bluuebunny/crossref_metadata_2025 huggingface dataset:
Cortico-cortical connectivity is influenced by levodopa in tremor-dominant Parkinson’s disease
Authors: Rurak B.K. , Tan J. , Rodrigues J.P. , Power B.D. , Drummond P.D. , Vallence A.M.
Published: February 2022

Background

Resting tremor is the most common presenting motor symptom in Parkinson’s disease (PD). The supplementary motor area (SMA) is one of the main targets of the basal ganglia-thalamo-cortical circuit and has direct, facilitatory connections with the primary motor cortex (M1), which is important for the execution of voluntary movement. Dopamine potentially modulates SMA and M1 activity, and both regions have been implicated in resting tremor.

Objective

To examine SMA-M1 connectivity in individuals with PD ON and OFF dopamine medication, and whether SMA-M1 connectivity is implicated in resting tremor.

Methods

Dual-site transcranial magnetic stimulation was used to measure SMA-M1 facilitatory connectivity in PD participants ON and OFF levodopa. Resting tremor was measured using electromyography and accelerometry.

Results

Stimulating SMA had an inhibitory influence on M1 excitability OFF levodopa, and a facilitatory influence on M1 excitability ON levodopa. ON medication, correlational analysis showed an association between tremor severity and SMA-M1 connectivity, with SMA-M1 facilitation associated with smaller tremor than SMA-M1 inhibition.

Conclusions

The current findings contribute to our understanding of the neural networks involved in PD which are altered by levodopa medication and provide a neurophysiological basis for the development of interventions to treat resting tremor.
MRI connectivity-based spread of microglial activation in early Alzheimer's disease
Authors: Rauchmann Boris-Stephan , Brendel Matthias , Franzmeier Nicolai , Trappmann Lena , Zaganjori Mirlind , Morenas-Rodriguez Estrella , Guersel Selim , Burow Lena , Kurz Carolin , Haeckert Jan , Tato Maia , Utecht Julia , Papazov Boris , Pogarell Oliver , Janowitz Daniel , Buerger Katharina , Ewers Michael , Palleis Carla , Weidinger Endy , Biechele Gloria , Schuster Sebastian , Finze Anika , Eckenweber Florian , Rupprecht Rainer , Rominger Axel , Goldhardt Oliver , Grimmer Timo , Keeser Daniel , Stoecklein Sophia , Dietrich Olaf , Bartenstein Peter , Levin Johannes , Hoeglinger Guenter , Perneczky Robert
Published: February 2022

Background: Alzheimer′s disease (AD) is characterized by amyloid-β; (Aβ) plaques, neurofibrillary tau tangles and neuroinflammation leading to brain functional connectivity changes and cognitive decline. There is evidence, that microglial activity is increased in AD and cognitive decline. Aβ and tau pathology appear to spread along pathways of highly connected brain regions, but it remains elusive if microglial activation follows a similar distribution pattern.
Methods: Thirty-two early AD subjects and 18 age-matched healthy cognitively normal controls were included from the prospective ActiGliA study. Differences between the diagnostic groups were explored for translocator protein (TSPO) positron emission tomography (PET) microglial activation, diffusion tensor imaging (DTI) structural connectivity and magnetic resonance imaging (MRI) functional connectivity. Associations between PET microglial activation with cognitive impairment, dementia severity and MRI connectivity measures were investigated within the diagnostic groups.
Results: AD patients showed increased TSPO PET tracer uptake bilaterally in the parahippocampal region compared to cognitively normal controls. Higher TSPO PET was associated with cognitive impairment and dementia severity in a disease stage dependent fashion. Inter-regional covariance in TSPO PET and standardized uptake value ratio (SUVR) was found to be preferentially distributed along functionally highly connected brain regions, with MRI structural connectivity showing a weaker association with microglial activation.
Conclusion: Neuroinflammation in AD is associated with clinical disease presentation, and like tau pathology, microglial activation seems to spread preferentially along highly connected brain regions. These findings support the important role of microglia in neurodegeneration and suggest that disease spreading throughout the brain along vulnerable connectivity pathways could guide future interventional anti-inflammatory therapy approaches to prevent disease progression.
Safety of COVID-19 vaccines in pregnancy: a Canadian National Vaccine Safety (CANVAS) Network study
Authors: Sadarangani Manish , Soe Phyumar , Shulha Hennady , Valiquette Louis , Vanderkooi Otto G , Kellner James D , Muller Matthew P , Top Karina A , Isenor Jennifer E , McGeer Allison , Irvine Mike , De Serres Gaston , Marty Kimberly , Bettinger Julie A. ,   Canadian Immunization Research Network
Published: February 2022

