bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interoceptive Awareness of the Breath Preserves Dorsal Attention Network Activity amidst Widespread Cortical Deactivation: A Within-Participant Neuroimaging Study
Authors: Farb Norman A. S. , Zuo Zoey , Price Cynthia J. 
Published: May 2022

AbstractInteroception, the representation of the body’s internal state, serves as a foundation for emotion, motivation, and wellbeing. Yet despite its centrality in human experience, the neural mechanisms of interoception are poorly understood. The Interoceptive/Exteroceptive Attention Task (IEAT) is a novel neuroimaging paradigm that compares behavioral tracking of the respiratory cycle (Active Interoception) to tracking of a visual stimulus (Active Exteroception). Twenty-two healthy participants completed the IEAT during two separate scanning sessions (N = 44) as part of a randomized control trial of Mindful Awareness in Body-oriented Therapy (MABT). Compared to Exteroception, Interoception deactivated somatomotor and prefrontal regions. Greater interoceptive sensibility (MAIA scale) predicted sparing from deactivation along the anterior cingulate cortex (ACC) and left-lateralized language regions. The right insula—typically described as a primary interoceptive cortex—was only implicated by its further deactivation during an exogenously paced respiration condition (Active Matching). Psychophysiological interaction analysis characterized Active Interoception as promoting greater ACC connectivity with lateral frontal and parietal regions commonly referred to as the Dorsal Attention Network. Interoception of the breath may therefore involve reduced corticalactivitybut greaterconnectivity, with greater sensibility sparing cortical inhibition within well-characterized attentional networks. In contrast to a literature that relates detection of liminal signals such as the heartbeat to anterior insula activity, attention towards accessible body sensations such as the breath may lead to a low activity, high connectivity state in which sensory signals from the body may be better discerned.Significance StatementInteroception, the representation of the body’s internal state, is poorly understood compared to the external senses, with existing neuroimaging studies failing to match task difficulty between interoceptive and exteroceptive tasks. The present study used a novel fMRI task to compare interoceptive and exteroceptive attention, and how this distinction was moderated by self-reported interoceptive awareness. The results implicate three novel interoceptive mechanisms: interoception reduces corticalactivitywhile increasingconnectivity, wherein awareness is linked to preserved activation of the brain’s salience network and left-lateralized language regions. These findings characterize interoception as a lower activity state in which awareness depends upon the ability to notice and report on body signals typically obscured by the processing of exteroceptive information and other forms of cognition.
Impaired hepatic autophagy exacerbates xenobiotics induced liver injury
Authors: Byrnes Katherine , Bailey Niani Tiaye , Mercer Arissa , Joshi Spandan , Liu Gang , Yin Xiao-Ming , Khambu Bilon 
Published: May 2022

ABSTRACTXenobiotics can activate the hepatic survival pathway, but it is not clear how impaired hepatic survival pathways may affect xenobiotic-induced liver injury. We investigated the role of hepatic autophagy, a cellular survival pathway, in cholestatic liver injury driven by a xenobiotic. Here we demonstrate that DDC diet impaired autophagic flux, resulting in the accumulation of p62-Ub-intrahyaline bodies (IHBs) but not the Mallory Denk-Bodies (MDBs). Impaired autophagic flux was linked to a deregulated hepatic protein-chaperonin system and a significant decline in Rab family proteins. In addition, we demonstrate that heterozygous deletion of Atg7, a key autophagy gene, aggravated the p62-Ub-IHB accumulation and cholestatic liver injury. Moreover, we showed that p62-Ub-IHB accumulation did not activate the proteostasis-related ER stress signaling pathway, but rather activated the NRF2 pathway and suppressed the FXR nuclear receptor, resulting in cholestatic liver injury. Conclusion: Impaired autophagy exacerbates xenobiotic-induced cholestatic liver injury. Promotion of autophagy may represent a new therapeutic approach for xenobiotic-induced liver injury.
Huntingtin S421 phosphorylation increases kinesin and dynein engagement on early endosomes and lysosomes
Authors: Prowse Emily N. P. , Chaudhary Abdullah R. , Sharon David , Hendricks Adam G. 
Published: May 2022

