bluuebunny/crossref_metadata_2025_split huggingface dataset:
Normalization strategies for lipidome data in cell line panels
Authors: Leegwater Hanneke , Zhang Zhengzheng , Zhang Xiaobing , Hankemeier Thomas , Harms Amy C. , Zweemer Annelien J. M. , Le Dévédec Sylvia E. , Kindt Alida 
Published: July 2024

AbstractSample collection can significantly affect measurements of relative lipid concentrations in cell line panels, hiding intrinsic biological properties of interest between cell lines. Most quality control steps in lipidomic data analysis focus on controlling technical variation. Correcting for the total amount of biological material remains an additional challenge for cell line panels. Here, we investigated how we can normalize lipidomic data acquired from multiple cell lines to correct for differences in sample biomass.We studied how commonly used data normalization and transformation steps during analysis influenced the resulting lipid data distributions. We compared normalization by biological properties such as cell count or total protein concentration, to statistical and data-based approaches, such as median, mean, or probabilistic quotient-based normalization and used intraclass correlation to estimate how similarity between replicates changed after normalization.Normalizing lipidomic data by cell count improved similarity between replicates, but only for a study with cell lines with similar morphological phenotypes. For cell line panels with multiple morphologies collected over a longer time, neither cell count nor protein concentration was sufficient to increase the similarity of lipid abundances between replicates of the same cell line. Data-based normalizations increased these similarities, but also created artifacts in the data caused by a bias towards the large and variable lipid class of triglycerides. This artifact was reduced by normalizing for the abundance of only structural lipids. We conclude that there is a delicate balance between improving the similarity between replicates and avoiding artifacts in lipidomic data and emphasize the importance of an appropriate normalization strategy in studying biological phenomena using lipidomics.
Multimodal MEG and microstructure-MRI investigations of the human hippocampal scene network
Authors: Lucie-Read Marie , Hodgetts Carl J. , Lawrence Andrew D. , Evans C. John , Singh Krish D. , Umla-Runge Katja , Graham Kim S. 
Published: July 2024

AbstractAlthough several studies have demonstrated that perceptual discrimination of complex scenes relies on an extended hippocampal network, distinct from an anterotemporal network supporting the perceptual discrimination of faces, we currently have limited insight into the specific functional and structural properties of these networks. Here, combining electrophysiological (magnetoencephalography, MEG) and microstructural (multi-shell diffusion MRI, dMRI) imaging in healthy human adults (30 female/10 male), we show that both hippocampal theta power modulation and fibre restriction of the fornix (a major input/output pathway of the hippocampus) independently related to accuracy during scene, but not face, perceptual discrimination. Conversely, microstructural features of the inferior longitudinal fasciculus (a long-range occipito- anterotemporal tract) correlated with face, but not scene, perceptual discrimination accuracy. Our results provide new mechanistic insight into the neurocognitive systems underpinning complex scene and face perception, providing support for multiple-system representation-based accounts of the medial temporal lobe.Significance StatementIn contrast to theories positing segregated cortical areas for perception and memory, the specialized representations of the hippocampus may support both the perception and memory of visual scenes. To investigate, we utilised the unique window into hippocampal electrophysiological activity offered by Magnetoencephalography (MEG). We found hippocampal theta activity modulations in the hippocampus and posteromedial cortex during scene, versus face and shape-size, perceptual oddity discrimination, the magnitude of which correlated with scene, but not face or shape- size, discrimination accuracy. Moreover, multimodal white matter imaging revealed that tissue restriction of the fornix – the major hippocampal output tract - independently predicted scene discrimination performance. Our multimodal MEG-microstructure study provides novel evidence that the hippocampus and connected structures conjointly support online scene processing.
Genetic Mapping of All Human Paralog Pairs to Characterize Synthetic Lethality and Buffering
Authors: Flister Michael J. , Verduzco Daniel , Petiwala Sakina , Carneiro-Lobo Tatiana C. , Ghekas Christos , Shi Xu , Lu Charles , Dezso Zoltan 
Published: July 2024