Background

Pregnant individuals have been receiving COVID-19 vaccines following pre-authorization clinical trials in non-pregnant people. This study aimed to determine significant health events amongst pregnant females after COVID-19 vaccination, compared with unvaccinated pregnant controls and vaccinated non-pregnant individuals.

Methods

Study participants were pregnant and non-pregnant females aged 15-49 years who had received any COVID-19 vaccine, and pregnant unvaccinated controls. Participants reported significant health events occurring within seven days of vaccination. We employed multivariable logistic regression to examine significant health events associated with mRNA vaccines.

Findings

Overall 226/5,597(4.0%) vaccinated pregnant females reported a significant health event after dose one of an mRNA vaccine, and 227/3,108(7.3%) after dose two, compared with 11/339(3.2%) pregnant unvaccinated females. Pregnant vaccinated females had an increased odds of a significant health event after dose two of mRNA-1273 (aOR 4.4,95%CI 2.4-8.3) compared to pregnant unvaccinated controls, but not after dose one of mRNA-1273 or any dose of BNT162b2. Pregnant females had decreased odds of a significant health event compared to non-pregnant females after both dose one (aOR 0.63,95%CI 0.55-0.72) and dose two (aOR 0.62,95%CI 0.54-0.71) of mRNA vaccination. There were no significant differences in any analyses when restricted to events which led to medical attention.

Interpretation

COVID-19 mRNA vaccines have a good safety profile in pregnancy. Rates of significant health events were higher after dose two of mRNA-1273 compared with unvaccinated controls, with no difference when considering events leading to medical consultation. Rates of significant health events were lower in pregnant females than similarly aged non-pregnant individuals.

Funding

This work was supported by the COVID-19 Vaccine Readiness funding from the Canadian Institutes of Health Research and the Public Health Agency of Canada CANVAS grant number CVV-450980 and by funding from the Public Health Agency of Canada, through the Vaccine Surveillance Reference Group and the COVID-19 Immunity Task Force.
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

Functional 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

Humans 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

Melanin 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 Abstract

Intracellular 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

Delta 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

Gq-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

Sensory 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

Ivermectin, 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

Macaque 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

Stress 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

The 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

Epstein-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

The 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

Transposons 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

Implementing 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 statement

Everyday 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.
The structural context of PTMs at a proteome wide scale
Authors: Bludau Isabell , Willems Sander , Zeng Wen-Feng , Strauss Maximilian T. , Hansen Fynn M. , Tanzer Maria C. , Karayel Ozge , Schulman Brenda A. , Mann Matthias
Published: February 2022

The recent revolution in computational protein structure prediction provides folding models for entire proteomes, which can now be integrated with large-scale experimental data. Mass spectrometry (MS)-based proteomics has identified and quantified tens of thousands of post-translational modifications (PTMs), most of them of uncertain functional relevance. In this study, we determine the structural context of these PTMs and investigate how this information can be leveraged to pinpoint potential regulatory sites. Our analysis uncovers global patterns of PTM occurrence across folded and intrinsically disordered regions. We found that this information can help to distinguish regulatory PTMs from those marking improperly folded proteins. Interestingly, the human proteome contains thousands of proteins that have large folded domains linked by short, unstructured regions that are strongly enriched in regulatory phosphosites. These include well-known kinase activation loops that induce protein conformational changes upon phosphorylation. This regulatory mechanism appears to be widespread in kinases but also occurs in other protein families such as solute carriers. It is not limited to phosphorylation but includes ubiquitination and acetylation sites as well. Furthermore, we performed three-dimensional proximity analysis which revealed examples of spatial co-regulation of different PTM types and potential PTM crosstalk. To enable the community to build upon these first analyses, we provide tools for 3D visualization of proteomics data and PTMs as well as python libraries for data accession and processing.
Distinct glycerophospholipids potentiate Gsα-activated adenylyl cyclase activity
Authors: Seth Anubha , Landau Marius , Shevchenko Andrej , Traikov Sofia , Schultz Anita , Elsabbagh Sherif , Schultz Joachim E.
Published: February 2022