AbstractHuntingtin (HTT) is a scaffolding protein that recruits motor proteins to vesicular cargoes, enabling it to regulate kinesin-1, dynein, and myosin-VI-dependent transport. To maintain the native stoichiometry of huntingtin with its interacting partners, we used CRISPR/Cas9 to induce a phosphomimetic mutation of the endogenous HTT at S421 (HTT-S421D). Using single particle tracking, optical tweezers, and immunofluorescence, we examined the effects of this mutation on the motility of early endosomes and lysosomes. In HTT-S421D cells, lysosomes exhibit longer displacements and higher processive fractions compared to wild-type (HTT-WT) cells. Kinesins and dyneins exert greater forces on early endosomes and lysosomes in cells expressing HTT-S421D. Additionally, endosomes bind to microtubules faster and are more resistant to detachment under load. The recruitment of kinesins and dyneins to microtubules is enhanced in HTT-S421D cells. In contrast, overexpression of HTT had variable effects on the processivity, displacement, and directional bias of both early endosomes and lysosomes. These data indicate that phosphorylation of the endogenous huntingtin causes early endosomes and lysosomes to move longer distances and more processively by recruiting and activating both kinesin-1 and dynein.Statement of SignificanceThe ubiquitous scaffolding protein huntingtin regulates the recruitment and activity of microtubule motors. Huntingtin phosphorylation at S421 enhances the microtubule binding and force generation of kinesin and dynein on early endosomes and lysosomes. Using optical tweezers to measure the forces exerted on endosomes in CRISPR-engineered cells, we find that a phosphomimetic huntingtin mutation (S421D) enhances both kinesin- and dynein-driven forces on early endosomes and lysosomes. The ability to modulate motor activity on a range of organelles makes huntingtin unique and suggests a significant role for huntingtin in regulating intracellular transport.
The combination of feedforward and feedback processing accounts for contextual effects in visual cortex
Authors: Di Santo Serena , Dipoppa Mario , Keller Andreas , Roth Morgane , Scanziani Massimo , Miller Kenneth D. 
Published: May 2022

AbstractSensory systems must combine local features with context to infer meaning. Accordingly, context profoundly influences neural responses. We developed a unified circuit model demonstrating how feedforward and feedback inputs are integrated to produce three forms of contextual effects in mouse primary visual cortex (V1). First, reanalyzing existing data, we discovered that increasing stimulus size only weakly increases the area of V1 neural response, conflicting with previous models of surround suppression (SS). Second, through modeling, we found that, in Layer 2/3, (1) SS and its contrast dependence are largely inherited from Layer 4; (2) Inverse responses (IR) – size-tuned responses to a gray “hole” in a full-field grating – are driven by feedback connections provided they are sufficiently wide; (3) Cross-orientation surround facilitation is induced by the summation of feedback input driving IR with the feedforward-driven classical center response. The model accounts for many previous findings and makes multiple testable predictions.HighlightsOne model explains three different types of contextual modulationThe widths of spatial response patterns grow much more slowly than stimulus size.Inverse responses depend on the geometry of feedback response fields and projectionsSummation of classical and inverse response accounts for surround facilitation.
Connecting Covert Attention and Visual Perception to the Spatiotemporal Dynamics of Alpha Band Activity, Cross-Frequency Coupling (CFC), and Functional Connectivity using Multivariate Pattern Analysis (MVPA)
Authors: Sheldon Sarah S. , Fyshe Alona , Mathewson Kyle E. 
Published: May 2022

AbstractSome evidence suggests that alpha activity is directly related to the baseline firing rate of sensory neurons which alters the probability of responding to a stimulus. Other evidence points to alpha indirectly modulating cortical excitability through its interactions with gamma oscillations. A third possibility is that alpha-based functional connectivity better explains attentional modulation and perceptual responses. To test this, alpha amplitude, CFC, and functional connectivity measures were extracted from EEG data recorded while participants performed a cued orientation perception task. Using pre-target data, the spatiotemporal activity of each metric was submitted to a SVM classifier to determine which activity pattern best distinguished trials with covert attention from trials without. The same metrics were submitted to SVR to find the activity that best predicted task performance. Results indicate the best metric for classifying trials with and without covert attention was alpha amplitude. This indicates that, prior to target onset, alpha amplitude alone is most sensitive to the presence of covert attention. In contrast, none of the metrics were strong predictors of task performance. Overall, our results support the idea that alpha activity is directly related to changes in the baseline firing rate of sensory neurons which changes responsiveness but not performance.
A multi-functional small molecule alleviates fracture pain and promotes bone healing
Authors: Shih Yu-Ru V. , Kingsley David , Newman Hunter , Hoque Jiaul , Gupta Ankita , Lascelles B. Duncan X. , Varghese Shyni 
Published: May 2022

