bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting brain age across the adult lifespan with spontaneous oscillations and functional coupling in resting brain networks captured with magnetoencephalography
Authors: Hardy Samuel , Roberts Gill , Ventresca Matthew , Dunkley Benjamin T 
Published: January 2024

AbstractThe functional repertoire of the human brain changes dramatically throughout the developmental trajectories of early life and even all the way throughout the adult lifespan into older age. Capturing this arc is important to understand healthy brain ageing, and conversely, how injury and diseased states can lead to accelerated brain ageing. Regression modelling using lifespan imaging data can reliably predict an individual’s brain age based on expected arcs of ageing. One feature of brain function that is important in this respect, and understudied to date, is neural oscillations - the rhythmic fluctuations of brain activity that index neural cell assemblies and their functioning, as well as coordinating information flow around networks. Here, we analysed resting-state magnetoencephalography (MEG) recordings from 367 healthy participants aged 18 to 83, using two distinct statistical approaches to link neural oscillations & functional coupling with that of healthy ageing. Spectral power and leakage-corrected amplitude envelope correlations were calculated for each canonical frequency band from delta through gamma ranges. Spatially and spectrally consistent associations between healthy ageing and neurophysiological features were found across the applied methods, showing differential effects on neural oscillations, with decreasing amplitude of low frequencies throughout the adult lifespan, and increasing high frequency amplitude. Functional connectivity within and between resting-state brain networks mediated by alpha coupling generally decreased throughout adulthood and increased in the beta band. Predictive modelling of brain age via regression showed an age dependent prediction bias resulting in overestimating the age of younger people (<40 years old) and underestimating the age of older individuals. These findings evidence strong age-related neurophysiological changes in oscillatory activity and functional networks of the brain as measured by resting-state MEG and that cortical oscillations are moderately reliable markers for predictive modelling. For researchers in the field of predictive brain age modelling with neurophysiological data, we recommend attention is paid to predictive biases for younger and older age ranges and consider using specific models for different age brackets. Nevertheless, these results suggest brain age prediction from MEG data can be used to model arcs of ageing throughout the adult lifespan and predict accelerated ageing in pathological brain states.
Designer micro/nano-crumpled MXene multilayer coatings accelerate osteogenesis and regulate macrophage polarization
Authors: Tokmedash Mohammad Asadi , Min Jouha 
Published: January 2024

ABSTRACTEffective tissue regeneration and immune responses are essential for the success of biomaterial implantation. Although the interaction between synthetic materials and biological systems is well-recognized, the role of surface topographical cues in regulating the local osteoimmune microenvironment—specifically, their impact on host tissue and immune cells and their dynamic interactions—remains underexplored. This study addresses this gap by investigating the impact of surface topography on osteogenesis and immunomodulation. We fabricated MXene/Hydroxyapatite (HAP)-coated surfaces with controlled 2.5D nano-, submicro-, and micro-scale topographical patterns using our custom bottom-up pattering method. These engineered surfaces were employed to assess the behavior of osteoblast precursor cells and macrophage polarization. Our results demonstrate that MXene/HAP-coated surfaces with microscale crumpled topography significantly influence osteogenic activity and macrophage polarization: These surfaces notably enhanced osteoblast precursor cell spreading, proliferation, differentiation, and facilitated a shift in macrophages towards an anti-inflammatory, pro-healing M2 phenotype. The observed cell responses indicate that the physical cues from the crumpled topographies, combined with the chemical cues from the MXene/HAP coatings, synergistically create a favorable osteoimmune microenvironment. This study presents the first evidence of employing MXene/HAP-multilayer coated surfaces with finely crumpled topography to concurrently facilitate osteogenesis and immunomodulation for improved implant-to-tissue integration. The tunable topographic patterns of these coatings, coupled with a facile and scalable fabrication process, make them widely applicable for various biomedical purposes. Our results highlight the potential of these novel coatings to improve thein vivoperformance and fate of implants by modulating the host response at the material interface.
Enhanced PI3K/Akt Signaling in Response to p85α Loss is Regulated by Endosomal PI3Kα and PI3P
Authors: Thapa Narendra , Chen Mo , Cryns Vincent L. , Anderson Richard 
Published: January 2024

