The targeted choice of specific photocatalysts has been shown to play a critical role for the successful realization of challenging photoredox catalytic transformations. Herein, we demonstrate the ...successful implementation of a rational design strategy for a series of deliberate structural manipulations of cyanoarene-based, purely organic donor–acceptor photocatalysts, using 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) as a starting point. Systematic modifications of both the donor substituents as well as the acceptors’ molecular core allowed us to identify strongly oxidizing as well as strongly reducing catalysts (e.g., for an unprecedented detriflation of unactivated naphthol triflate), which additionally offer remarkably balanced redox potentials with predictable trends. Especially halogen arene core substitutions are instrumental for our targeted alterations of the catalysts’ redox properties. Based on their preeminent electrochemical and photophysical characteristics, all novel, purely organic photoredox catalysts were evaluated in three challenging, mechanistically distinct classes of benchmark reactions (either requiring balanced, highly oxidizing or strongly reducing properties) to demonstrate their enormous potential as customizable photocatalysts, that outperform and complement prevailing typical best photocatalysts.
The ability to learn not only from experienced but also from merely fictive outcomes without direct rewarding or punishing consequences should improve learning and resulting value-guided choice. ...Using an instrumental learning task in combination with multiple single-trial regression of predictions derived from a computational reinforcement-learning model on human EEG, we found an early temporospatial double dissociation in the processing of fictive and real feedback. Thereafter, real and fictive feedback processing converged at a common final path, reflected in parietal EEG activity that was predictive of future choices. In the choice phase, similar parietal EEG activity related to certainty of the impending response was predictive for the decision on the next trial as well. These parietal EEG effects may reflect a common adaptive cortical mechanism of updating or strengthening of stimulus values by integrating outcomes, learning rate, and certainty, which is active during both decision making and evaluation. Neuronal processing of real (rewarding, punishing) and fictive action outcomes (which would have happened had one acted differently) differs for 400 ms and then converges on a common adaptive mechanism driving future decision making and learning.
•Humans are able to learn comparably and effectively from real and fictive events•Processing of fictive events shows an early double dissociation compared to real ones•Both processes converge on a common final pathway•This pathway can be used to predict future adaptations
Fischer and Ullsperger show that neuronal processing of real (rewarding, punishing) and fictive action outcomes differs for 400 ms and then converges on a common adaptive mechanism driving future decision making and learning.
Endogenous viral elements are increasingly found in eukaryotic genomes, yet little is known about their origins, dynamics, or function. Here we provide a compelling example of a DNA virus that ...readily integrates into a eukaryotic genome where it acts as an inducible antiviral defence system. We found that the virophage mavirus, a parasite of the giant Cafeteria roenbergensis virus (CroV), integrates at multiple sites within the nuclear genome of the marine protozoan Cafeteria roenbergensis. The endogenous mavirus is structurally and genetically similar to eukaryotic DNA transposons and endogenous viruses of the Maverick/Polinton family. Provirophage genes are not constitutively expressed, but are specifically activated by superinfection with CroV, which induces the production of infectious mavirus particles. Virophages can inhibit the replication of mimivirus-like giant viruses and an anti-viral protective effect of provirophages on their hosts has been hypothesized. We find that provirophage-carrying cells are not directly protected from CroV; however, lysis of these cells releases infectious mavirus particles that are then able to suppress CroV replication and enhance host survival during subsequent rounds of infection. The microbial host-parasite interaction described here involves an altruistic aspect and suggests that giant-virus-induced activation of provirophages might be ecologically relevant in natural protist populations.
The specific role of serotonin and its interplay with dopamine (DA) in adaptive, reward guided behavior as well as drug dependance, still remains elusive. Recently, novel methods allowed cell type ...specific anatomical, functional and interventional analyses of serotonergic and dopaminergic circuits, promising significant advancement in understanding their functional roles. Furthermore, it is increasingly recognized that co-release of neurotransmitters is functionally relevant, understanding of which is required in order to interpret results of pharmacological studies and their relationship to neural recordings. Here, we review recent animal studies employing such techniques with the aim to connect their results to effects observed in human pharmacological studies and subjective effects of drugs. It appears that the additive effect of serotonin and DA conveys significant reward related information and is subjectively highly euphorizing. Neither DA nor serotonin alone have such an effect. This coincides with optogenetically targeted recordings in mice, where the dopaminergic system codes reward prediction errors (PE), and the serotonergic system mainly unsigned PE. Overall, this pattern of results indicates that joint activity between both systems carries essential reward information and invites parallel investigation of both neurotransmitter systems.
