bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcranial electrical stimulation over premotor cortex mimics attentional modulation of visual processing
Authors: Misselhorn Jonas , Fiene Marina , Radecke Jan-Ole , Engel Andreas K. , Schneider Till R. 
Published: August 2023

AbstractAttentional control over sensory processing has been linked to neural alpha oscillations and related pulsed inhibition of the human cortex. Despite the wide consensus on the functional relevance of alpha oscillations for attention, precise neural mechanisms of how alpha oscillations shape perception and how this top-down modulation is implemented in cortical networks remain unclear. Here, we tested the hypothesis that alpha oscillations in premotor cortex are causally involved in top-down regulation of visual cortex responsivity to contrast. We applied intermittent transcranial alternating current stimulation (tACS) over bilateral premotor cortex to manipulate attentional preparation in a visual discrimination task. tACS was applied at 10 Hz (alpha) and controlled with 40 Hz (gamma) and sham stimulation. Importantly, we used a novel linear mixed modeling approach for statistical control of neurosensory side-effects of the electric stimulation. We found a frequency-specific effect of alpha tACS on the slope parameter, leading to enhanced low-contrast perception and decreased perception of high-contrast stimuli. Side-effects affected both threshold and slope parameters, leading to high variability in parameter estimates. Controlling the impact of side-effects on psychometric parameters by linear mixed model analysis reduced variability and clarified the existing effect. We conclude that alpha tACS over premotor cortex mimicked a state of increased endogenous attention potentially by modulation of fronto-occipital connectivity in the alpha band. We speculate that this network modulation allowed for improved sensory readout from visual cortex which led to a decrease in psychometric slope, effectively broadening the dynamic range for contrast perception.Significance statementAttention is fundamental to voluntary control of perception and behavior. Yet, despite extensive scientific efforts, precise underlying neural mechanisms remain elusive. We contribute to this ongoing discussion by providing evidence for a vital role of frontal alpha oscillations in regulating the responsivity of visual cortex. By controlled neuromodulation with intermittent transcranial alternating current stimulation (tACS), we show that alpha tACS modulates psychometric properties of visual contrast perception. This study fills an important gap between work on alpha oscillations in spatial attention and studies on the psychometrics of attention. Furthermore, we pioneered an approach for the statistical control of tACS side-effects with linear mixed modeling and thereby add to the ongoing debate on outcome variability in studies using transcranial neurostimulation methods.
Distinguishing preferences of human APOBEC3A and APOBEC3B for cytosines in hairpin loops, and reflection of these preferences in APOBEC-signature cancer genome mutations
Authors: Butt Yasha , Sakhtemani Ramin , Mohamad-Ramshan Rukshana , Lawrence Michael S. , Bhagwat Ashok S. 
Published: August 2023

AbstractThe APOBEC3 family of enzymes convert cytosines in single-stranded DNA to uracils thereby causing mutations. These enzymes protect human cells against viruses and retrotransposons, but in many cancers they contribute to mutations that diversify the tumors and help them escape anticancer drug treatments. To understand the mechanism of mutagenesis by APOBEC3B, we expressed the complete enzyme or its catalytic carboxy-terminal domain (CTD) in repair-deficientEschericia coliand mapped the resulting uracils using uracil pull-down and sequencing technology. The uracilomes of A3B-full and A3B-CTD showed peaks in many of the same regions where APOBEC3A also created uracilation peaks. Like A3A, the two A3B enzymes also preferred to deaminate cytosines near transcription start sites and in the lagging-strand template at replication forks. In contrast to an earlier report that A3B does not favor hairpin loops over linear DNA, we found that both A3B-full and A3B-CTD showed a strong preference for cytosines in hairpin loops. The major difference between A3A and A3B was that while the former enzyme prefers 3 nt loops the best, A3B prefers loops of 4 nt over those of other lengths. Furthermore, within 5 nt loops, A3A prefers cytosine to be in the penultimate position, while A3B prefers it to be at the 3’ end of the loop. We confirmed these loop size and sequence preferences experimentally using purified A3A and A3B-CTD proteins. Reanalysis of hairpin loop mutations in human tumors using the size, sequence and position preferences of the two enzymes found that the tumors displayed mutations with intrinsic characteristics of both the enzymes with a stronger contribution from A3A.
Comparative pathogenesis of two lineages of Powassan virus reveals distinct clinical outcome, neuropathology, and inflammation
Authors: Reynolds Erin S. , Hart Charles E. , Nelson Jacob T. , Marzullo Brandon J. , Esterly Allen T. , Paine Dakota N. , Crooker Jessica , Massa Paul T. , Thangamani Saravanan 
Published: August 2023