Nine mammalian adenylyl cyclases (AC) are pseudoheterodimers with two hexahelical membrane domains which are isoform-specifically conserved. Previously we proposed that these membrane domains are orphan receptors (10.7554/eLife.13098; 10.1016/j.cellsig.2020.109538). Lipids extracted from fetal bovine serum at pH 1 inhibited several mAC activities. Guided by a lipidomic analysis we tested glycerophospholipids as potential ligands. Contrary to expectations we surprisingly discovered that 1-stearoyl-2-docosahexaenoyl-phosphatidic acid (SDPA) potentiated Gsα-activated activity of human AC isoform 3 seven-fold. The specificity of fatty acyl esters at glycerol positions 1 and 2 was rather stringent. 1-Stearoyl-2-docosahexaenoyl-phosphatidylserine and 1-stearoyl-2-docosahexaenoyl-phosphatidylethanolamine significantly potentiated several Gsα-activated mAC isoforms to different extents. SDPA appears not interact with forskolin activation of AC isoform 3. SDPA enhanced Gsα-activated AC activities in membranes from mouse brain cortex. The action of SDPA was reversible. Unexpectedly, SDPA did not affect cAMP generation in HEK293 cells stimulated by isoproterenol, PGE2 and adenosine, virtually excluding a role as an extracellular ligand and, instead, suggesting an intracellular role. In summary, we discovered a new dimension of intracellular AC regulation by chemically defined glycerophospholipids.
Structural and temporal basis for agonism in the α4β2 nicotinic acetylcholine receptor
Authors: Oliveira A. Sofia F. , Bermudez Isabel , Gallagher Timothy , Wonnacott Susan , Ciccotti Giovanni , Sessions Richard B. , Mulholland Adrian J.
Published: February 2022

Despite decades of study, the structural mechanisms underpinning agonist efficacy in pentameric ligand-gated ion channels remain poorly understood. Here, a combination of extensive equilibrium and dynamical-nonequilibrium molecular dynamics simulations was used to obtain a detailed description of the structural and dynamic changes induced within the human α4β2 nicotinic acetylcholine receptor by a full and a partial agonist, namely acetylcholine and nicotine, and map how these rearrangements propagate within this receptor. These simulations reveal how the agonists modulate the patterns associated with intra and inter-domain communication and the evolution of the agonist-specific structural rearrangements. For the first time, we show that full and partial agonists, although generally using similar routes for through-receptor signal transmission, induce different amplitudes of conformational rearrangements in key functional motifs, thus impacting the rates of signal propagation within the protein. The largest agonist-induced conformational differences are located in the Cys loop, loops C and α1-β1 in the α4 subunit, loops F and β1-β2 in the β2 subunit and in the extracellular selectivity filter.
Sporulation activated via σW protects Bacillus from a Tse1 peptidoglycan hydrolase T6SS effector
Authors: Pérez-Lorente Alicia I. , Molina-Santiago Carlos , de Vicente Antonio , Romero Diego
Published: February 2022

