bluuebunny/crossref_metadata_2025_split huggingface dataset:
An atlas of trait associations with resting-state and task-evoked human brain functional architectures in the UK Biobank
Authors: Zhao Bingxin , Li Tengfei , Li Yujue , Fan Zirui , Xiong Di , Wang Xifeng , Gao Mufeng , Smith Stephen M. , Zhu Hongtu 
Published: February 2022

AbstractFunctional magnetic resonance imaging (fMRI) has been widely used to identify brain regions linked to critical functions, such as language and vision, and to detect tumors, strokes, brain injuries, and diseases. It is now known that large sample sizes are necessary for fMRI studies to detect small effect sizes and produce reproducible results. Here we report a systematic association analysis of 647 traits with imaging features extracted from resting-state and task-evoked fMRI data of more than 40,000 UK Biobank participants. We used a parcellation-based approach to generate 64,620 functional connectivity measures to reveal fine-grained details about cerebral cortex functional architectures. The difference between functional organizations at rest and during task has been quantified, and we have prioritized important brain regions and networks associated with a variety of human traits and clinical outcomes. For example, depression was most strongly associated with decreased connectivity in the somatomotor network. We have made our results publicly available and developed a browser framework to facilitate exploration of brain function-trait association results (http://165.227.92.206/).
Rats emit unique distress calls in social inequality conditions
Authors: Okabe Shota , Takayanagi Yuki , Yoshida Masahide , Onaka Tatsushi 
Published: February 2022

SummaryHumans show aversion toward inequality of social reward, and this aversion plays important roles for the establishment of social cooperation. However, it has remained unknown whether commonly used experimental animals show negative responses to social reward inequality. In this study, we found that rats showed bonding-like behavior to an affiliative human who repeatedly stroked the rats. In addition, these rats emitted distress calls, an index of negative emotion, when an affiliative human stroked another rat in front of them. These distress calls had acoustic characteristics different from those emitted in response to physical stress stimuli such as air-puff. Rats emitted calls with higher frequency (28 kHz) and shorter durations (0.05 sec) in an inequality condition than the frequency and durations of calls emitted when receiving air-puff. Our results suggested that rats exhibited negative emotion with unique distress calls in response to a social inequality condition.
Melanin Nanoparticles as an Alternative to Natural Melanin in Retinal Pigment Epithelium Cells and Their Therapeutic Effects against Age-Related Macular Degeneration
Authors: Kwon Yong-Su , Zheng Min , Zhang Alice Yang , Han Zongchao 
Published: February 2022

AbstractMelanin is a natural pigment that is widely distributed in many parts of the human body, such as the skin and retinal pigment epithelium (RPE) in eyes. In contrast to skin melanin, which is being constantly synthesized by the epidermal melanocytes, melanin in the RPE does not regenerate. Melanin is known to function as a potential radical scavenger and photoprotective agent. However, the protective effects of melanin against oxidative stress decline with increasing age. This phenomenon has been significantly correlated with the pathogenesis of age-related macular degeneration (AMD). To increase the potential antioxidant and photoprotective characteristics of the melanin, we designed a new strategy by replenishment of melanin using PEGylated-synthetic melanin nanoparticles (MNPs) in the RPE for the treatment of AMD. We performed experiments using AMD-like cellular and mouse models and demonstrated that MNPs are safe, biocompatible, and selectively target reactive oxygen species (ROS) with powerful antioxidant properties. MNPs can traffic and accumulate in the RPE and are exclusively located in cytosol, but not the nucleus and mitochondria of the cells, for up to three months after a single-dose intravitreal (IVT) injection. Our findings demonstrate, for the first time, that MNPs are able to substitute for natural melanin in the RPE of eyes and suggest the potential efficacy of MNPs as a natural radical scavenger against oxidative stress in ROS-related diseases, such as AMD.Graphical AbstractIntracellular trafficking showing that PEGylated-synthetic melanin nanoparticles (MNPs) reach their target and are stable in the retinal pigment epithelial cells for up to 3 months via a single-dose intravitreal (IVT) injection.
SARS-CoV-2 Variant Delta Potently Suppresses Innate Immune Response and Evades Interferon-Activated Antiviral Responses
Authors: Tandel Dixit , Sah Vishal , Singh Nitesh Kumar , Potharaju Poojitha Sai , Gupta Divya , Shrivastava Sauhard , Sowpati Divya Tej , Harshan Krishnan H 
Published: February 2022