AbstractTick-borne flaviviruses (TBFV) can cause severe neuroinvasive disease which may result in death or long-term neurological deficit in over 50% of survivors. Multiple mechanisms for invasion of the central nervous system (CNS) by flaviviruses have been proposed including axonal transport, transcytosis, endothelial infection, and Trojan horse routes. Flaviviruses may utilize different or multiple mechanisms of neuroinvasion depending on the specific virus, infection site, and host variability. In this work we have shown that infection of BALB/cJ mice with either Powassan virus lineage I (Powassan virus) or lineage II (deer tick virus) results in distinct spatial tropism of infection in the CNS which correlated with unique clinical presentation for each lineage. Comparative transcriptomics of infected brains demonstrates activation of different immune pathways and downstream host responses. Ultimately the comparative pathology and transcriptomics are congruent with different clinical signs in a murine model. These results suggest that different disease presentations would be occur in clinical cases due to the innate differences in the two lineages of Powassan virus.Author SummaryPowassan virus causes a nationally notifiable disease which can cause severe neurological disease in humans and has no approved vaccines or therapeutics. Although two distinct lineages circulate in North America, clinical differentiation is not typically performed, and pathology has been assumed to be similar between lineages. In this work, a direct comparison of lineage I (Powassan virus) and lineage II (deer tick virus) demonstrated distinct differences in the clinical presentation, pathology of the central nervous system, and immune response in immunocompetent mice. These differences suggest that deer tick virus and Powassan virus do not utilize the same mechanisms for neuroinvasion and dissemination within the CNS. This is clinically relevant as the development of treatment plans and therapeutics need to be evaluated for these virus lineages.
Grid-like entorhinal representation of an abstract value space during prospective decision making
Authors: Nitsch Alexander , Garvert Mona M. , Bellmund Jacob L. S. , Schuck Nicolas W. , Doeller Christian F. 
Published: August 2023

AbstractEveryday decisions require us to predict how valuable different choice options will be in the future. Prior studies have identified a cognitive map in the hippocampal-entorhinal system that encodes relationships between states and enables prediction of future states, but does not inherently convey value during prospective decision making. Here, we investigated whether the entorhinal cortex integrates relational information about changing values by representing an abstract value space. To this end, we combined fMRI with a prospective decision making task that required participants to track and predict changing values of two choice options in a sequence. Such a sequence formed a trajectory through an underlying two-dimensional value space. Our results show that participants successfully integrated and extrapolated changes along the two value dimensions. Participants’ choice behavior was explained by a prospective reinforcement learning model and the degree to which they updated values over time correlated with self-reported navigational abilities and preferences. Crucially, while participants traversed the abstract value space, the entorhinal cortex exhibited a grid-like representation, with the phase of the hexadirectional fMRI signal (i.e., the orientation of the estimated grid) being aligned to the most informative axis through the value space. A network of brain regions, including the ventromedial prefrontal cortex (vmPFC), tracked the prospective value difference between options and the occipital-temporal cortex represented the more valuable option. These findings suggest that the entorhinal grid system might support the prediction of future values by representing a cognitive map, which might be used to generate lower-dimensional signals of the value difference between options and their identities for choices. Thus, these findings provide novel insight for our understanding of cognitive maps as a mechanism to guide prospective decision making in humans.
A transient modified mRNA encoding Myc and Cyclin T1 induces cardiac regeneration and improves cardiac function after myocardial injury
Authors: Boikova Aleksandra , Quaife-Ryan Gregory A. , Batho Christopher A.P. , Lawrence Elsa , Robinson Harley , Ascanelli Camilla , Jennbacken Karin , Wang Qing-Dong , Hansson Kenny M. , Seaton Adam , Noci Victoria Rodriguez , Bywater Megan , Straube Jasmin , Sokolowski Kamil A. , Tse Brian W.C. , Krieg Thomas , Vujic Ana , Porrello Enzo R. , Sinha Sanjay , Hudson James E. , Wilson Catherine H. 
Published: August 2023

