bluuebunny/crossref_metadata_2025 huggingface dataset:
Emotional prosody modulates visual mental imagery
Authors: Huang Weifang , Zhang Fengxiang , Zhang Chenghui , Wang Can , Zhang Shiyu , Pu Yi , Kong Xiang-Zhen
Published: January 2024

Perceptual stimuli’s emotional properties are vital for human evolution and adaptation. While visual imagery is predominantly regarded as a weak form of perception, the influence of cross-modal emotional features on imagery is still unknown. The present study aims to investigate how emotional prosody modulates imagery quality (i.e., accuracy and clarity) and neural mechanisms using a combination of behavioral tasks and functional magnetic resonance imaging (fMRI). At the behavioral level, our results showed that frustrated conditions induced significant prosody effects on visual mental imagery quality measures, and the effects were particularly pronounced in individuals with lower imagery use tendency. At the neural level, compared with the neutral condition, the emotional prosody conditions (both happy and frustrated) showed stronger activation in various regions including the middle occipital gyrus, supporting the critical role of primary visual system in imagery. Moreover, compared to the frustrated prosody condition, the happy prosody showed stronger activation in the precuneus and anterior cingulate cortex, which are core components of the default mode network. A machine learning prediction analysis with a random forest model identified a significant brain-behavioral correlation between prosody-linked neural activity and individual imagery use tendency. A subsequent Shapley Additive exPlanations (SHAP) analysis further highlighted the primary visual and default mode regions as top contributors to this prediction. Taken together, these results provide new insights for the understanding of how emotional prosody modulates visual mental imagery, considering individual differences, and provide compelling evidence for incorporating emotion as important shaping factor in more general model for imagery.
Photoswitchable endocytosis of biomolecular condensates in giant vesicles
Authors: Mangiarotti Agustín , Aleksanyan Mina , Siri Macarena , Lipowsky Reinhard , Dimova Rumiana
Published: January 2024

Interactions between membranes and biomolecular condensates can give rise to complex phenomena such as wetting transitions, mutual remodeling, and endocytosis. In this study, we demonstrate a light-triggered manipulation of condensate engulfment using giant vesicles containing photoswitchable lipids. UV irradiation increases the membrane area, facilitating a rapid condensate endocytosis, which can be reverted by blue light. The affinity of the protein-rich condensates to the membrane and the reversibility of the engulfment processes is quantified from confocal microscopy images. The degree of engulfment, whether partial or complete, depends on the initial membrane excess area and the relative sizes of vesicles and condensates. Theoretical estimates suggest that utilizing the light-induced excess area to increase the vesicles-condensate adhesion interface is energetically more favorable than the energy gain from folding the membrane into invaginations and tubes. Our overall findings demonstrate that membrane-condensate interactions can be easily and quickly modulated via light, providing a versatile system for building platforms to control cellular events and design intelligent drug delivery systems for cell repair.
Starvation resistant cavefish reveal conserved mechanisms of starvation-induced hepatic lipotoxicity
Authors: Pozo-Morales Macarena , Cobham Ansa E , Centola Cielo , McKinney Mary Cathleen , Liu Peiduo , Perazzolo Camille , Lefort Anne , Libert Frédérick , Bai Hua , Rohner Nicolas , Singh Sumeet Pal
Published: January 2024

Starvation causes the accumulation of lipid droplets in the liver, a somewhat counterintuitive phenomenon that is nevertheless conserved from flies to humans. Much like fatty liver resulting from overfeeding, hepatic lipid accumulation (steatosis) during undernourishment can lead to lipotoxicity and atrophy of the liver. Here, we found that while surface populations of Astyanax mexicanus undergo this evolutionarily conserved response to starvation, the starvation-resistant cavefish larvae of the same species do not display an accumulation of lipid droplets upon starvation. Moreover, cavefish are resistant to liver atrophy during starvation, providing a unique system to explore strategies for liver protection. Using comparative transcriptomics between zebrafish, surface fish, and cavefish, we identified the fatty acid transporter slc27a2a/fatp2 to be correlated with the development of fatty liver. Pharmacological inhibition of slc27a2a in zebrafish rescues steatosis and atrophy of the liver upon starvation. Further, down-regulation of FATP2 in drosophila larvae inhibits the development of starvation-induced steatosis, suggesting the evolutionary conserved importance of the gene in regulating fatty liver upon nutrition deprivation. Overall, our study identifies a conserved, druggable target to protect the liver from atrophy during starvation.