ABSTRACTDelta variant of SARS-CoV-2 has caused more severe infections than its previous variants. We studied the host innate immune response to Delta, Alpha and two earlier variants to map the evolution of the recent ones. Our biochemical and transcriptomic studies reveal that Alpha and Delta have progressively evolved over the ancestral variants by silencing innate immune response, thereby limiting cytokine and chemokine production. Though Alpha silenced RLR pathway just as Delta, it failed to persistently silence the innate immune response unlike Delta. Both Alpha and Delta have evolved to resist IFN treatment while they are still susceptible to RLR activation, further highlighting the importance of RLR-mediated, IFN-independent mechanisms in restricting SARS-CoV-2. Our studies reveal that SARS-CoV-2 Delta has integrated multiple mechanisms to silence host innate immune response and evade IFN response. Delta’s silent replication and sustained suppression of host innate immune response, possibly resulting in delayed or reduced intervention by the adaptive immune response, could potentially contribute to the severe symptoms and poor recovery index associated with it.
A Neuropsin-based Optogenetic Tool for Precise Control of Gq signaling
Authors: Dai Ruicheng , Yu Tao , Weng Danwei , Li Heng , Cui Yuting , Wu Zhaofa , Guo Qingchun , Zou Haiyue , Wu Wenting , Gao Xinwei , Qi Zhongyang , Ren Yuqi , Wang Shu , Li Yulong , Luo Minmin 
Published: February 2022

AbstractGq-coupled receptors regulate numerous physiological processes by activating enzymes and inducing intracellular Ca2+ signals. There is a strong need for an optogenetic tool that enables powerful experimental control over Gq signaling. Here, we present chicken opsin 5 (cOpn5) as the long sought-after, single-component optogenetic tool that mediates ultra-sensitive optical control of intracellular Gq signaling with high temporal and spatial resolution. Expressing cOpn5 in mammalian cells enables blue light-triggered, Gq-dependent Ca2+ release from intracellular stores and protein kinase C activation. Strong Ca2+ transients were evoked by brief light pulses of merely 10 ms duration and at 3 orders lower light intensity of that for common optogenetic tools. Photostimulation of cOpn5-expressing cells at the subcellular and single-cell levels generated intracellular and intercellular Ca2+ wave propagation, respectively, thus demonstrating the high spatial precision of cOpn5 optogenetics. The cOpn5-mediated optogenetics could also be applied to activate neurons and control animal behavior in a circuit-dependent manner. We further revealed that optogenetic activation of cOpn5-expressing astrocytes induced massive ATP release and modulation neuronal activation in the brain of awake, behaving mice. cOpn5 optogenetics may find broad applications in studying the mechanisms and functional relevance of Gq signaling in both non-excitable cells and excitable cells in all major organ systems.
Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults
Authors: Lukasz Daria , Beirl Alisha , Kindt Katie 
Published: February 2022