Bacterial communities constantly interact with various community members employing diverse offensive and defensive tools to reach coexistence. The extracellular matrix and sporulation are defensive mechanisms used by Bacillus cells when they interact with Pseudomonas strains expressing a type VI secretion system (T6SS). Here, we define Tse1 as the main toxin mobilized by the Pseudomonas T6SS that triggers sporulation in Bacillus. We characterize Tse1 as a peptidoglycan hydrolase that indirectly alters the dynamics and functionality of the Bacillus cell membrane. We also delineate the response of Bacillus cells to Tse1, which through the coordinated actions of the extracellular sigma factor σW and the cytoplasmic histidine kinases KinA and KinB, culminates in activation of the sporulation cascade. We propose that this cellular developmental response is conserved in Bacilli to defend against the toxicity of T6SS-mobilized Tse1 effector.
Resistance of Dickeya solani strain IPO 2222 to lytic bacteriophage vB_Dsol_D5 (ΦD5) results in fitness tradeoffs for the bacterium during infection
Authors: Bartnik Przemyslaw , Lewtak Kinga , Fiołka Marta , Czaplewska Paulina , Narajczyk Magdalena , Czajkowski Robert
Published: February 2022

Resistance to bacteriophage infections protects bacteria in phage-full environments, allowing them to survive and multiply in the presence of their viral predators. However, such resistance may cause direct costs for strains linked with the ecological fitness expressed as reduced competitiveness for resources or reduced virulence or both. Unfortunately, limited knowledge exists about such costs paid by phage-resistant plant pathogenic bacteria in their natural environments. This study analyzed the costs of phage resistance paid by broad host phytopathogenic pectinolytic bacterium Dickeya solani both in vitro and in potato (Solanum tuberosum L.) plants. Thirteen D. solani IPO 2222 Tn5 mutants were identified that exhibited resistance to infection caused by lytic bacteriophage vB_Dsol_D5 (ΦD5). The genes disrupted in these 13 mutants encoded proteins involved in the synthesis of the bacterial envelope components (viz. LPS, EPS and capsule). The ability of ΦD5-resistant D. solani mutants to colonize and cause symptoms on potato plants as well as other phenotypes that are known to contribute to the ecological fitness of D. solani in-plant environment, including growth rate, production of effectors, swimming and swarming motility, use of various carbon and nitrogen sources and biofilm formation were assessed. Although phage resistance did not affect most of the phenotypes of ΦD5-resistant D. solani evaluated in vitro, all phage resistant mutants were significantly compromised in their ability to survive on and colonize and cause disease symptoms in potato plants. This study is, to our knowledge, one of few to show the direct link between phage resistance and the fitness of plant pathogenic bacteria and the first one to assess phage-host associations for D. solani.
The extracellular sialidase NEU3 induces neutrophil priming
Authors: Kirolos Sara A. , Gomer Richard H.
Published: February 2022

Some extracellular glycoconjugates have sialic acid as the terminal sugar, and sialidases are enzymes that remove this sugar. Mammals have four sialidases, but their biological functions are unclear. In this report, we show that incubation of human neutrophils with the human sialidase NEU3, but not NEU1, NEU2 or NEU4, inducess human male and female neutrophils to change from a round to a more amoeboid morphology, causes the primed neutrophil markers CD66, CD11B, and CD18 to localize to the cell cortex, and decreases the localization of the unprimed neutrophil markers CD43 and CD62L at the cell cortex. NEU3, but not the other 3 sialidases, also causes human male and female neutrophils to increase their F-actin content. The inhibition of NEU3 by the NEU3 inhibitor 2-acetylpyridine attenuated the NEU3 effect on neutrophil morphology, indicating that the effect of NEU3 is dependent on its enzymatic activity. Together, these results indicate that NEU3 can prime human male and female neutrophils, and that NEU3 is a potential regulator of inflammation.
Enrichment of somatic mutations in schizophrenia brain targets prenatally active transcription factor bindings sites
Authors: Maury Eduardo A. , Jones Attila , Seplyarskiy Vladimir , Rosenbluh Chaggai , Bae Taejong , Wang Yifan , Abyzov Alexej , Khoshkoo Sattar , Chahine Yasmine ,   Brain Somatic Mosaicism Network, Park Peter J. , Akbarian Schahram , Lee Eunjung Alice , Sunyaev Shamil R. , Walsh Christopher A. , Chess Andrew
Published: February 2022