One-Sentence Summary

Cavefish evolved protection from starvation-induced liver damage through reduction of fatty acid uptake regulated byFATP2, a mechanism conserved through 400 million years of animal evolution.
Genetic legacies of mega-landslides: cycles of isolation and contact across flank collapses in an oceanic island
Authors: Noguerales Víctor , Arjona Yurena , García-Olivares Víctor , Machado Antonio , López Heriberto , Patiño Jairo , Emerson Brent C.
Published: January 2024

Catastrophic flank collapses are recognised as important drivers of insular biodiversity dynamics, through the disruption of species ranges and subsequent allopatric divergence. However, little empirical data supports this conjecture, with their evolutionary consequences remaining poorly understood. Using genome-wide data within a population genomics and phylogenomics framework, we evaluate how mega-landslides have impacted evolutionary and demographic history within a species complex of weevils (Curculionidae) within the Canary island of Tenerife. We reveal a complex genomic landscape, within which individuals of single ancestry were sampled in areas characterised by long-term geological stability, relative to the timing of flank collapses. In contrast, individuals of admixed ancestry were almost exclusively sampled within the boundaries of flank collapses. Estimated divergence times among ancestral populations aligned with the timings of mega-landslide events. Our results provide first evidence for a cyclical dynamic of range fragmentation and secondary contact across flank collapse landscapes, with support for a model where this dynamic is mediated by Quaternary climate oscillations. The context within which we reveal climate and topography to interact cyclically through time to shape the geographic structure of genetic variation, together with related recent work, highlights the importance of topoclimatic phenomena as an agent of diversification within insular invertebrates.
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

The 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

Effective 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.
How smart wasT. rex? Testing claims of exceptional cognition in dinosaurs and the application of neuron count estimates in palaeontological research
Authors: Caspar Kai R , Gutierrez-Ibanez Cristian , Bertrand Ornella C , Carr Thomas , Colbourne Jennifer , Erb Arthur , George Hady , Holtz Thomas R , Naish Darren , Wylie Douglas R , Hurlburt Grant R
Published: January 2024

Recent years have seen increasing scientific interest in whether neuron counts can act as correlates of diverse biological phenomena. Lately, Herculano-Houzel (2023) argued that fossil endocasts and comparative neurological data from extant sauropsids allow to reconstruct telencephalic neuron counts in Mesozoic dinosaurs and pterosaurs, which might act as proxies for behaviors and life history traits in these animals. According to this analysis, large theropods such asTyrannosaurus rexwere long-lived, exceptionally intelligent animals equipped with 'macaque- or baboon-like cognition' whereas sauropods as well as most ornithischian dinosaurs would have displayed significantly smaller brains and an ectothermic physiology. Besides challenging established views on Mesozoic dinosaur biology, these claims raise questions on whether neuron count estimates could benefit research on fossil animals in general. Here, we address these findings by revisiting Herculano-Houzel's (2023) work, identifying several crucial shortcomings regarding analysis and interpretation. We present revised estimates of encephalization and telencephalic neuron counts in dinosaurs, which we derive from phylogenetically informed modeling and an amended dataset of endocranial measurements. For large-bodied theropods in particular, we recover significantly lower neuron counts than previously proposed. Furthermore, we review the suitability of neurological variables such as neuron numbers and relative brain size to predict cognitive complexity, metabolic rate and life history traits in dinosaurs, coming to the conclusion that they are flawed proxies of these biological phenomena. Instead of relying on such neurological estimates when reconstructing Mesozoic dinosaur biology, we argue that integrative studies are needed to approach this complex subject.
Liver cancer initiation is dependent on metabolic zonation but decoupled from premalignant clonal expansion
Authors: Chung Andrew , Guo Jason , Wang Yunguan , Jia Yuemeng , Corbitt Natasha , Li Lin , Wei Yonglong , Zhu Min , Wang Zixi , Guo Holly , Gopal Purva , Xiao Guanghua , Wang Tao , Zhu Hao
Published: January 2024

The origin of cancer is poorly understood because cells that obtain truncal mutations are rarely fate mapped in their native environments. A defining feature of the liver is zonation, or the compartmentalization of metabolic functions in hepatocytes located in distinct regions of the lobule1. However, it is unknown if cancers develop in some zones but not others, and if there are metabolic determinants of cancer risk that track with cellular position. To study cancer initiation, we examined the effect of activating mutations inCtnnb1and loss of function mutations inArid2, two of the most commonly co-mutated genes in hepatocellular carcinoma (HCC)2. We exploited glutamine synthetase (GS) as a faithful fate mapping marker ofCtnnb1mutant hepatocytes. By introducing mutations in distinct zones in a mosaic fashion, we showed that position and metabolic context regulate clone expansion. Mutant clones were maintained in zone 1 but largely outcompeted in zone 3. Paradoxically, clonal maintenance was anti-correlated with cancer initiation, as zone 3 mutant livers showed increased tumorigenesis. To define mechanisms, we individually deleted eleven zone specific genes in HCC mouse models, revealing thatGstm2andGstm3were required for efficient HCC initiation in zone 3. These data indicate that liver cancer initiation is dependent on zonation but independent of clonal expansion.
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

PI3Kα 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 BRIEF

This 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

As 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

Microglia 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/SUMMARY

The 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.