SUMMARYParalogs are abundant in the human genome and thought to be a primary source of synthetic lethality, yet the vast paralogome remains largely uncharacterized. A digenic screen of all paralogous gene pairs in the human genome revealed that synthetic lethalities were infrequent and varied in penetrance in different tumor backgrounds. We hypothesized that the variable penetrance of synthetic lethalities resulted from complex polygenic interactions with different cellular contexts. A machine learning classifier of a subset of paralog pairs tested across 49 cancer models revealed that endogenous perturbations in related pathways predicted paralog synthetic lethality. Further, predictive modeling of paralog synthetic lethality revealed that the strength of synthetic lethal interactions were largely due to the overlap and essentiality of the protein-protein interaction networks shared by the paralogs pairs. Collectively, this study tested all digenic paralog interactions and delineated the key feature classes that underlie the heterogeneity of paralog synthetic lethalities.HighlightsSynthetic lethal paralogs have long been known, yet most paralog interactions are untested.We report the first combinatorial screen of all 36,648 known human paralog pairs.A meta-analysis of 461 paralog pairs in 49 cell models revealed context-dependent interactions.The essentiality of paralog interaction networks dictate the strength of synthetic lethality.eTOCSynthetic lethal paralogs have long been known, yet most paralog interactions are untested. Flister et al report a screen of all 36,648 known human paralog pairs. These data combined with a meta-analysis of 461 pairs across 49 cell models revealed insights to the molecular underpinnings of context-dependent synthetic lethality.Graphical Abstract
Interaction range of common goods shapes Black Queen dynamics beyond the cheater-cooperator narrative
Authors: Fullmer Matthew S. , van Dijk Bram , Takeuchi Nobuto 
Published: July 2024

AbstractDependencies among microorganisms often appear mutualistic in the lab, as microbes grow faster together than alone. However, according to the Black Queen (BQ) hypothesis, these dependencies are underpinned by the evolutionary benefits from loss-of-function mutations when others in the community can supply the necessary common goods. BQ dynamics often describe a cheater-cooperator scenario, where some ecotypes, the “cheaters,” produce no common goods and rely on others, the “cooperators”, for survival. We have previously proposed that in systems with multiple common goods, an alternative endpoint for BQ dynamics can emerge. This endpoint describes an ecosystem of interdependent ecotypes engaging in “mutual cheating”, i.e. where common good production isdistributed. However, even with multiple goods the common good production can becentralized, i.e. with one ecotype providing all common goods for the ecosystem. Here, we present an eco-evolutionary model that reveals that BQ dynamics can result in both distributed- or centralized common good production. The interaction range,i.e. the number of beneficiaries a producer can support, distinguishes between these two endpoints. While many ecosystems evolve to bemaximally distributedormaximally centralized, we also find intermediate ecosystems, where ecotypes that appear redundant are coexisting for long periods of time. Due to the limited interaction range, these redundant ecotypes are unable to distribute the production of common goods fully due to the presence of non-producing types. Despite non-producers thus stalling the division of labor, we observe that sudden structural shifts can occur that purge the non-producers from the ecosystem. Overall, our findings broaden the understanding of BQ dynamics, unveiling complex interactions beyond the simple cheater-cooperator narrative.
Weighted Ensemble Approach for Knowledge Graph completion improves performance
Authors: Sinha Meghamala , Tu Roger , González Carolina , Su Andrew I. 
Published: July 2024

ABSTRACTThis study introduces a weighted ensemble method called “WeightedKgBlend” for link prediction in knowledge graphs which combines the predictive capabilities of two types of Knowledge Graph completion methods: knowledge graph embedding and path based reasoning. By dynamically assigning weights based on individual model performance, WeightedKgBlend surpasses standalone methods, demonstrating superior predictive accuracy when tested to discover drug-disease candidates over a large-scale biomedical knowledge graph called Mechanistic Repositioning Network. This research highlights the efficacy of an integrated approach combining multiple methods in drug discovery, showcasing improved performance and the potential for transformative insights in the realm of biomedical knowledge discovery.
Cognitive hyperplasticity drives insomnia
Authors: Huang Sheng , Piao Chengji , Zhao Zhiying , Beuschel Christine B. , Turrel Oriane , Toppe David , Sigrist Stephan J. 
Published: July 2024