AbstractCardiac injury, such as myocardial infarction (MI), results in permanent loss of cardiomyocytes and in many cases heart failure. Transgenic expression of the pro-proliferative transcription factor Myc and Cyclin T1 can drive substantial adult cardiomyocyte proliferation to replace lost cardiomyocytes. Herein, we show that Myc and Cyclin T1 induced cardiomyocyte proliferation leads to myocardial repair and functional (long-term) recovery post-MI in mice. To provide a more translational approach, we developed modified mRNA (modRNA) encoding Myc-Ccnt1 as a transient and non-integrating strategy for regeneration. One dose of Myc-Ccnt1 modRNA is sufficient to transiently drives cardiomyocyte proliferation in human pluripotent stem cell-derived cardiomyocytes and a mouse MI model, where it leads to better heart function. Using single nuclei sequencing and proteomics, we show this was functionally mediated by transcriptional activation of cell-cycle regulating genes, which ultimately results in mitosis and cytokinesis of cardiomyocytes. Collectively, these findings indicate that Myc-Ccnt1 modRNA has the potential to be an effective regenerative therapeutic.
Proteome and phospholipidome interrelationship of synovial fluid-derived extracellular vesicles in equine osteoarthritis: An exploratory ‘multi-omics’ study to identify composite biomarkers
Authors: Clarke Emily J , Varela Laura , Jenkins Rosalind E , Lozano−Andrés Estefanía , Cywińska Anna , Przewozny Maciej , van Weeren P. René , van de Lest Chris H.A. , Peffers Mandy , Wauben Marca H.M. 
Published: August 2023

ABSTRACTOsteoarthritis causes progressive joint deterioration, severe morbidity, and reduced mobility in both humans and horses. Currently, osteoarthritis is diagnosed at late stages through clinical examination and radiographic imaging, hence it is challenging to address and provide timely therapeutic interventions to slow disease progression or ameliorate symptoms. Extracellular vesicles are cell–derived vesicles that play a key role in cell–to–cell communication and are potential sources for specific composite biomarker panel discovery. We here used a multi–omics strategy combining proteomics and phospholipidomics in an integral approach to identify composite biomarkers associated to purified extracellular vesicles from synovial fluid of healthy, mildly and severely osteoarthritic equine joints. Although the number of extracellular vesicles was unaffected by osteoarthritis, proteome profiling of extracellular vesicles by mass spectrometry identified 40 differentially expressed proteins (non–adjusted p<0.05) in osteoarthritic joints associated with 7 significant canonical pathways in osteoarthritis. Moreover, pathway analysis unveiled changes in disease and molecular functions during osteoarthritis development. Phospholipidome profiling by mass spectrometry showed a relative increase in sphingomyelin and a decrease in phosphatidylcholine, phosphatidylinositol, and phosphatidylserine in extracellular vesicles derived from osteoarthritic joints compared to healthy joints. Unsupervised data integration revealed positive correlations between the proteome and the phospholipidome. Comprehensive analysis showed that some phospholipids and their related proteins increased as the severity of osteoarthritis progressed, while others decreased or remained stable. Altogether our data show interrelationships between synovial fluid extracellular vesicle–associated phospholipids and proteins responding to osteoarthritis pathology and which could be explored as potential composite diagnostic biomarkers of disease.
Mosquito midgut stem cell cellular defense response limitsPlasmodiumparasite infection
Authors: Barletta Ana-Beatriz F. , Smith Jamie C. , Burkart Emily , Bondarenko Simon , Sharakhov Igor , Criscione Frank , O’Brochta David , Barillas-Mury Carolina 
Published: August 2023