MOTIVATION

The 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

Iron 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

Non-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

Background

A 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.

Methods

Cell 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.

Results

The 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.

Conclusion

The 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

Background

The 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/Hypothesis

Investigate 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).

Methods

N = 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.

Results

LIFU 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.

Conclusions

LIFU 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

Premise

Leaf 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.

Methods

To 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 Results

Leaf 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.

Conclusions

Differences 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

Chronic 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.
Type I interferon governs immunometabolic checkpoints that coordinate inflammation duringStaphylococcalinfection
Authors: Reynolds Mack B. , Klein Benjamin , McFadden Michael J. , Judge Norah K. , Navarrete Hannah E. , Michmerhuizen Britton C , Awad Dominik , Schultz Tracey L. , Harms Paul W. , Zhang Li , O’Meara Teresa R. , Sexton Jonathan Z. , Lyssiotis Costas A. , Kahlenberg J. Michelle , O’Riordan Mary X.
Published: January 2024

Fine-tuned inflammation during infection enables pathogen clearance while minimizing host damage. Inflammation regulation depends on macrophage metabolic plasticity, yet coordination of metabolic and inflammatory programs is underappreciated. Here we show that type I interferon (IFN) temporally guides metabolic control of inflammation during methicillin-resistant Staphylococcus aureus (MRSA) infection. In macrophages, staggered Toll-like receptor and type I IFN signaling permitted a transient respiratory burst followed by inducible nitric oxide synthase (iNOS)-mediated OXPHOS disruption. OXPHOS disruption promoted type I IFN, suppressing other pro-inflammatory cytokines, notably IL-β. iNOS expression peaked at 24h post-infection, followed by lactate-driven iNOS repression via histone lactylation. In contrast, type I IFN pre-conditioning sustained infection-induced iNOS expression and amplified type I IFN. Cutaneous MRSA infection in mice constitutively expressing epidermal type I IFN led to elevated iNOS levels, impaired wound healing, vasculopathy, and lung infection. Thus, kinetically regulated type I IFN signaling coordinates immunometabolic checkpoints that control infection-induced inflammation.

Graphical abstract
Devaluing memories of reward: A case for dopamine
Authors: Fry B.R. , Russell N. , Fex V. , Mo B. , Pence N. , Beatty J.A , Manfreddsson F. P. , Toth B.A. , Burgess C.R. , Gershman S. , Johnson A.W.
Published: January 2024

We describe a novel role for dopamine in devaluing sensory memories of reward. Mesencephalic dopamine cells activated during a mediated devaluation phase were later chemogenetically reactivated. This retrieval of the devalued reward memory elicited a reduction in the hedonic evaluation of sucrose reward. Through optogenetic and chemogenetic manipulations, we confirm dopamine cells are both sufficient and necessary for mediated devaluation, and retrieval of these memories reflected dopamine release in the nucleus accumbens. Consistent with our computational modelling data, our findings indicate a critical role for dopamine in encoding predictive representations of the sensory features of reinforcement. Overall, we illuminate the elaborate nature of reinforcement signals encoded by dopamine and suggest novel approaches to treating a host of psychobiological disorders.
Stopping Speed in Response to Auditory and Visual Stop Signals Depends on Go Signal Modality
Authors: Weber Simon , Salomoni Sauro E. , St George Rebecca J. , Hinder Mark R.
Published: January 2024

Past research has found that the speed of the action cancellation process is influenced by the sensory modality/modalities of the environmental change that triggers it. However, the effect on selective stopping processes (where participants must cancel only one component of a multi-component movement) remains unknown, despite these complex movements often being required as we navigate our busy modern world.

Thirty healthy adults (mean age = 31.1 years, SD = 10.5) completed five response-selective stop signal tasks featuring different combinations of “go signal” modality (the environmental change baring an imperative to initiate movement; auditory or visual) and “stop signal” modality (the environmental change indicating that action cancellation is required; auditory, visual, or audiovisual). Electromyographical (EMG) recordings of effector muscles allowed detailed comparison of the characteristics of voluntary action and cancellation between tasks.