SUMMARYPI3Kα is a heterodimer of p110α catalytic subunit and p85 adaptor subunit that is activated by agonist-stimulated receptor tyrosine kinases. Although the interaction of p85α with activated receptors recruits p110α to membranes, studies have demonstrated that p85α loss, which occurs commonly in cancer, paradoxically promotes agonist-stimulated PI3K/Akt signaling. We recently demonstrated that p110α localizes to microtubules via MAP4, facilitating its interaction with activated receptor kinases in endosomes to initiate PI3K/Akt signaling. Here, we demonstrate that in response to agonist stimulation and p85α knock down the residual p110α, coupled predominantly to p85β, exhibits enhanced microtubule localization, MAP4 binding and interaction with endosomal receptor tyrosine kinases, thereby augmenting PI3K/Akt signaling. The interaction of the C2 domain of p110α with PI3P is required for recruiting p110α into endomembranes and enhancing PI3K/Akt signaling. These findings provide a mechanism for the augmented agonist-stimulated PI3K/Akt signaling upon p85α loss and point to novel therapeutic targets for cancer.IN BRIEFThis study provides the comprehensive mechanism for p85α loss induced and receptor tyrosine kinase stimulated PI3K/Akt signaling.
Propofol directly binds and inhibits skeletal muscle ryanodine receptor 1 (RyR1)
Authors: Joseph Thomas T. , Bu Weiming , Haji-Ghassemi Omid , Chen Yu Seby , Woll Kellie , Allen Paul D. , Brannigan Grace , van Petegem Filip , Eckenhoff Roderic G. 
Published: January 2024

AbstractAs the primary Ca2+release channel in skeletal muscle sarcoplasmic reticulum (SR), mutations in the type 1 ryanodine receptor (RyR1) or its binding partners underlie a constellation of muscle disorders, including malignant hyperthermia (MH). In patients with MH mutations, exposure to triggering drugs such as the halogenated volatile anesthetics biases RyR1 to an open state, resulting in uncontrolled Ca2+release, sarcomere tension and heat production. Restoration of Ca2+into the SR also consumes ATP, generating a further untenable metabolic load.When anesthetizing patients with known MH mutations, the non-triggering intravenous general anesthetic propofol is commonly substituted for triggering anesthetics. Evidence of direct binding of anesthetic agents to RyR1 or its binding partners is scant, and the atomic-level interactions of propofol with RyR1 are entirely unknown. Here, we show that propofol decreases RyR1 opening in heavy SR vesicles and planar lipid bilayers, and that it inhibits activator-induced Ca2+release from SR in human skeletal muscle. In addition to confirming direct binding, photoaffinity labeling usingm-azipropofol (AziPm) revealed several putative propofol binding sites on RyR1. Prediction of binding affinity by molecular dynamics simulation suggests that propofol binds at least one of these sites at clinical concentrations. These findings invite the hypothesis that in addition to propofol not triggering MH, it may also be protective against MH by inhibiting induced Ca2+flux through RyR1.
Regional Microglial Response in Enthorino-hippocampal Slice Cultures to Schaffer Collateral Lesion and Metalloproteinases Modulation
Authors: Virtuoso A. , Galanis C. , Lenz M. , Papa M. , Vlachos A 
Published: January 2024

AbstractMicroglia and astrocytes are essential in sustaining physiological networks on the central nervous system, with their ability to remodel the extracellular matrix, being pivotal for synapse plasticity. Recent findings challenge the traditional view of homogenous glial populations in the brain, uncovering morphological, functional and molecular heterogeneity among glial cells. This diversity has significant implications for both physiological and pathological brain states. In the present study, we mechanically induced a Schaffer collateral lesion (SCL) in mouse enthorino-hippocampal slice cultures to investigate glial behavior, i.e., microglia and astrocytes, under metalloproteinases (MMPs) modulation in the lesioned area, CA3, and the denervated region, CA1. We observed distinct response patterns in microglia and astrocytes 3 days after the lesion. Notably, GFAP-expressing astrocytes showed no immediate changes post-SCL. Microglia responses varied depending on their anatomical location. The MMPs inhibitor GM6001 did not affect microglial reactions in CA3, while increasing the Iba1 cells numbers in CA1, underscoring the complexity of the hippocampal neuroglial network post-injury. These findings highlight the importance of understanding glial regionalization following neural injury and MMPs modulation, and pave the way for further research into glia-targeted therapeutic strategies for neurodegenerative disorders.
Detection of Fluorescent Protein Mechanical Switching in Cellulo
Authors: Shoyer T. Curtis , Collins Kasie L. , Ham Trevor R. , Blanchard Aaron T. , Malavade Juilee N. , West Jennifer L. , Hoffman Brenton D. 
Published: January 2024