AbstractSleep is vital for maintenance of cognitive functions and lifespan across the animal kingdom. Here, we report our surprising findings that insomniac (inc)Drosophilashort sleep mutants, which lack a crucial adaptor protein for the autism-associated Cullin-3 ubiquitin ligase, exhibited excessive olfactory memory. Through a genetic modifier screen, we find that a mild attenuation of Protein Kinase A (PKA) signaling specifically rescued the sleep and longevity phenotypes ofincmutants. Surprisingly, this mild PKA signaling reduction further boosted the excessive memory inincmutants, coupled with further exaggerated mushroom body overgrowth phenotypes. We propose that an intrinsic hyperplasticity scenario genuine toincmutants enhances cognitive functions. Elevating PKA signaling seems to serve as a checkpoint which allows to constrain the excessive memory and mushroom body overgrowth in these animals, albeit at the sacrifice of sleep and longevity. Our data offer a mechanistic explanation for the sleep deficits ofincmutants, which challenges traditional views on the relation between sleep and memory, and suggest that behavioral hyperplasticity, e.g., prominent in autistic patients, can provoke sleep deficits.
PROTEORIZER: A holistic approach to untangle functional consequences of variants of unknown significance
Authors: Schmenger Torsten , Diwan Gaurav , Russell Robert B. 
Published: July 2024

AbstractMostin silicotools only use data closely related to the gene-of-interest or initial research question. This gene-focused research is prone to ignoring low-count and rare variants in the same or similar genes, even if available informational could be sufficient to deduce functional consequences by combining knowledge from many similar genes.Proteorizer is a web tool that aims to bridge the gap between protein-centric knowledge and the functional context this knowledge creates. We use curated and reviewed data from UniProt to collect available residue information for the queried protein as well as orthologs. By defining functional clusters based on intramolecular distances of residues with available functional information it is possible to use these to extrapolate the effect of a VUS solely based on known functions of nearby residues, hence contextualizing the variant with pre-existing knowledge. We show that pathogenic variants are more likely to be a part of functional hotspots and present several case studies (ALPP p.Ser244Gly, CANT1 p.Ile171Phe, ARL3 p.Tyr90Cys, IL6R p.His280Pro and RAF1 p.Ser259Ala) to highlight the applicability and usefulness of this approach.Graphical AbstractProteorizeris an explorative tool that takes variants from laboratory or clinical settings and contextualizes the variants based on prior information from the protein of interest and similar proteins according to where these functional positions are located in the 3D structure of the protein of interest.
PicoCam: High-resolution 3D imaging of live animals and preserved specimens
Authors: Medina Josh , Irschick Duncan , Epperly Kevin , Cuban David , Elting Rosalee , Mansfield Lucas , Lee Nora , Fernandes Ana Melisa , Garzón-Agudelo Felipe , Rico-Guevara Alejandro 
Published: July 2024

Abstract1. The PicoCam system is a multi-camera photogrammetry rig used for generating high-resolution 3D models of animals in the field, or preserved specimens in laboratory or museum settings. The digital measurement of 3D models is increasingly useful for studying body shape. However, methods that capture sub-millimetric detail often do so at the cost of portability and versatility; this system aims to bridge this gap.2. The PicoCam system employs 3D digital photogrammetry, a process that generates accurate, full-color, 3D models from sequences of photographs. By using six cameras and a rotating base, the system is able to capture multiple angles in rapid succession – a key advantage for both 3D-imaging live specimens and efficiently scanning museum specimens. Through the use of macro lenses and high-resolution camera sensors, this system can capture sub-millimetric detail without sacrificing portability.3. In this study, we 3D imaged the bills of 19 species of hummingbirds using the PicoCam system and measured length, height, width, surface area, and volume of their bills. We examined eight species in the field and 11 from the Burke Museum in Seattle. We chose Hummingbird bills as a model system, as their fine-scale interspecific differences in 3D shape can have significant functional and behavioral implications, and could tell us more about how these traits predict habitat and resource use.4. The prospect of a common 3D-imaging method for both museum and field use is compelling when documenting structures’ shape within and among species. The PicoCam system is also valuable for quantifying the 3D shape of fine-scale phenotypes (like hummingbird bills) that benefit from digital measurement, preservation, and improved accessibility. Lastly, the PicoCam system allows “digital 3D collection”, by which the shape of biological structures in the field can be recorded and stored in a public database without the need to collect a specimen. This opens the door to studies in which multiple 3D image captures of the same individual across different time scales permit 3D shape/color comparisons (e.g., seasonal, ontogenetic changes).
Distinct tissue-niche localization and function of synovial tissue myeloid DC subsets in health, and in active and remission Rheumatoid Arthritis
Authors: MacDonald Lucy , Elmesmari Aziza , Somma Domenico , Frew Jack , Di Mario Clara , Madhu Roopa , Paoletti Audrey , Simakou Theodoros , Hardy Olympia M. , Tolusso Barbara , Campobasso Denise , Perniola Simone , Gessi Marco , Gigante Maria Rita , Petricca Luca , Bruno Dario , Coletto Lavinia Agra , Benvenuto Roberta , Isaacs John D. , Filby Andrew , McDonald David , Sim Jasmine P. X. , Jamieson Nigel , Wei Kevin , D’Agostino Maria Antonietta , Millar Neal L. , Milling Simon , McSharry Charles , Gremese Elisa , Affleck Karen , Baker Kenneth F. , McInnes Iain B. , Otto Thomas D. , Korsunsky Ilya , Alivernini Stefano , Kurowska-Stolarska Mariola 
Published: July 2024