Behavioural and physiological measures of stopping speed demonstrated that the modality of thegosignal influenced how quickly participants cancelled movement in response to the stop signal: stopping was faster in two cross-modal experimental conditions (auditory go - visual stop; visual go - auditory stop), than in two conditions using the same modality for both signals. A separate condition testing for multisensory facilitation revealed that stopping was fastest when the stop signal consisted of acombinedaudiovisual stimulus, compared to all other go-stop stimulus combinations. These findings provide novel evidence regarding the role of attentional networks in action cancellation and suggest modality specific cognitive resources influence the latency of the stopping process.
Improved Detection of Drug-Induced Liver Injury by Integrating Predictedin vivoandin vitroData
Authors: Seal Srijit , Williams Dominic P. , Hosseini-Gerami Layla , Mahale Manas , Carpenter Anne E. , Spjuth Ola , Bender Andreas
Published: January 2024

Drug-induced liver injury (DILI) has been significant challenge in drug discovery, often leading to clinical trial failures and necessitating drug withdrawals. The existing suite of in vitro proxy-DILI assays is generally effective at identifying compounds with hepatotoxicity. However, there is considerable interest in enhancing in silico prediction of DILI because it allows for the evaluation of large sets of compounds more quickly and cost-effectively, particularly in the early stages of projects. In this study, we aim to study ML models for DILI prediction that first predicts nine proxy-DILI labels and then uses them as features in addition to chemical structural features to predict DILI. The features includein vitro(e.g., mitochondrial toxicity, bile salt export pump inhibition) data,in vivo(e.g., preclinical rat hepatotoxicity studies) data, pharmacokinetic parameters of maximum concentration, structural fingerprints, and physicochemical parameters. We trained DILI-prediction models on 888 compounds from the DILIst dataset and tested on a held-out external test set of 223 compounds from DILIst dataset. The best model, DILIPredictor, attained an AUC-ROC of 0.79. This model enabled the detection of top 25 toxic compounds compared to models using only structural features (2.68 LR+ score). Using feature interpretation from DILIPredictor, we were able to identify the chemical substructures causing DILI as well as differentiate cases DILI is caused by compounds in animals but not in humans. For example, DILIPredictor correctly recognized 2-butoxyethanol as non-toxic in humans despite its hepatotoxicity in mice models. Overall, the DILIPredictor model improves the detection of compounds causing DILI with an improved differentiation between animal and human sensitivity as well as the potential for mechanism evaluation. DILIPredictor is publicly available athttps://broad.io/DILIPredictorfor useviaweb interface and with all code available for download and local implementation viahttps://pypi.org/project/dilipred/.

GRAPHICAL ABSTRACT
Neuromark PET: A multivariate method for estimating whole brain fMRI guided intrinsic networks and connectomes from fMRI and PET data
Authors: Saha Debbrata K. , Bohsali Anastasia , Saha Rekha , Hajjar Ihab , Calhoun Vince D.
Published: January 2024

Positron emission tomography (PET) and magnetic resonance imaging (MRI) are both widely used neuroimaging techniques to study brain functional and molecular connec-tivity. Although whole brain resting functional MRI (fMRI) connectomes (a matrix describing the inter-regional connectivity patterns) are widely used, the integration or association of whole brain molecular connectomes with PET data are rarely done. This likely stems from the fact that PET data is typically analyzed by using a region of inter-est approach, while whole brain spatial networks and their connectivity (covariation) receive much less attention. As a result, to date, there have been little focus on di-rectly comparing whole brain PET and fMRI connectomes. In this study, we present a method that uses spatially constrained independent component analysis (scICA) (uti-lizing fMRI components as spatial priors) to estimate corresponding (Amyloid) PET and fMRI connectomes and examine the relationship between them using datasets that include individuals with mild cognitive impairment (MCI). Our results demonstrate highly modularized PET connectome patterns that complement those identified from resting fMRI. In particular, fMRI showed strong intra-domain connectivity with inter-domain anticorrelation in sensorimotor and visual domains as well as default mode network. PET amyloid data showed similar strong intra-domain effects, but showed much higher correlations within cognitive control and default mode domains, as well as anticorrelation between cerebellum and other domains. The estimated fMRI informed PET networks have similar, but not identical, network spatial patterns to the resting fMRI networks, with the fMRI informed PET networks being slightly smoother and, in some cases, showing variations in subnodes. To further compare the two modalities, we also analyzed the differences between individuals with MCI receiving medication versus a placebo. Results show both common and modality specific treatment effects on fMRI and PET connectomes. From our fMRI analysis, we observed higher connec-tivity differences in various regions, such as the connection between the thalamus and middle occipital gyrus, as well as the insula and right middle occipital gyrus. Mean-while, the PET analysis revealed increased activation between the anterior cingulate cortex and the left inferior parietal lobe, along with other regions, in individuals who received medication versus placebo. In sum, our novel approach identifies correspond-ing whole-brain fMRI informed PET and fMRI networks and connectomes. While we observed common patterns of network connectivity, our analysis of the MCI treatment and placebo groups revealed that each modality captures modality and group specific information about brain networks, highlighting differences between the two groups in both network expression and network connectivity.
An arms race between 5’ppp-RNA virus and its alternative recognition receptor MDA5 in RIG-I-lost teleost fish
Authors: Geng Shang , Lv Xing , Zheng Weiwei , Xu Tianjun
Published: January 2024

