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The ability to handle approximate quantities, or number sense, has been recurrently linked to mathematical skills, although the nature of the mechanism allowing to extract numerical information (i.e., numerosity) from environmental stimuli is still debated. A set of objects is indeed not only characterized by its numerosity but also by other features, such as the summed area occupied by the elements, which often covary with numerosity. These intrinsic relations between numerosity and nonnumerical magnitudes led some authors to argue that numerosity is not independently processed but extracted through a weighting of continuous magnitudes. This view cannot be properly tested through classic behavioral and neuroimaging approaches due to these intrinsic correlations. The current study used a frequency-tagging EEG approach to separately measure responses to numerosity as well as to continuous magnitudes. We recorded occipital responses to numerosity, total area, and convex hull changes but not to density and dot size. We additionally applied a model predicting primary visual cortex responses to the set of stimuli. The model output was closely aligned with our electrophysiological data, since it predicted discrimination only for numerosity, total area, and convex hull. Our findings thus demonstrate that numerosity can be independently processed at an early stage in the visual cortex, even when completely isolated from other magnitude changes. The similar implicit discrimination for numerosity as for some continuous magnitudes, which correspond to basic visual percepts, shows that both can be extracted independently, hence substantiating the nature of numerosity as a primary feature of the visual scene. Copyright © 2020 the Author(s). Published by PNAS.Marine microbes form the base of ocean food webs and drive ocean biogeochemical cycling. Yet little is known about the ability of microbial populations to adapt as they are advected through changing conditions. