Experimental findings show the ubiquitous presence of graded responses and tuning curves in the neocortex, particularly in visual areas [1-15]. Among these, inferotemporal-cortex (IT) neurons respond to complex visual stimuli, but differences in the neurons' responses can be used to distinguish the stimuli eliciting the responses [8, 9, 16-18]. The IT projects directly to the medial temporal lobe (MTL) [19], where neurons respond selectively to different pictures of specific persons and even to their written and spoken names [20-22]. However, it is not clear whether this is done through a graded coding, as in the neocortex, or a truly invariant code, in which the response-eliciting stimuli cannot be distinguished from each other. To address this issue, we recorded single neurons during the repeated presentation of different stimuli (pictures and written and spoken names) corresponding to the same persons. Using statistical tests and a decoding approach, we found that only in a minority of cases can the different pictures of a given person be distinguished from the neurons' responses and that in a larger proportion of cases, the responses to the pictures were different to the ones to the written and spoken names. We argue that MTL neurons tend to lack a representation of sensory features (particularly within a sensory modality), which can be advantageous for the memory function attributed to this area [23-25], and that a full representation of memories is given by a combination of mostly invariant coding in the MTL with a representation of sensory features in the neocortex. Memory consolidation can be promoted via targeted memory reactivation (TMR) that re-presents training cues or context during sleep. Whether TMR acts locally or globally on cortical sleep oscillations remains unknown. Here, we exploit the unique functional neuroanatomy of olfaction with its ipsilateral stimulus processing to perform local TMR in one brain hemisphere. Participants learned associations between words and locations in left or right visual fields with contextual odor throughout. We found lateralized event-related potentials during task training that indicate unihemispheric memory processes. During post-learning naps, odors were presented to one nostril in non-rapid eye movement (NREM) sleep. Memory for specific words processed in the cued hemisphere (ipsilateral to stimulated nostril) was improved after local TMR during sleep. Unilateral odor cues locally modulated slow-wave (SW) power such that regional SW power increase was lower in the cued hemisphere relative to the uncued hemisphere and negatively correlated with select memories for cued words. Moreover, local TMR improved phase-amplitude coupling (PAC) between slow oscillations and sleep spindles specifically in the cued hemisphere. The effects on memory performance and cortical sleep oscillations were not observed when unilateral olfactory stimulation during sleep followed learning without contextual odor. Thus, TMR in human sleep transcends global action by selectively promoting specific memories associated with local sleep oscillations. The jasmonate signaling pathway regulates development, growth, and defense responses in plants. Studies in the model eudicot, Arabidopsis thaliana, have identified the bioactive hormone (jasmonoyl-isoleucine [JA-Ile]) and its Coronatine Insensitive 1 (COI1)/Jasmonate-ZIM Domain (JAZ) co-receptor. https://www.selleckchem.com/products/mitopq.html In bryophytes, a conserved signaling pathway regulates similar responses but uses a different ligand, the JA-Ile precursor dinor-12-oxo-10,15(Z)-phytodienoic acid (dn-OPDA), to activate a conserved co-receptor. Jasmonate responses independent of JA-Ile and COI1, thought to be mediated by the cyclopentenone OPDA, have also been suggested, but experimental limitations in Arabidopsis have hindered attempts to uncouple OPDA and JA-Ile biosynthesis. Thus, a clear understanding of this pathway remains elusive. Here, we address the role of cyclopentenones in COI1-independent responses using the bryophyte Marchantia polymorpha, which is unable to synthesize JA-Ile but does accumulate OPDA and dn-OPDA. We demonstrate that OPDA and dn-OPDA activate a COI1-independent pathway that regulates plant thermotolerance genes, and consequently, treatment with these oxylipins protects plants against heat stress. Furthermore, we identify that these molecules signal through their electrophilic properties. By performing comparative analyses between M. polymorpha and two evolutionary distant species, A. thaliana and the charophyte alga Klebsormidium nitens, we demonstrate that this pathway is conserved in streptophyte plants and pre-dates the evolutionary appearance of the COI1-dependent jasmonate pathway, which later co-opted the pre-existing dn-OPDA as its ligand. Taken together, our data indicate that cyclopentenone-regulated COI1-independent signaling is an ancient conserved pathway, whose ancestral role was to protect plants against heat stress. This pathway was likely crucial for plants' successful land colonization and will be critical for adaption to current climate warming. Two recent studies have uncovered a novel means by which bacteriophages thwart host immunity. Mendoza et al. (2020) and Malone et al. (2020) demonstrate that a nucleus-like proteinaceous structure shields phage DNA from CRISPR-associated nucleases encompassing Cascade-Cas3, Cas9, and Cas12. While gapmers efficiently knock down as well as terminate transcription of nascent lncRNAs and mRNAs, Lee and Mendell (2020) and Lai et al. (2020) also demonstrate that Pol II termination is not observed with gapmers targeting the 3' terminal portions of the transcript. Okazaki and colleagues report that PD-1 signaling mainly restrains effector function at the early stage of T cell activation. The authors find that cytokine genes require strong antigen stimulation and are more susceptible to PD-1 inhibition. The ubiquitin ligase Parkin, protein kinase PINK1, USP30 deubiquitylase, and p97 segregase function together to regulate turnover of damaged mitochondria via mitophagy, but our mechanistic understanding in neurons is limited. Here, we combine induced neurons (iNeurons) derived from embryonic stem cells with quantitative proteomics to reveal the dynamics and specificity of Parkin-dependent ubiquitylation under endogenous expression conditions. Targets showing elevated ubiquitylation in USP30-/- iNeurons are concentrated in components of the mitochondrial translocon, and the ubiquitylation kinetics of the vast majority of Parkin targets are unaffected, correlating with a modest kinetic acceleration in accumulation of pS65-Ub and mitophagic flux upon mitochondrial depolarization without USP30. Basally, ubiquitylated translocon import substrates accumulate, suggesting a quality control function for USP30. p97 was dispensable for Parkin ligase activity in iNeurons. This work provides an unprecedented quantitative landscape of the Parkin-modified ubiquitylome in iNeurons and reveals the underlying specificity of central regulatory elements in the pathway.
Experimental findings show the ubiquitous presence of graded responses and tuning curves in the neocortex, particularly in visual areas [1-15]. Among these, inferotemporal-cortex (IT) neurons respond to complex visual stimuli, but differences in the neurons' responses can be used to distinguish the stimuli eliciting the responses [8, 9, 16-18]. The IT projects directly to the medial temporal lobe (MTL) [19], where neurons respond selectively to different pictures of specific persons and even to their written and spoken names [20-22]. However, it is not clear whether this is done through a graded coding, as in the neocortex, or a truly invariant code, in which the response-eliciting stimuli cannot be distinguished from each other. To address this issue, we recorded single neurons during the repeated presentation of different stimuli (pictures and written and spoken names) corresponding to the same persons. Using statistical tests and a decoding approach, we found that only in a minority of cases can the different pictures of a given person be distinguished from the neurons' responses and that in a larger proportion of cases, the responses to the pictures were different to the ones to the written and spoken names. We argue that MTL neurons tend to lack a representation of sensory features (particularly within a sensory modality), which can be advantageous for the memory function attributed to this area [23-25], and that a full representation of memories is given by a combination of mostly invariant coding in the MTL with a representation of sensory features in the neocortex. Memory consolidation can be promoted via targeted memory reactivation (TMR) that re-presents training cues or context during sleep. Whether TMR acts locally or globally on cortical sleep oscillations remains unknown. Here, we exploit the unique functional neuroanatomy of olfaction with its ipsilateral stimulus processing to perform local TMR in one brain hemisphere. Participants learned associations between words and locations in left or right visual fields with contextual odor throughout. We found lateralized event-related potentials during task training that indicate unihemispheric memory processes. During post-learning naps, odors were presented to one nostril in non-rapid eye movement (NREM) sleep. Memory for specific words processed in the cued hemisphere (ipsilateral to stimulated nostril) was improved