The incessant arms race between viruses and hosts has led to numerous evolutionary innovations that shape life’s evolution. During this process, the interactions between viral receptors and viruses have garnered significant interest since viral receptors are cell surface proteins exploited by viruses to initiate infection. Our study sheds light on the arms race between the MDA5 receptor and 5’ppp-RNA virus in a lower vertebrate fish,M. miiuy. Firstly, the frequent and independent loss events of RIG-I in vertebrates prompted us to search for alternative immune substitutes, with homology-dependent genetic compensation response (HDGCR) being the main pathway. Our further analysis suggested that MDA5 ofM. miiuy and G. gallus, the homolog of RIG-I, can replace RIG-I in recognizing 5’ppp-RNA virus, which may lead to redundancy of RIG-I and loss from the species genome during evolution. Secondly, as an adversarial strategy, 5’ppp-RNA SCRV can utilize the m6A methylation mechanism to degrade MDA5 and weaken its antiviral immune ability, thus promoting its own replication and immune evasion. In summary, our study provides a snapshot into the interaction and coevolution between vertebrate and virus, offering valuable perspectives on the ecological and evolutionary factors that contribute to the diversity of the immune system.
Assessing complex member composition and insecticide resistance status ofAnopheles gambiae s.l.in three coastal health districts of Côte d’Ivoire
Authors: Kouamé Jackson IK , Edi Constant VA , Zahouli Julien BZ , Kouamé Ruth MA , Kacou Yves AK , Yokoly Firmain N , Gbalegba Constant GN , Malone David , Koudou Benjamin G
Published: January 2024

Although malaria is endemic in Coastal Côte d’Ivoire, updated data on the resistance profile of the main vector,Anopheles gambiae sensu lato(s.l.), are still lacking, thus compromising decision-making for an effective vector control intervention. This study investigated the complex members and the insecticide resistance in theAnopheles gambiae s.l.populations in coastal Côte d’Ivoire. Between 2018 and 2020, bioassays were conducted on femaleAn. gambiae s.l.mosquitoes in three coastal health districts (Aboisso, Jacqueville and San Pedro) of Côte d’Ivoire. Pyrethroids deltamethrin, permethrin and alphacypermethrin (1X, 5X and 10X), clothianidin and synergist piperonyl butoxide (PBO) combined with pyrethroid 1X were tested using WHO tube bioassays. Chlorfenapyr was evaluated using CDC bottle bioassays.An. gambiaecomplex members andVgsc995F,Vgsc995S and Ace-1 280S mutations were identified using polymerase chain reaction (PCR) technique. Overall,Anopheles. gambiae s.l.populations were primarily composed ofAnopheles coluzzii(88.24%, n = 312), followed byAnopheles gambiae sensu stricto(s.s.) (7.56%) and hybrids (4.17%). These populations displayed strong resistance to pyrethroids at standard diagnostic doses, with mortality remaining below 98% even at 10X doses, except for alphacypermethrin in Aboisso. Pre-exposure to PBO significantly increased mortality but did not fully restore susceptibility, except for alphacypermethrin in Jacqueville. Clothianidin restored full susceptibility in Jacqueville and San Pedro, while chlorfenapyr restored susceptibility in Aboisso at 100 µg ai/bottle and all three districts at 200 μg ai/bottle.Vgsc995F mutation dominated, with frequencies varying from 71.2% to 79.3%.Vgsc995S had low, and showed frequencies ranging from 2.3% to 5.7%. Ace-1 280S prevalence varied between 4.2% and 42.9%. Coastal Côte d’Ivoire’sAn. gambiae s.l.populations were mainly composed ofAnopheles coluzziiand showed high resistance to pyrethroids. Clothianidin, chlorfenapyr, and PBO with pyrethroids increased mortality, indicating their potential use as an alternative for malaria vector control.