AbstractA novel cellular response of midgut progenitors (stem cells and enteroblasts) toPlasmodium bergheiinfection was investigated inAnopheles stephensi. The presence of developing oocysts triggers proliferation of midgut progenitors that is modulated by the Jak/STAT pathway, and proportional to the number of oocysts on individual midguts. The percentage of parasites in direct contact with enteroblasts increases over time, as progenitors proliferate. Enhancing proliferation of progenitors significantly decreases oocyst numbers, while limiting proliferation increases oocyst survival. Live imaging revealed that enteroblasts interact directly with oocysts and eliminate them. Midgut progenitors sense the presence ofPlasmodiumoocysts and mount a cellular defense response that involves extensive proliferation and tissue remodeling, followed by oocysts lysis and phagocytosis of parasite remnants by enteroblasts.One-Sentence SummaryMosquito midgut stem cells detectPlasmodiumparasites, proliferate and enteroblasts actively eliminate oocysts.
Requirement of GrgA forChlamydiainfectious progeny production, optimal growth, and efficient plasmid maintenance
Authors: Lu Bin , Wang Yuxuan , Wurihan Wurihan , Cheng Andrew , Yeung Sydney , Fondell Joseph D. , Lai Zhao , Wan Danny , Wu Xiang , Li Wei Vivian , Fan Huizhou 
Published: August 2023

ABSTRACTChlamydia, an obligate intracellular bacterial pathogen, has a unique developmental cycle involving the differentiation of invading elementary bodies (EBs) to noninfectious reticulate bodies (RBs), replication of RBs, and redifferentiation of RBs into progeny EBs. Progression of this cycle is regulated by three sigma factors, which direct the RNA polymerase to their respective target gene promoters. We hypothesized that theChlamydia-specific transcriptional regulator GrgA, previously shown to activate σ66 and σ28, plays an essential role in chlamydial development and growth. To test this hypothesis, we applied a novel genetic tool known as dependence on plasmid-mediated expression (DOPE) to createChlamydia trachomatiswith conditional GrgA-deficiency. We show that GrgA-deficientC. trachomatisRBs have a growth rate that is approximately half of the normal rate and fail to transition into progeny EBs. In addition, GrgA-deficientC. trachomatisfail to maintain its virulence plasmid. Results of RNA-seq analysis indicate that GrgA promotes RB growth by optimizing tRNA synthesis and expression of nutrient-acquisition genes, while it enables RB-to-EB conversion by facilitating the expression of a histone and outer membrane proteins required for EB morphogenesis. GrgA also regulates numerous other late genes required for host cell exit and subsequent EB invasion into host cells. Importantly, GrgA stimulates the expression of σ54, the third and last sigma factor, and its activator AtoC, and thereby indirectly upregulating the expression of σ54-dependent genes. In conclusion, our work demonstrates that GrgA is a master transcriptional regulator inChlamydiaand plays multiple essential roles in chlamydial pathogenicity.IMPORTANCEHallmarks of the developmental cycle of the obligate intracellular pathogenic bacteriumChlamydiaare the primary differentiation of the infectious elementary body (EB) into the proliferative reticulate body (RB) and the secondary differentiation of RBs back into EBs. The mechanisms regulating these transitions remain unclear. In this report, we developed an effective novel strategy termed DOPE that allows for the knockdown of essential genes inChlamydia. We demonstrate that GrgA, aChlamydia-specific transcription factor, is essential for the secondary differentiation and optimal growth of RBs. We also show that GrgA, a chromosome-encoded regulatory protein, controls the maintenance of the chlamydial virulence plasmid. Transcriptomic analysis further indicates that GrgA functions as a critical regulator of all three sigma factors that recognize different promoter sets at developmental stages. The DOPE strategy outlined here should provide a valuable tool for future studies examining chlamydial growth, development, and pathogenicity.
Local adaptation to an altitudinal gradient: the interplay between mean phenotypic trait variation and phenotypic plasticity inMimulus laciniatus
Authors: Syrotchen Jill M. , Ferris Kathleen G. 
Published: August 2023