ABSTRACT/SUMMARYThe ability of cells to sense and respond to mechanical forces is critical in many physiological and pathological processes. However, the mechanisms by which forces affect protein function inside cells remain unclear. Motivated by in vitro demonstrations of fluorescent proteins (FPs) undergoing reversible mechanical switching of fluorescence, we investigated if force-sensitive changes in FP function could be visualized in cells. Guided by a computational model of FP mechanical switching, we develop a formalism for its detection in Förster resonance energy transfer (FRET)-based biosensors and demonstrate its occurrencein celluloin a synthetic actin-crosslinker and the mechanical linker protein vinculin. We find thatin cellulomechanical switching is reversible and altered by manipulation of cellular force generation as well as force-sensitive bond dynamics of the biosensor. Together, this work describes a new framework for assessing FP mechanical stability and provides a means of probing force-sensitive protein function inside cells.MOTIVATIONThe ability of cells to sense mechanical forces is critical in developmental, physiological, and pathological processes. Cells sense mechanical cues via force-induced alterations in protein structure and function, but elucidation of the molecular mechanisms is hindered by the lack of approaches to directly probe the effect of forces on protein structure and function inside cells. Motivated by in vitro observations of reversible fluorescent protein mechanical switching, we developed an approach for detecting fluorescent protein mechanical switchingin cellulo. This enables the visualization of force-sensitive protein function inside living cells.
Visualizing Mitochondrial Heme Flow through GAPDH to Targets in Living Cells and its Regulation by NO
Authors: Biswas Pranjal , Palazzo Joseph , Schlanger Simon , Jayaram Dhanya Thamaraparambil , Islam Sidra , Page Richard C. , Stuehr Dennis J. 
Published: January 2024

AbstractIron protoporphyrin IX (heme) is an essential cofactor that is chaperoned in mammalian cells by GAPDH in a process regulated by NO. To gain further understanding we generated a tetra-Cys human GAPDH reporter construct (TC-hGAPDH) which after being expressed and labeled with fluorescent FlAsH reagent could indicate heme binding by fluorescence quenching. When purified or expressed in HEK293T mammalian cells, FlAsH-labeled TC-hGAPDH displayed physical, catalytic, and heme binding properties like native GAPDH and its heme binding (2 mol per tetramer) quenched its fluorescence by 45-65%. In live HEK293T cells we could visualize TC-hGAPDH binding mitochondrially-generated heme and releasing it to the hemeprotein target IDO1 by monitoring cell fluorescence in real time. In cells with active mitochondrial heme synthesis, a low-level NO exposure increased heme allocation into IDO1 while keeping steady the level of heme-bound TC-hGAPDH. When mitochondrial heme synthesis was blocked at the time of NO exposure, low NO caused cells to reallocate existing heme from TC-hGAPDH to IDO1 by a mechanism requiring IDO1 be present and able to bind heme. Higher NO exposure had an opposite effect and caused cells to reallocate existing heme from IDO1 to TC-hGAPDH. Thus, with TC-hGAPDH we could follow mitochondrial heme as it travelled onto and through GAPDH to a downstream target (IDO1) in living cells, and to learn that NO acted at or downstream from the GAPDH heme complex to promote a heme reallocation in either direction depending on the level of NO exposure.
Cholesterol-Dependent Membrane Deformation by Metastable Viral Capsids Facilitates Entry
Authors: Jiao Mengchi , Danthi Pranav , Yu Yan 
Published: January 2024