AbstractSensory hair cells receive near constant stimulation by omnipresent auditory and vestibular stimuli. To detect and encode these stimuli, hair cells require steady ATP production, which can be accompanied by a buildup of mitochondrial byproducts called reactive oxygen species (ROS). ROS buildup is thought to sensitize hair cells to ototoxic insults, including the antibiotic neomycin. Work in neurons has shown that neurotransmission is a major driver of ATP production and ROS buildup. Therefore, we tested whether neurotransmission is a significant contributor to ROS buildup in hair cells. Using genetics and pharmacology, we disrupted two key aspects of neurotransmission in zebrafish hair cells: presynaptic calcium influx and the fusion of synaptic vesicles. We find that chronic block of neurotransmission enhances hair-cell survival when challenged with the ototoxin neomycin. This reduction in ototoxin susceptibility is accompanied by reduced mitochondrial activity, likely due to a reduced ATP demand. In addition, we show that mitochondrial oxidation and ROS buildup is reduced when neurotransmission is blocked. Mechanistically, we find that it is the synaptic vesicle cycle rather than presynaptic- or mitochondrial-calcium influx that contributes most significantly to this metabolic stress. Our results comprehensively indicate that, over time, neurotransmission causes ROS buildup that increases the susceptibility of hair cells to ototoxins.
Ivermectin does not protect against SARS-CoV-2 infection in the Syrian hamster model
Authors: Foo Caroline S. , Abdelnabi Rana , Vangeel Laura , De Jonghe Steven , Jochamns Dirk , Weynand Birgit , Neyts Johan 
Published: February 2022

AbstractIvermectin, an FDA-approved antiparasitic drug, has been reported to havein vitroactivity against SARS-CoV-2. An increasing off-label use of Ivermectin for COVID-19 has been reported. We here assessed the effect of Ivermectin in Syrian hamsters infected with the SARS-CoV-2 Beta (B.1.351) variant. Infected animals received a clinically relevant dose of Ivermectin (0.4 mg/kg subcutaneously dosed) once daily for four consecutive days after which the effect was quantified. Ivermectin monotherapy did not reduce lung viral load and even significantly worsened the SARS-CoV-2-induced lung pathology. Additionally, it did not potentiate the activity of Molnupiravir (Lagevrio™) when combined with this drug. This study contributes to the growing body of evidence that Ivermectin does not result in a beneficial effect in the treatment of COVID-19. These findings are important given the increasing, dangerous off-label use of Ivermectin for the treatment of COVID-19.
Temporal continuity shapes visual responses of macaque face patch neurons
Authors: Russ Brian E. , Koyano Kenji W. , Day-Cooney Julian , Perwez Neda , Leopold David A. 
Published: February 2022

AbstractMacaque inferior temporal cortex neurons respond selectively to complex visual images, with recent work showing that they are also entrained reliably by the evolving content of natural movies. To what extent does visual continuity itself shape the responses of high-level visual neurons? We addressed this question by measuring how cells in face-selective regions of the macaque temporal cortex were affected by the manipulation of a movie’s temporal structure. Sampling the movie at 1s intervals, we measured neural responses to randomized, brief stimuli of different lengths, ranging from 800 ms dynamic movie snippets to 100 ms static frames. We found that the disruption of temporal continuity strongly altered neural response profiles, particularly in the early onset response period of the randomized stimulus. The results suggest that models of visual system function based on discrete and randomized visual presentations may not translate well to the brain’s natural modes of operation.
Cellular Allostatic Load is linked to Increased Energy Expenditure and Accelerated Biological Aging
Authors: Bobba-Alves Natalia , Sturm Gabriel , Lin Jue , Ware Sarah A , Karan Kalpita R. , Monzel Anna S. , Bris Celine , Procaccio Vincent , Lenaers Guy , Higgins-Chen Albert , Levine Morgan , Horvath Steve , Santhanam Balaji S , Kaufman Brett A , Hirano Michio , Epel Elissa , Picard Martin 
Published: February 2022

AbstractStress triggers anticipatory physiological responses that promote survival, a phenomenon termed allostasis. However, the chronic activation of energy-dependent allostatic responses results in allostatic load, a dysregulated state that predicts functional decline, accelerates aging, and increases mortality in humans. The energetic cost and cellular basis for the damaging effects of allostatic load have not been defined. Here, by longitudinally profiling three unrelated primary human fibroblast lines across their lifespan, we find that chronic glucocorticoid exposure increases cellular energy expenditure by ∼60%, along with a metabolic shift from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This state of stress-induced hypermetabolism is linked to mtDNA instability, non-linearly affects age-related cytokines secretion, and accelerates cellular aging based on DNA methylation clocks, telomere shortening rate, and reduced lifespan. Pharmacologically normalizing OxPhos activity while further increasing energy expenditure exacerbates the accelerated aging phenotype, pointing to total energy expenditure as a potential driver of aging dynamics. Together, our findings define bioenergetic and multi-omic recalibrations of stress adaptation, underscoring increased energy expenditure and accelerated cellular aging as interrelated features of cellular allostatic load.
Biochemical characterization of RAD52-mediated D-loop formation using fluorophore-labeled DNA substrates
Authors: Kamoi Kazuki , Saotome Mika , Kinoshita Chiaki , Tsuchiya Ryohei , Kagawa Wataru 
Published: February 2022