SummaryCurrent rheumatoid arthritis (RA) treatments do not restore immune tolerance. Investigating dendritic cell (DC) populations in human synovial tissue (ST) may reveal pathways to re-instate tolerance in RA. With single-cell and spatial-transcriptomics of synovial tissue biopsies, validated by micro co-culture systems, we identified condition and niche-specific myeloid DC clusters with distinct differentiation trajectories and functions. Healthy synovium contains a unique tolerogenic AXLposDC2 cluster in the superficial sublining layer. In active RA, a macrophage-rich lining-layer niche becomes populated with inflammatory DC3 clusters that specifically activate memory CCL5posTEM and CCL5posCXCL13posTPH, promoting synovitis. In the sublining lymphoid niche, CCR7posDC2 mReg specifically interact with naïve-T-cells, potentially driving the local expansion of new effector T-cells. Sustained remission sees the resolution of these niches but lacks the recovery of tolerogenic AXLposDC2, indicating latent potential for disease flare. A human RA disease-flare model showed that the activation of blood predecessor of ST-DC3 clusters precedes the onset of inflammation in joints. Therapeutic strategies targeting pathogenic ST-DC3 clusters, or reinstating tolerogenic AXLposDC2, may restore immune homeostasis in RA.In briefDeconstruction of human RA synovium, using single-cell spatial transcriptomics and micro-culture systems, reveals distinct neighbourhoods within the synovial architecture across health, and RA patients with active disease or sustained remission. Discrete niches are identified that contain distinct myeloid DC clusters that differ in frequency, differentiation trajectories, and effector functions.HighlightsHuman RA synovium exhibits condition and niche specific myeloid DC clusters that vary in their tissue differentiation trajectories and functions.ST-CD14posDC3 (iDC3) support inflammatory CCL5posTEM and CCL5posTPH cell activation in the hyperplastic lining layer.ST-CCR7posDC2 (mReg), driven by MIR155, interact with naïve-T-cells in sublining lymphoid niches.A specific inflammatory signature of blood predecessors of ST-DC3s predict flare in RA.Graphical abstract
The chemopreventive effects of Curcumin against oxidative stress induced by Cadmium or H2O2are mediated by Nrf2/ARE signaling and protective autophagy in myeloid cells
Authors: Russo Maria , Di Giacomo Annamaria , Fiore Federica , Spagnuolo Carmela , Carbone Virginia , Minasi Paola , Russo Gian Luigi 
Published: July 2024