AbstractNon-enveloped viruses employ unique entry mechanisms to breach and infect host cells. Understanding these mechanisms is crucial for developing antiviral strategies. Prevailing perspective suggests that non-enveloped viruses release membrane lytic peptides to breach host membranes. However, the precise involvement of the viral capsid in this entry remains elusive. Our study presents direct observations elucidating the dynamically distinctive steps through which metastable reovirus capsids disrupt host lipid membranes as they uncoat into partially hydrophobic intermediate particles. Using both live cells and model membrane systems, our key finding is that reovirus capsids actively deform and permeabilize lipid membranes in a cholesterol-dependent process. Unlike membrane lytic peptides, these metastable viral capsids induce more extensive membrane perturbations, including budding, bridging between adjacent membranes, and complete rupture. Notably, cholesterol enhances subviral particle adsorption, resulting in the formation of pores equivalent to the capsid size. This cholesterol dependence is attributed to the lipid condensing effect, particularly prominent at intermediate cholesterol level. Furthermore, our results reveal a positive correlation between membrane disruption extent and efficiency of viral variants in establishing infection. This study unveils the crucial role of capsid-lipid interaction in non-enveloped virus entry, providing new insights into how cholesterol homeostasis influences virus infection dynamics.
PCTA, A PAN-CANCER CELL LINE TRANSCRIPTOME ATLAS
Authors: Cheng Siyuan , Li Lin , Yu Xiuping 
Published: January 2024

ABSTRACTBackgroundA substantial volume of RNA sequencing data were generated from cancer cell lines. However, it requires specific bioinformatics skills to compare gene expression levels across cell lines. This has hindered non-bioinformaticians from fully utilizing these valuable datasets in their research. To bridge this gap, we established a curated Pan-cancer Cell Line Transcriptome Atlas (PCTA) dataset. This resource aims to provide a user-friendly platform, allowing researchers without extensive bioinformatics expertise to access and leverage the wealth of information within the dataset for their studies. Importantly, PCTA stands out by offering sufficient sample numbers per cell line in comparison to other pan-cancer datasets.MethodsCell lines’ meta data and RNA sequencing data were retrieved from the Cancer Cell Line Encyclopedia (CCLE), SRA and ARCHS4 databases. Utilizing the programming language R, we conducted data retrieval, normalization, and visualization. Only expression data for protein-coding genes and long-non-coding RNAs (LncRNAs) were considered in this study, streamlining the focus to enhance the precision and relevance of the analysis.ResultsThe resulting PCTA dataset encompasses the expression matrix of 24,965 genes, featuring data from 84,385 samples derived from 5,677 studies. This comprehensive compilation spans 535 cell lines, representing a spectrum of 114 cancer types originating from 30 diverse tissue types. On UMAP plots, cell lines originating from the same type of tissue tend to cluster together, illustrating the dataset’s ability to capture biological relationships. To unravel molecular signatures, marker genes were identified for each cancer type. Additionally, an interactive and user-friendly web application (https://pcatools.shinyapps.io/PCTA_app/) was developed for researchers to explore the PCTA dataset. This platform allows users to examine the expression pattern of their genes of interest across a diverse array of samples. Data are visualized as violin-, box-, and point-plots, enhancing the interpretability of the findings.ConclusionThe PCTA stands as a comprehensive resource, offering insights into gene expression patterns across diverse cancer cell lines and providing a valuable tool to explore molecular signatures and potential therapeutic targets in cancer research.
Low-intensity focused ultrasound to the insula and dorsal anterior cingulate has site-specific and pressure dependent effects on pain during measures of central sensitization
Authors: In Alexander , Strohman Andrew , Payne Brighton , Legon Wynn 
Published: January 2024