AbstractThe human RAD52 protein is thought to have multiple roles in the mechanisms of repairing DNA double-strand breaks that are caused by replication errors and reactive oxygen species. One such role is to mediate the formation of a displacement loop (D-loop), which is a critical reaction intermediate in homologous recombinational repair. RAD52 is suggested to promote the formation of D-loops when facilitating DNA synthesis at stalled or collapsed replication forks during mitosis. However, RAD52-mediated D-loop formation remains poorly characterized, and the detailed molecular mechanism of the D-loop formation reaction catalyzed by RAD52 is still unclear. In the present study, we developed a gel-based assay that enables rapid detection of RAD52-mediated D-loop formation. This assay utilizes a fluorophore-labeled, single-stranded DNA substrate. In addition to the rapid detection of D-loops, D-loop extension was observed when DNA polymerase was added to the reaction. This assay can also be used for screening large numbers of compounds that either stimulate or inhibit RAD52-mediated D-loop formation. The D-loop formation assay developed in this study is potentially useful for mechanistic studies of DSB repair involving RAD52-mediated D-loop formation, as well as for screening compounds with potential therapeutic effects.
Fate-resolved gene regulatory signatures of individual B lymphocytes in the early stages of Epstein-Barr Virus infection
Authors: SoRelle Elliott D. , Dai Joanne , Reinoso-Vizcaino Nicolás M. , Barry Ashley P. , Chan Cliburn , Luftig Micah A. 
Published: February 2022

AbstractEpstein-Barr Virus (EBV) infection of B lymphocytes elicits diverse host responses via complex, well-adapted transcriptional control dynamics. Consequently, this host-pathogen interaction provides a powerful system to explore fundamental cellular processes that contribute to consensus fate decisions including cell cycle arrest, apoptosis, proliferation, and differentiation. Here we capture these responses and fates with matched single-cell transcriptomics and chromatin accessibility, from which we construct a genome-wide multistate model of early infection dynamics. Notably, our model captures a previously uncharacterized EBV+analog of a multipotent activated precursor state that can yield early memory B cells. We also find that a marked global reduction in host chromatin accessibility occurs during the first stages of infection in subpopulations of EBV+cells that display senescent and pre-apoptotic hallmarks induced by innate antiviral sensing and proliferation-linked DNA damage. However, cells in proliferative infection trajectories exhibit greater accessibility at select host sites linked to B cell activation and survival genes as well as key regions within the viral genome. To further investigate such loci, we implement a bioinformatic workflow (crisp-ATAC) to identify phenotype-resolved regulatory signatures. This customizable method applies user-specified logical criteria to produce genome-wide single-cell ATAC-and ChIP-seq range intersections that are used as inputs forcis-linkage prediction and ontology tools. The resulting tri-modal data yield exquisitely detailed hierarchical perspectives of the transforming regulatory landscape during critical stages of an oncogenic viral infection that simulates antigen-induced B cell activation and differentiation. We anticipate these resources will guide investigations of gene regulatory modules controlling EBV-host dynamics, B cell effector fates, and lymphomagenesis. To demonstrate the utility of this resource, this work concludes with the discovery of EBV infection dynamics in FCRL4+/ TBX21+Tissue-Like Memory B cells, an unconventional subset with notable associations to numerous immune disorders.
Live-Cell Imaging in Human Colonic Monolayers Reveals Erk Waves Limit the Stem Cell Compartment to Maintain Epithelial Homeostasis
Authors: Pond Kelvin W , Alkhimenok Olga , Chakrabarti Jayati , Zavros Yana , Thorne Curtis A , Paek Andrew L 
Published: February 2022