after local TMR during sleep. Unilateral odor cues locally modulated slow-wave (SW) power such that regional SW power increase was lower in the cued hemisphere relative to the uncued hemisphere and negatively correlated with select memories for cued words. Moreover, local TMR improved phase-amplitude coupling (PAC) between slow oscillations and sleep spindles specifically in the cued hemisphere. The effects on memory performance and cortical sleep oscillations were not observed when unilateral olfactory stimulation during sleep followed learning without contextual odor. Thus, TMR in human sleep transcends global action by selectively promoting specific memories associated with local sleep oscillations. The jasmonate signaling pathway regulates development, growth, and defense responses in plants. Studies in the model eudicot, Arabidopsis thaliana, have identified the bioactive hormone (jasmonoyl-isoleucine [JA-Ile]) and its Coronatine Insensitive 1 (COI1)/Jasmonate-ZIM Domain (JAZ) co-receptor. https://www.selleckchem.com/products/mitopq.html In bryophytes, a conserved signaling pathway regulates similar responses but uses a different ligand, the JA-Ile precursor dinor-12-oxo-10,15(Z)-phytodienoic acid (dn-OPDA), to activate a conserved co-receptor. Jasmonate responses independent of JA-Ile and COI1, thought to be mediated by the cyclopentenone OPDA, have also been suggested, but experimental limitations in Arabidopsis have hindered attempts to uncouple OPDA and JA-Ile biosynthesis. Thus, a clear understanding of this pathway remains elusive. Here, we address the role of cyclopentenones in COI1-independent responses using the bryophyte Marchantia polymorpha, which is unable to synthesize JA-Ile but does accumulate OPDA and dn-OPDA. We demonstrate that OPDA and dn-OPDA activate a COI1-independent pathway that regulates plant thermotolerance genes, and consequently, treatment with these oxylipins protects plants against heat stress. Furthermore, we identify that these molecules signal through their electrophilic properties. By performing comparative analyses between M. polymorpha and two evolutionary distant species, A. thaliana and the charophyte alga Klebsormidium nitens, we demonstrate that this pathway is conserved in streptophyte plants and pre-dates the evolutionary appearance of the COI1-dependent jasmonate pathway, which later co-opted the pre-existing dn-OPDA as its ligand. Taken together, our data indicate that cyclopentenone-regulated COI1-independent signaling is an ancient conserved pathway, whose ancestral role was to protect plants against heat stress. This pathway was likely crucial for plants' successful land colonization and will be critical for adaption to current climate warming. Two recent studies have uncovered a novel means by which bacteriophages thwart host immunity. Mendoza et al. (2020) and Malone et al. (2020) demonstrate that a nucleus-like proteinaceous structure shields phage DNA from CRISPR-associated nucleases encompassing Cascade-Cas3, Cas9, and Cas12. While gapmers efficiently knock down as well as terminate transcription of nascent lncRNAs and mRNAs, Lee and Mendell (2020) and Lai et al. (2020) also demonstrate that Pol II termination is not observed with gapmers targeting the 3' terminal portions of the transcript. Okazaki and colleagues report that PD-1 signaling mainly restrains effector function at the early stage of T cell activation. The authors find that cytokine genes require strong antigen stimulation and are more susceptible to PD-1 inhibition. The ubiquitin ligase Parkin, protein kinase PINK1, USP30 deubiquitylase, and p97 segregase function together to regulate turnover of damaged mitochondria via mitophagy, but our mechanistic understanding in neurons is limited. Here, we combine induced neurons (iNeurons) derived from embryonic stem cells with quantitative proteomics to reveal the dynamics and specificity of Parkin-dependent ubiquitylation under endogenous expression conditions. Targets showing elevated ubiquitylation in USP30-/- iNeurons are concentrated in components of the mitochondrial translocon, and the ubiquitylation kinetics of the vast majority of Parkin targets are unaffected, correlating with a modest kinetic acceleration in accumulation of pS65-Ub and mitophagic flux upon mitochondrial depolarization without USP30. Basally, ubiquitylated translocon import substrates accumulate, suggesting a quality control function for USP30. p97 was dispensable for Parkin ligase activity in iNeurons. This work provides an unprecedented quantitative landscape of the Parkin-modified ubiquitylome in iNeurons and reveals the underlying specificity of central regulatory elements in the pathway.
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