Schizophrenia (SCZ) is a complex neuropsychiatric disorder in which both germline genetic mutations and maternal factors, such as infection and immune activation, have been implicated, but how these two strikingly different mechanisms might converge on the same phenotype is unknown. During development, cells accumulate somatic, mosaic mutations in ways that can be shaped by the cellular environment or endogenous processes, but these early developmental mutational patterns have not been studied in SCZ. Here we analyzed deep (267x) whole-genome sequencing (WGS) of DNA from cerebral cortical neurons isolated from 61 SCZ and 25 control postmortem brains to capture mutations occurring before or during fetal neurogenesis. SCZ cases showed a >15% increase in genome-wide sSNV compared to controls (p < 2e-10). Remarkably, mosaic T>G mutations and CpG transversions (CpG>GpG or CpG>ApG) were 79- and 62-fold enriched, respectively, at transcription factor binding sites (TFBS) in SCZ, but not in controls. The pattern of T>G mutations resembles mutational processes in cancer attributed to oxidative damage that is sterically blocked from DNA repair by transcription factors (TFs) bound to damaged DNA. The CpG transversions similarly suggest unfinished DNA demethylation resulting in abasic sites that can also be blocked from repair by bound TFs. Allele frequency analysis suggests that both localized mutational spikes occur in the first trimester. We call this prenatal mutational process “skiagenesis” (from the Greekskia, meaning shadow), as these mutations occur in the shadow of bound TFs. Skiagenesis reflects as-yet unidentified prenatal factors and is associated with SCZ risk in a subset (∼13%) of cases. In turn, mutational disruption of key TFBS active in fetal brain is well positioned to create SCZ-specific gene dysregulation in concert with germline risk genes.Skiagenesisprovides a fingerprint for exploring how epigenomic regulation and prenatal factors such as maternal infection or immune activation may shape the developmental mutational landscape of human brain.
ATPase activity of DFCP1 controls selective autophagy
Authors: Nähse Viola , Raiborg Camilla , Tan Kia Wee , Mørk Sissel , Torgersen Maria Lyngaas , Wenzel Eva Maria , Nager Mireia , Salo Veijo T. , Johansen Terje , Ikonen Elina , Schink Kay Oliver , Stenmark Harald
Published: February 2022

Cellular homeostasis is governed by removal of damaged organelles and protein aggregates by selective autophagy mediated by cargo adaptors such as p62/SQSTM1. Autophagosomes can assemble in specialized cup-shaped regions of the endoplasmic reticulum (ER) known as omegasomes, which are characterized by the presence of the ER protein DFCP1/ZFYVE1. The function of DFCP1 is unknown, as are the mechanisms of omegasome formation and constriction. Here, we demonstrate that DFCP1 is an ATPase that dimerizes in an ATP-dependent fashion. Whereas depletion of DFCP1 had a minor effect on bulk autophagic flux, DFCP1 was required to maintain the autophagic flux of p62 under both fed and starved conditions, and this was dependent on its ability to bind and hydrolyse ATP. While DFCP1 mutants defective in ATP binding or hydrolysis localized to forming omegasomes, these omegasomes failed to constrict. Consequently, the release of nascent autophagosomes from omegasomes was markedly delayed. DFCP1 was found to associate with ubiquitinated proteins, and degradation of ubiquitinated cargoes such as protein aggregates, mitochondria and micronuclei was strongly inhibited when DFCP1 was knocked out or mutated. Thus, DFCP1 mediates ATPase-driven constriction of omegasomes to release autophagosomes for selective autophagy.
QTL analysis reveals an oligogenic architecture of a rapidly adapting trait during the European invasion of common ragweed
Authors: Prapas Diana , Scalone Romain , Lee Jacqueline , Nurkowski Kristin A , Bou-assi Sarah , Rieseberg Loren , Battlay Paul , Hodgins Kathryn A
Published: February 2022