ABSTRACTOrganisms can adapt to environmental heterogeneity through two mechanisms: (1) expression of population genetic variation or (2) phenotypic plasticity. In this study we investigated whether patterns of variation in both trait means and phenotypic plasticity along elevational and latitudinal clines in a North American endemic plant,Mimulus laciniatus, were consistent with local adaptation. We grew inbred lines ofM. laciniatusfrom across the species’ range in two common gardens varying in day length to measure mean and plastic trait expression in several traits previously shown to be involved in adaptation toM. laciniatus’srocky outcrop microhabitat: flowering time, size-related traits, and leaf shape. We examined correlations between the mean phenotype and phenotypic plasticity, and tested for a relationship between trait variation and population elevation and latitude. We did not find a strong correlation between mean and plastic trait expression at the individual genotype level suggesting that they operate under independent genetic controls. We identified multiple traits that show patterns consistent with local adaptation to elevation: critical photoperiod, flowering time, flower size, mean leaf lobing, and leaf lobing plasticity. These trends occur along multiple geographically independent altitudinal clines indicating that selection is a more likely cause of this pattern than gene flow among nearby populations with similar trait values. We also found that population variation in mean leaf lobing is associated with latitude. Our results indicate that both having more highly lobed leaves and greater leaf shape plasticity may be adaptive at high elevation withinM. laciniatus.Our data strongly suggest that traits known to be under divergent selection betweenM. laciniatusand close relativeMimulus guttatusare also under locally varying selection withinM. laciniatus.
WITHDRAWN: Alpha oscillations support the efficiency of guided visual search by inhibiting both target and distractor features in early visual cortex
Authors: Duecker Katharina , Shapiro Kimron L. , Hanslmayr Simon , Wolfe Jeremy , Pan Yali , Jensen Ole 
Published: August 2023

Withdrawal StatementThe authors have withdrawn this manuscript owing to having received feedback that prompted a reconsideration of the findings in light of potential confounds associated with time-on-task effects, as highlighted by Benwell et al. (2019, NeuroImage). Subsequent in-depth analysis has led the authors to reassess the central assertions made in our original manuscript, and the main claims can no longer be supported. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Presence of the ER-Golgi intermediate compartment that matures into the Golgi in yeast
Authors: Tojima Takuro , Suda Yasuyuki , Jin Natsuko , Kurokawa Kazuo , Nakano Akihiko 
Published: August 2023

AbstractCargo traffic through the Golgi apparatus is mediated by cisternal maturation, but it remains largely unclear how thecis-cisternae, the earliest Golgi sub-compartment, is generated. Here, we use high-speed, high-resolution confocal microscopy to analyze the spatiotemporal dynamics of a diverse set of proteins that reside in and around the Golgi in budding yeast. We find many mobile punctate structures that harbor yeast counterparts of mammalian endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) proteins, which we term “yeast ERGIC”. It occasionally attaches onto the ER exit sites and gradually matures into thecis-Golgi. Upon treatment with the Golgi-disrupting agent brefeldin A, the ERGIC proteins form larger aggregates corresponding to the Golgi entry core compartment in plants, whilecis- and medial-Golgi proteins are absorbed into the ER. We further analyze the dynamics of several late Golgi proteins. Together with our previous studies, we demonstrate a detailed spatiotemporal profile of the cisternal maturation process from ERGIC to Golgi and further to thetrans-Golgi network.SummaryTojima et al. perform spatiotemporal mapping of a variety of proteins residing in and around the Golgi apparatus in budding yeast using super-resolution live imaging microscopy. They identified the ER-Golgi intermediate compartment that matures into the Golgi.
How future innovations benefit from current innovations
Authors: Shi Yan , Zou Bo , Xin Hao 
Published: August 2023

PurposeIn high-tech markets, innovation is always generative and continuous both within the iteration in a product's development process and throughout the upgrade of multi-generational products. Inspired by this practical phenomenon, this study aims to explore the mechanism of innovation generativity and continuity to explain how future innovations benefit from current innovations.Design/methodology/approachThe study conducted qualitative research to explore innovation generativity and continuity by investigating five electronic information enterprises. The authors employed the ambidexterity perspective to explore the research question.FindingsThe authors found innovation generativity has three dimensions: inheritance, metabolism and inspection. These three dimensions and their interactions are what forms the mechanism of innovation generativity and continuity. The authors also found many paradoxes that prompt enterprises to pursue innovation generativity and continuity, and through this innovation process, enterprises are able to attain continuous innovation.Originality/valueThis study theoretically uncovers “how” to carry out innovation generativity and continuity, as well as the antecedents and the outcome. The findings contribute to research on product innovation, continuous innovation and ambidexterity, and have implications for managers who seek to improve innovation generativity and continuity.