AbstractSkeletal injuries are a major cause of morbidities worldwide with bone fractures accounting for a substantial portion. Patients suffering from bone fractures and undergoing surgery experience different levels of pain throughout the healing process requiring pain-mitigating interventions. Furthermore, a considerable number of bone fractures suffer from delayed healing, and unresolved acute pain may transition to chronic and maladaptive pain. Current management of pain involves treatment with NSAIDs and opioids, however, these analgesics have substantial drawbacks including delaying healing, systemic side effects, and potential for addiction. Hence, a therapeutic approach that concomitantly attenuates pain locally and actively promotes healing would address a significant clinical problem and improve the overall functional outcome for patients. Herein, we tested the hypothesis that the purine molecule, adenosine, could simultaneously alleviate fracture pain and promote healing by targeting different adenosine receptor subtypes in different cell populations. Our results demonstrate that local delivery of adenosine inhibited nociceptive activity of peripheral neurons through activation of adenosine A1 receptor (ADORA1) and mitigates pain. Concurrently, localization of adenosine at the fracture site also promoted osteogenic differentiation of mesenchymal stromal cells through adenosine A2B receptor (ADORA2B) and improved bone healing. Although further work is needed to extend the findings to human patients, this study provides evidence that the unique functional properties of adenosine along with its local delivery could provide an innovative, safe, and translatable therapeutic strategy to treat bone trauma and associated pain.One Sentence SummaryAdenosine as a therapeutic for fracture pain and healing
Recurrent loss of an immunity gene that protects Drosophila against a major natural parasite
Authors: Arunkumar Ramesh , Zhou Shuyu Olivia , Day Jonathan P. , Bakare Sherifat , Pitton Simone , Hsing Chi-Yun , O’Boyle Sinead , Pascual-Gil Juan , Clark Belinda , Chandler Rachael J. , Leitão Alexandre B. , Jiggins Francis M. 
Published: May 2022

AbstractPolymorphisms in immunity genes can have large effects on susceptibility to infection. To understand the origins of this variation, we investigated the genetic basis of resistance to the parasitoid wasp Leptopilina boulardi in Drosophila melanogaster. A cis-regulatory polymorphism in the gene Lectin-24A abolishes expression after infection, strongly reducing survival. Other null mutations have arisen repeatedly in this gene, with additional loss-of-expression and premature stop codons segregating in nature. The frequency of these alleles varies greatly, and in some populations natural selection has driven them near to fixation. We conclude that there is a pleiotropic cost to Lectin-24A expression, and in some populations this outweighs the benefit of resistance, resulting in natural selection causing the repeated loss of this important immune defense.Significance StatementGenetic differences between individuals can have a large effect on susceptibility to infectious disease. We have identified a gene called Lectin-24A that is important in the immune response that protects fruit flies against one of their main natural enemies—parasitic wasps. However, in nature many flies carry mutated copies of this gene that are no longer functional. We found that the high frequency of these loss-of-function mutations can only be explained if they have a selective advantage in some populations. Therefore, we can conclude that this immune defiance is costly, and genetic variation in susceptibility is maintained because in some locations susceptible flies are fitter than resistant flies.
Plasticity in airway smooth muscle differentiation during mouse lung development
Authors: Goodwin Katharine , Lemma Bezia , Boukind Adam , Nelson Celeste M. 
Published: May 2022