Astrocytic tumors are known for their high progression capacity and high mortality rates; in this regard, proteins correlated to prognosis can aid medical conduct. Although several genetic changes ...related to progression from grade 2 to grade 4 astrocytoma are already known, mRNA copies do not necessarily correlate with protein abundance and therefore could shadow further comprehension about this tumor's biology. This motivates us to seek for complementary strategies to study tumor progression at the protein level. Here we compare the proteomic profile of biopsies from patients with grade 2 (diffuse, n = 6) versus grade 4 astrocytomas (glioblastomas, n = 10) using shotgun proteomics. Data analysis performed with PatternLab for proteomics identified 5,206 and 6,004 proteins in the 2- and 4-grade groups, respectively. Our results revealed seventy-four differentially abundant proteins (p < 0.01); we then shortlist those related to greater malignancy. We also describe molecular pathways distinctly activated in the two groups, such as differences in the organization of the extracellular matrix, decisive both in tumor invasiveness and in signaling for cell division, which, together with marked contrasts in energy metabolism, are determining factors in the speed of growth and dissemination of these neoplasms. The degradation pathways of GABA, enriched in the grade 2 group, is consistent with a favorable prognosis. Other functions such as platelet degranulation, apoptosis, and activation of the MAPK pathway were correlated to grade 4 tumors and, consequently, unfavorable prognoses. Our results provide an important survey of molecular pathways involved in glioma pathogenesis for these histopathological groups.
Highlights • Uniform sequence of EEG activity at all stages of performance monitoring (PM) • PM signals reflect weighted signed and unsigned prediction errors. • Current theories of PM only partly ...fit with neurobiological evidence. • Cortical dopamine release cannot cause rapid cortical correlates of PM. • Glutamate and GABA may contribute to transmitting these rapid signals.
About the Authors: Sarah Duponchel Affiliation: Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Heidelberg, Germany Matthias G. Fischer * E-mail: mfischer@mr.mpg.de ...Affiliation: Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Heidelberg, Germany ORCID logo http://orcid.org/0000-0002-4014-3626 Introduction Viruses are obligate intracellular parasites and thus cannot replicate outside a living cell. APMV and CroV share the late gene promoter motifs and transcription termination signals with their associated virophages, Sputnik and mavirus, suggesting that virophage gene expression is initiated by GV-encoded transcription factors during the late phase of GV infection 4,15. ...their high genomic mobility, close connection to eukaryotes, and frequent interaction with other mobile genetic elements may have contributed to the evolutionary success of virophages. ...virophages are fascinating eukaryotic DNA viruses that have evolved to depend on a co-infecting GV instead of replicating in the host cell nucleus.
Bioadhesive membranes with controllable and reversible underwater adhesion are desirable for several biomedical applications ranging from biosensing, drug/therapeutic delivery, and tissue ...regeneration. Here, we present dual soft mucosal and hard bone/enamel tissue adhesive nanofiber membranes composed of chitosan and pectin derivatives for pH-controlled delivery of antimicrobial peptides (AMPs) in the oral cavity. Ex vivo testing with porcine esophagus (soft mucosal mimic) indicated a 2-fold increase in the mucoadhesion of chitosan membranes with 0.05 wt % oxidized pectin coating, while the uncoated membranes exhibited 3–4-fold stronger adhesion to hydroxyapatite discs (enamel/hard bone mimic) compared to the coated membranes. The former is attributed to a synergistic interaction of surface nanofiber topography, intermolecular hydrogen bonding, and aldehyde–amine chemistry between surface polar groups and mucosal proteins, while the latter may arise from electrostatic interactions between cationic amines (−NH3 +) in chitosan and anionic phosphates (−PO4 3–) in hydroxyapatite. Further, the dual hard–soft oral tissue adhesive nanofiber membranes loaded with cationic amphipathic AMPs (D-GL13K and IDR-1018) elicited pH-responsive AMP delivery and antimicrobial action comparable to chlorhexidine (CHX) against oral streptococci. Concurrently, the AMP loaded membranes were cytocompatible to both soft epithelial tissue-derived human oral keratinocytes and hard calvarial murine pre-osteoblast cells. We envision these membranes to function as adhesive gingival grafts and guided bone regeneration (GBR) membranes at the hard–soft tissue interface while simultaneously protecting against oral infections.
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