AbstractThe establishment and maintenance of different cellular compartments in tissues is a universal requirement across all metazoans. Maintaining the correct ratio of cell types in time and space allows tissues to form patterned compartments and perform complex functions. Patterning is especially evident in the human colon, where tissue homeostasis is maintained by stem cells in crypt structures that balance proliferation and differentiation. Here we developed a 2D patient derived organoid (PDO) screening platform to study tissue patterning and kinase pathway dynamics in single cells across hundreds of conditions. Using this system, we discovered that waves of Erk signaling induced by apoptotic cells play a critical role in maintaining tissue patterning and homeostasis. If Erk is activated acutely across all cells instead of in wavelike patterns, then tissue patterning, and stem cell maintenance are lost. Conversely, if Erk activity is inhibited, then stem cells become unrestricted and expand dramatically. This work demonstrates that the colonic epithelium requires coordinated Erk signaling dynamics to maintain patterning and tissue homeostasis. Our work reveals how Erk can antagonize stem cells yet support cell replacement and the function of the gut.
Metamorphism of catalytic domain controls transposition in Tn3 family transposases
Authors: Shkumatov Alexander V. , Aryanpour Nicolas , Oger Cédric A. , Goossens Gérôme , Hallet Bernard F. , Efremov Rouslan G. 
Published: February 2022

AbstractTransposons account for a remarkable diversity of mobile genetic elements that play the role of genome architects in all domains of life. Tn3 is a family of widespread and among first identified bacterial transposons notorious for their contribution to dissemination of antibiotic resistance. Transposition within this family is mediated by a large TnpA transposase facilitating both transposition and target immunity. The structural framework for understanding the mechanism of the TnpA transposition is however absent. Here, we describe the cryo-EM structures of TnpA from Tn4430 in apo form and paired with transposon ends. We show that TnpA has a unique architecture and exhibits a family-specific regulation mechanism involving metamorphic refolding of the RNase H-like catalytic domain. The TnpA structure, constrained by a double dimerization interface, creates a unique topology that suggests a specific role for target DNA in transpososome assembly, activation, and target immunity.
Theta-phase connectivity between medial prefrontal and posterior areas underlies novel instructions implementation
Authors: Formica Silvia , González-García Carlos , Senoussi Mehdi , Marinazzo Daniele , Brass Marcel 
Published: February 2022

AbstractImplementing novel instructions is a complex and uniquely human cognitive ability, that requires the rapid and flexible conversion of symbolic content into a format that enables the execution of the instructed behavior. Preparing to implement novel instructions, as opposed to their mere maintenance, involves the activation of the instructed motor plans, and the binding of the action information to the specific context in which this should be executed. Recent evidence and prominent computational models suggest that this efficient configuration of the system might involve a central role of frontal theta oscillations in establishing top-down long-range synchronization between distant and task-relevant brain areas. In the present EEG study (human subjects, 30 females, 4 males), we demonstrate that proactively preparing for the implementation of novels instructions, as opposed to their maintenance, involves a strengthened degree of connectivity in the theta frequency range between medial prefrontal and motor/visual areas. Moreover, we replicated previous results showing oscillatory features associated specifically with implementation demands, and extended on them demonstrating the role of theta oscillations in mediating the effect of task demands on behavioral performance. Taken together, these findings support our hypothesis that the modulation of connectivity patterns between frontal and task-relevant posterior brain areas is a core factor in the emergence of a behavior-guiding format from novel instructions.Significance statementEveryday life requires the use and manipulation of currently available information to guide behavior and reach specific goals. In the present study we investigate how the same instructed content elicits different neural activity depending on the task being performed. We show that medial prefrontal theta oscillations are larger when novel instructions have to be implemented, rather than simply maintained. Crucially, connectivity between medial prefrontal cortex and posterior areas is strengthened during instructions implementation, suggesting that theta oscillations play a role in setting up a dynamic and flexible network of task-relevant regions optimized for the execution of the instructed behavior.