SummarySmooth muscle differentiation has been proposed to sculpt airway epithelial branches in mammalian lungs. Serum response factor (SRF) acts with its cofactor myocardin to promote the expression of contractile smooth muscle markers. However, smooth muscle cells exhibit a variety of phenotypes beyond contractile that are independent of SRF/myocardin-induced transcription. To determine whether airway smooth muscle exhibits phenotypic plasticity during embryonic development, we deleted Srf from the pulmonary mesenchyme. Srf-mutant lungs branch normally, and the mesenchyme exhibits normal cytoskeletal features and patterning. scRNA-seq revealed an Srf-null smooth muscle cluster wrapping the airways of mutant lungs that lacks contractile smooth muscle markers but retains many features of control smooth muscle. Srf-null airway smooth muscle exhibits a synthetic phenotype, compared to the contractile phenotype of mature wildtype airway smooth muscle. Our findings reveal plasticity in airway smooth muscle differentiation and demonstrate that a synthetic smooth muscle layer is sufficient for airway branching morphogenesis.
MoBIE: A Fiji plugin for sharing and exploration of multi-modal cloud-hosted big image data
Authors: Pape Constantin , Meechan Kimberly , Moreva Ekaterina , Schorb Martin , Chiaruttini Nicolas , Zinchenko Valentyna , Vergara Hernando , Mizzon Giulia , Moore Josh , Arendt Detlev , Kreshuk Anna , Schwab Yannick , Tischer Christian 
Published: May 2022

AbstractFacing the challenge of exploring and sharing multi-terabyte, multi-modal and multi-scale image data of heterogeneous dimensionality, we developed MoBIE, a Fiji plugin that provides rich visualization features to enable browsing data from numerous biomedical applications on a standard laptop computer. MoBIE also supports segmentations, associated measurements and annotations. Users can configure complex views of datasets, share them with collaborators, and use them for interactive figure panels. The MoBIE plugin also offers a convenient interface for converting data into compatible data formats; an additional Python library facilitates managing diverse MoBIE projects.
Dynamic genome-scale modeling ofSaccharomyces cerevisiaeunravels mechanisms for ester formation during alcoholic fermentation
Authors: Scott William T. , Henriques David , Smid Eddy J. , Notebaart Richard A. , Balsa-Canto Eva 
Published: May 2022

SUMMARYFermentation employingSaccharomyces cerevisiaehas produced alcoholic beverages and bread for millennia. More recently,S. cerevisiaehas been used to manufacture specific metabolites for the food, pharmaceutical, and cosmetic industries. Among the most important of these metabolites are compounds associated with desirable aromas and flavors, including higher alcohols and esters. Although the physiology of yeast has been well-studied, its metabolic modulation leading to aroma production in relevant industrial scenarios such as winemaking is still unclear. Here we ask what are the underlying metabolic mechanisms that explain the conserved and varying behavior of different yeasts regarding aroma formation under enological conditions? We employed dynamic flux balance analysis (dFBA) to answer this key question using the latest genome-scale metabolic model (GEM) ofS. cerevisiae. The model revealed several conserved mechanisms among wine yeasts, e.g., acetate ester formation is dependent on intracellular metabolic acetyl-CoA/CoA levels, and the formation of ethyl esters facilitates the removal of toxic fatty acids from cells using CoA. Species-specific mechanisms were also found, such as a preference for the shikimate pathway leading to more 2-phenylethanol production in the Opale strain as well as strain behavior varying notably during the carbohydrate accumulation phase and carbohydrate accumulation inducing redox restrictions during a later cell growth phase for strain Uvaferm. In conclusion, our new metabolic model of yeast under enological conditions revealed key metabolic mechanisms in wine yeasts, which will aid future research strategies to optimize their behavior in industrial settings.
Functional imaging and quantification of multi-neuronal olfactory responses in C. elegans
Authors: Lin Albert , Qin Shanshan , Casademunt Helena , Wu Min , Hung Wesley , Cain Greg , Tan Nicolas Z. , Valenzuela Raymond , Lesanpezeshki Leila , Venkatachalam Vivek , Pehlevan Cengiz , Zhen Mei , Samuel Aravinthan D.T. 
Published: May 2022

AbstractMany animals perceive odorant molecules by collecting information from ensembles of olfactory neurons. Each neuron employs receptors that are tuned to recognize certain odorant molecules by chemical binding affinity. Olfactory systems are able, in principle, to detect and discriminate diverse odorants by using combinatorial coding strategies. Multineuronal imaging with high-throughput stimulus delivery allows comprehensive measurement of ensemble-level sensory representations. We have used microfluidics and multineuronal imaging to study ensemble-level olfactory representations at the sensory periphery of the nematode C. elegans. The collective activity of nematode chemosensory neurons reveals high-dimensional representations of olfactory information across a broad space of odorant molecules. We reveal diverse tuning properties and dose-response curves across chemosensory neurons and across odorants. We describe the unique contribution of each sensory neuron to an ensemble-level code for volatile odorants. We also show how natural stimuli, a set of nematode pheromones, are encoded by the sensory periphery. The integrated activity of the C. elegans chemosensory neurons contains sufficient information to robustly encode the intensity and identity of diverse chemical stimuli.
CELL-E: A Text-To-Image Transformer for Protein Localization Prediction
Authors: Khwaja Emaad , Song Yun S. , Huang Bo 
Published: May 2022