ABSTRACTBackgroundThe insula and dorsal anterior cingulate cortex (dACC) are core brain regions involved in pain processing and central sensitization, a shared mechanism across various chronic pain conditions. Methods to modulate these regions may serve to reduce central sensitization, though it is unclear which target may be most efficacious for different measures of central sensitization.Objective/HypothesisInvestigate the effect of low-intensity focused ultrasound (LIFU) pressure to the anterior insula (AI), posterior insula (PI) or dACC on conditioned pain modulation (CPM) and temporal summation of pain (TSP).MethodsN = 16 volunteers underwent TSP and CPM pain tasks pre/post a 10 minute LIFU intervention to either the AI, PI, dACC or Sham stimulation. Pain ratings were collected pre/post LIFU.ResultsLIFU to the PI significantly attenuated pain ratings in both TSP and the CPM protocols. LIFU to the dACC only affected TSP pain ratings. LIFU to AI had no effect on either TSP or CPM pain ratings. LIFU pressure modulated group means but did not affect overall group differences.ConclusionsLIFU to the PI and dACC differentially affected central sensitization. This may, in part, be due to dosing (pressure) of LIFU. Inhibition of the PI with LIFU may be a future potential therapy in chronic pain populations demonstrating central sensitization. The minimal effective dose of LIFU for efficacious neuromodulation will help to translate LIFU for therapeutic options.
The shared genetic basis of leaf morphology and tensile resistance underlies the effect of growing season length in a widespread perennial grass
Authors: Durant P. C. , Bhasin Amit , Juenger Thomas E. , Heckman Robert W. 
Published: January 2024

AbstractPremiseLeaf tensile resistance, a leaf’s ability to withstand pulling forces, is an important determinant of plant ecological strategies. One potential driver of leaf tensile resistance is growing season length. When growing seasons are long, strong leaves—which often require more time and resources to construct than weak leaves—may be more advantageous than when growing seasons are short. Growing season length and other ecological conditions may also impact the morphological traits that underlie leaf tensile resistance.MethodsTo understand variation in leaf tensile resistance, we measured size-dependent leaf strength and size-independent leaf toughness in diverse genotypes of the widespread perennial grassPanicum virgatum(switchgrass) in a common garden. We then used quantitative genetic approaches to estimate the heritability of leaf tensile resistance and whether there were genetic correlations between leaf tensile resistance and other morphological traits.Key ResultsLeaf tensile resistance was positively associated with aboveground biomass (a proxy for fitness). Moreover, both measures of leaf tensile resistance exhibited high heritability and were positively genetically correlated with leaf lamina thickness and leaf mass per area (LMA). Leaf tensile resistance also increased with habitat-of-origin growing season length and this effect was mediated by both LMA and leaf thickness.ConclusionsDifferences in growing season length may promote selection for different leaf lifespans and may explain existing variation in leaf tensile resistance inP. virgatum. In addition, the high heritability of leaf tensile resistance suggests thatP. virgatumwill be able to respond to climate change as growing seasons lengthen.
Non-Necroptotic Roles of MLKL in Diet-Induced Obesity, Liver Pathology, and Insulin Sensitivity: Insights from a High Fat, High Fructose, High Cholesterol Diet Mouse Model
Authors: Ohene-Marfo Phoebe , Nguyen Hoang Van M , Mohammed Sabira , Thadathil Nidheesh , Tran Albert , Nicklas Evan H , Wang Dawei , Selvarani Ramasamy , Farriester Jacob , Varshney Rohan , Kinter Michael , Richardson Arlan , Rudolph Michael , Deepa Sathyaseelan S. 
Published: January 2024

ABSTRACTChronic inflammation is a key player in metabolic dysfunction-associated fatty liver disease (MAFLD) progression. Necroptosis, an inflammatory cell death pathway, is elevated in MAFLD patients and mouse models, yet its role is unclear due to diverse mouse models and inhibition strategies. In our study, we inhibited necroptosis by targeting mixed lineage kinase domain like pseudokinase (MLKL), the terminal effector of necroptosis, in a high-fat, high-fructose, high-cholesterol (HFHFrHC) mouse model of diet-induced MAFLD mouse model. Despite HFHFrHC diet upregulating MLKL (2.5-fold), WT mice livers showed no increase in necroptosis markers or associated proinflammatory cytokines. Surprisingly,Mlkl−/−mice experienced exacerbated liver inflammation without protection from diet-induced liver damage, steatosis, or fibrosis. In contrast,Mlkl+/−mice showed significant reduction in these parameters that was associated with elevated Pparα and Pparγ levels. BothMlkl−/−andMlkl+/−mice on HFHFrHC diet resisted diet-induced obesity, attributed to increased beiging, enhanced oxygen consumption and energy expenditure due to adipose tissue, and exhibited improved insulin sensitivity. These findings highlight the tissue specific effects of MLKL on the liver and adipose tissue, and suggest a dose-dependent effect of MLKL on liver pathology.