AbstractThe evidence linking high levels of environmental pollutants to chronic degenerative diseases is alarming, with heavy metals (HM) identified as a key factor. Research suggests that certain phytochemicals in the diet can reduce HM levels and mitigate their adverse health effects.Curcumin (Cur), a natural polyphenol, is particularly effective in protecting against Cadmium (Cd) toxicity. The present study demonstrates that preincubation with low doses of Cur (1 μM) in differentiated HL-60 and K-562 human myeloid cells can significantly protect against cytotoxicity induced by Cd and or H2O2. Cur reduced the increased levels of reactive oxygen species (ROS) generated by Cd or H2O2by inducing a protective form of autophagy. Cur activated mild oxidative stress that triggers the expression of Nrf2-dependent transcripts, such as HO and NQO1. The potential chemopreventive effects of Cur against redox stress have been strengthened by the observation that free and unmetabolized Cur is detectable inside the cells after 5 minutes of treatment, and its presence parallels with increased levels of intracellular GSH. These findings suggest that supplementation with Cur in the form of nutraceuticals may represent a promising way to protect people living in highly polluted areas against the adverse effects of HM contaminants.
Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in male obese mice
Authors: Wu Dan , Eeda Venkateswararao , Maria Zahra , Rawal Komal , Wang Audrey , Herlea-Pana Oana , Undi Ram Babu , Lim Hui-Ying , Wang Weidong 
Published: July 2024

AbstractOvernutrition engenders the expansion of adipose tissue and the accumulation of immune cells, in particular, macrophages, in the adipose tissue, leading to chronic low-grade inflammation and insulin resistance. In obesity, several proinflammatory subpopulations of adipose tissue macrophages (ATMs) identified hitherto include the conventional “M1-like” CD11C-expressing ATM and the newly discovered metabolically activated CD9-expressing ATM; however, the relationship among ATM subpopulations is unclear. The ER stress sensor inositol-requiring enzyme 1α (IRE1α) is activated in the adipocytes and immune cells under obesity. It is unknown whether targeting IRE1α is capable of reversing insulin resistance and obesity and modulating the metabolically activated ATMs. We report that pharmacological inhibition of IRE1α RNase significantly ameliorates insulin resistance and glucose intolerance in male mice with diet-induced obesity. IRE1α inhibition also increases thermogenesis and energy expenditure, and hence protects against high fat diet-induced obesity. Our study shows that the “M1-like” CD11c+ATMs are largely overlapping with but yet non-identical to CD9+ATMs in obese white adipose tissue. Notably, IRE1α inhibition diminishes the accumulation of obesity-induced metabolically activated ATMs and “M1-like” ATMs, resulting in the curtailment of adipose inflammation and ensuing reactivation of thermogenesis, without augmentation of the alternatively activated M2 macrophage population. Our findings suggest the potential of targeting IRE1α for the therapeutic treatment of insulin resistance and obesity.
Cytoplasmic ribosomes on mitochondria alter the local membrane environment for protein import
Authors: Chang Ya-Ting , Barad Benjamin A. , Rahmani Hamidreza , Zid Brian M. , Grotjahn Danielle A. 
Published: July 2024

ABSTRACTMost of the mitochondria proteome is nuclear-encoded, synthesized by cytoplasmic ribosomes, and targeted to mitochondria post-translationally. However, a subset of mitochondrial-targeted proteins is imported co-translationally, although the molecular mechanisms governing this process remain unclear. We employ cellular cryo-electron tomography to visualize interactions between cytoplasmic ribosomes and mitochondria inSaccharomyces cerevisiae. We use surface morphometrics tools to identify a subset of ribosomes optimally oriented on mitochondrial membranes for protein import. This allows us to establish the first subtomogram average structure of a cytoplasmic ribosome on the surface of the mitochondria in the native cellular context, which showed three distinct connections with the outer mitochondrial membrane surrounding the peptide exit tunnel. Further, this analysis demonstrated that cytoplasmic ribosomes primed for mitochondrial protein import cluster on the outer mitochondrial membrane at sites of local constrictions of the outer and inner mitochondrial membrane. Overall, our study reveals the architecture and the spatial organization of cytoplasmic ribosomes at the mitochondrial surface, providing a native cellular context to define the mechanisms that mediate efficient mitochondrial co-translational protein import.SUMMARYChang et al. present a membrane-guided approach for identifying a subset of cytoplasmic ribosomes oriented for protein import on the mitochondrial surface inSaccharomyces cerevisiaeusing cryo-electron tomography. They show that ribosomes cluster, make multiple contacts with, and induce local changes to the mitochondrial membrane ultrastructure at import sites.