Biological invasions offer a unique opportunity to investigate evolution over contemporary time-scales. Rapid adaptation to local climates during range expansion can be a major determinant of invasion success, yet fundamental questions remain about its genetic basis. This study sought to investigate the genetic basis of climate adaptation in invasive common ragweed (Ambrosia artemisiifolia). Flowering time adaptation is key to this annual species’ invasion success, so much so that it has evolved repeated latitudinal clines in size and phenology across its native and introduced ranges despite high gene flow among populations. Here, we produced a high-density linkage map (4,493 SNPs) and paired this with phenotypic data from an F2 mapping population (n=336) to identify one major and two minor quantitative trait loci (QTL) underlying flowering time and height differentiation in this species. Within each QTL interval, several candidate flowering time genes were also identified. Notably, the major flowering time QTL detected in this study was found to overlap with a previously identified haploblock (putative inversion). Multiple genetic maps of this region identified evidence of suppressed recombination in specific genotypes, consistent with inversions. These discoveries support the expectation that a concentrated genetic architecture with fewer, larger and more tightly-linked alleles should underlie rapid local adaptation during invasion, particularly when divergently-adapting populations experience high-levels of gene flow.
AIMP1-derived peptide secreted from hair follicle stem cells activates dermal papilla cells to promote hair growth
Authors: Kim YounHa , Lee Ho , Kim Doyeun , Bak Soon Sun , Yoon Ina , Paus Ralf , Cho Seongmin , Jeong Seung Jae , Jeon Yoon , Park Min Chul , Oh Ji Won , Park Jung Min , Kim Sang Bum , Sung Young Kwan , Kim Sunghoon
Published: February 2022

Hair follicle stem cells (HFSCs) and dermal papilla cells (DPCs) are crucial in the biogenesis and maintenance of hair follicles (HFs). In this study, a fragment derived from aminoacyl-tRNA synthetase-interacting multifunctional protein1 (AIMP1) was secreted from HFSCs to activate DPCs to maintain hair follicle homeostasis. A histological analysis revealed that AIMP1 levels in hair follicles decreased with hair loss. Hair regrowth in AIMP1-induced mice was faster than that in non-induced mice. Deletion mapping revealed 41 amino acids (TN41, aa 6-46) as the active region of AIMP1. The N-terminal peptide fragment of AIMP1 generated by MMP1 was secreted from Wnt-treated HFSCs to activate DPCs via FGFR2. TN41 activated Akt and ERK, increased β-catenin, and enhanced DPCs activation. TN41 also promoted hair shaft elongation in cultured human hair follicles and improved the hair-inducing activity of cultured DPC spheroids. In summation, the AIMP1 fragment secreted from HFSCs appears to stimulate active hair regrowth through activating DPCs.
Nr2f1a maintains atrial nkx2.5 expression to repress pacemaker identity within venous atrial cardiomyocytes
Authors: Martin Kendall E. , Ravisankar Padmapriyadarshini , Beerens Manu E. M. , MacRae Calum A. , Waxman Joshua S.
Published: February 2022

Maintenance of cardiomyocyte identity is vital for normal heart development and function. However, our understanding of cardiomyocyte plasticity remains incomplete. Here, we show that sustained expression of the zebrafish transcription factor (TF) Nr2f1a prevents the progressive acquisition of ventricular cardiomyocyte (VC) and pacemaker cardiomyocyte (PC) identities within distinct regions of the atrium. Transcriptomic analysis of isolated atrial cardiomyocytes (ACs) from nr2f1a mutant zebrafish embryos showed increased VC marker gene expression and altered expression of core PC regulatory genes, including decreased expression of nkx2.5, a critical repressor of PC differentiation. At the arterial pole of the atrium in nr2f1a mutants, cardiomyocytes resolve to VC identity within the expanded atrioventricular canal. However, at the venous pole, there is a progressive wave of AC transdifferentiation into PCs across the atrium toward the arterial pole. Restoring Nkx2.5 is sufficient to repress PC identity in nr2f1a mutant atria and analysis of chromatin accessibility identified a Nr2f1a-dependent nkx2.5 enhancer expressed in the atrial myocardium directly adjacent to PCs, supporting that Nr2f1a limits PC differentiation within venous ACs via maintaining nkx2.5 expression. The Nr2f-dependent maintenance of AC identity within discrete atrial compartments may provide insights into the molecular etiology of concurrent structural congenital heart defects and associated arrhythmias.