AbstractAccurately predicting cellular activities of proteins based on their primary amino acid sequences would greatly improve our understanding of the proteome. In this paper, we present CELL-E, a text-to-image transformer architecture that generates a 2D probability density map of protein distribution within cells. Given a amino acid sequence and a reference image for cell or nucleus morphology, CELL-E offers a more direct representation of protein localization, as opposed to previousin silicomethods that rely on pre-defined, discrete class annotations of protein localization to subcellular compartments.
Precipitation is the main axis of tropical phylogenetic turnover across space and time
Authors: Ringelberg Jens J. , Koenen Erik J.M. , Sauter Benjamin , Aebli Anahita , Rando Juliana G. , Iganci João R. , de Queiroz Luciano P. , Murphy Daniel J. , Gaudeul Myriam , Bruneau Anne , Luckow Melissa , Lewis Gwilym P. , Miller Joseph T. , Simon Marcelo F. , Jordão Lucas S.B. , Morales Matías , Bailey C. Donovan , Nageswara-Rao Madhugiri , Loiseau Oriane , Pennington R. Toby , Dexter Kyle G. , Zimmermann Niklaus E. , Hughes Colin E. 
Published: May 2022

AbstractEarly natural historians – Compte de Buffon, von Humboldt and De Candolle – established ecology and geography as two principal axes determining the distribution of groups of organisms, laying the foundations for biogeography over the subsequent 200 years, yet the relative importance of these two axes remains unresolved. Leveraging phylogenomic and global species distribution data for Mimosoid legumes, an pantropical plant clade of 3,400 species, we show that the water availability gradient from deserts to rainforests dictates turnover of lineages within continents across the tropics. We demonstrate that 95% of speciation occurs within a precipitation niche, showing profound phylogenetic niche conservatism, and that lineage turnover boundaries coincide with isohyets of precipitation. We reveal similar patterns on different continents, implying that evolution and dispersal follow universal processes.
Impaired BCAA catabolism during adipocyte differentiation decreases glycolytic flux
Authors: Green Courtney R. , Wessendorf-Rodriguez Karl A. , Turner Rory , Hover Justin D. , Murphy Anne N. , Metallo Christian M. , Wallace Martina 
Published: May 2022

AbstractDysregulated branched chain amino acid (BCAA) metabolism has emerged as a key metabolic feature associated with the obese insulin resistant state, and adipose BCAA catabolism is decreased in this context. BCAA catabolism is upregulated early in adipogenesis, but the impact of suppressing this pathway on the broader metabolic functions of the resultant adipocyte remain unclear. Here, we use CRISPR/Cas9 to targetBckdhaandAcad8in pre-adipocytes and induce a deficiency in BCAA or valine catabolism through differentiation. We characterise the transcriptional and metabolic phenotype of these cells using RNAseq and13C metabolic flux analysis within a network spanning glycolysis, tricarboxylic (TCA) acid metabolism, BCAA catabolism, and fatty acid synthesis. While lipid droplet accumulation is maintained inBckdha-deficient adipocytes, they display a more fibroblast-like transcriptional signature. In contrast,Acad8deficiency minimally impacts gene expression. Decreased glycolytic flux emerges as the most distinct metabolic feature ofBckdha-deficient cells, accompanied by a ∼40% decrease in lactate secretion, yet pyruvate oxidation and utilization forde novolipogenesis are increased to compensate for loss of BCAA carbon. Glutamine anaplerosis was also increased, though we observed a general decrease in levels of most non-essential amino acids consistent with an impact on nitrogen homeostasis. Overall, our data suggest that both metabolic and regulatory cross-talk exists between BCAA catabolism, glycolysis, and nitrogen metabolism in differentiated adipocytes. Suppression of BCAA catabolism associated with metabolic syndrome may result in a metabolically compromised adipocyte.