a PD pore gating complex consistent with liquid phase separation domains as diffusion barriers at PD.
Hypothermia protects against ventilator-induced lung injury by limiting IL-1β release and NETs formation
Authors: Nosaka Nobuyuki , Borges Vanessa , Martinon Daisy , Crother Timothy R , Arditi Moshe , Shimada Kenichi 
Published: September 2024

SummaryAlthough mechanical ventilation is a critical intervention for acute respiratory distress syndrome (ARDS), it can trigger an IL-1β-associated complication known as ventilator-induced lung injury. In mice, we found that LPS and high-volume ventilation, LPS-HVV, leads to hypoxemia with neutrophil extracellular traps (NETs) formation in the alveoli. Furthermore,Il1r1-/-LPS-HVV mice did not develop hypoxemia and had reduced NETs, indicating that IL-1R1 signaling is important for NETs formation and hypoxemia. Therapeutic hypothermia (TH) is known to reduce the release of inflammatory mediators. In LPS-HVV mice, TH (32 °C body temperature) prevented hypoxemia development, reducing albumin leakage, IL-1β, gasdermin D (GSDMD) and NETs formation. We also observed that LPS-primed macrophages, when stimulated at 32°C with ATP or nigericin, release less IL-1β associated with reduced GSDMD cleavage. Thus, hypothermia is an important modulating factor in the NLRP3 inflammasome activation, IL-1β release and NETs formation, preventing LPS-HVV-induced acute respiratory failure.
Design of an Artificial Natural Killer Cell Mimicking System to Target Tumour Cells
Authors: Chugh Vaishali , Krishna K. Vijaya , Quandt Dagmar , Kelly Suainibhe , King Damien , Jensen Lasse D. , Simpson Jeremy C , Pandit Abhay 
Published: September 2024

ABSTRACTNK cell mimics are assemblies of a cell membrane and a template that replicate biomimetic features and physicochemical properties, respectively. For the reported design, we used the cell membrane from human NK cell (KHYG-1) line and gelatin microspheres as a template. The gelatin microspheres were reinforced via DMTMM cross-linking in a water-in-oil emulsion to exhibit tunable Young’s modulus. These engineered NK cell mimics were found to be non-toxic, non-inflammatory, and capable of evading macrophage detection when tested with differentiated THP-1 cells.In vitrostudies showed significant interaction/proximity of the mimics with cancer cells when tested in 2D cultures of breast cancer cells (MDA-MB-231), 3D spheroids of liver (HepG2) and colon (HT-29) cancer cell models, and a zebrafish breast cancer xenograft (MDA-MB-231) model. The NK cell mimics also evaded macrophage detection in a Kdrl:EGFP Spil: Ds Red zebrafish model. In a pilot assessment, loading and release of the sialyltransferase inhibitor (STI, 3Fax-Peracetyl Neu5Ac) using NK cell mimics significantly reduced α-2,6 sialylation in 2D cultures of MDA-MB-231 cells, demonstrating the STI’s intact functionality in inhibiting sialylation. These findings collectively underscore the promising potential of engineered NK cell mimics as versatile tools in cancer research and therapeutic applications.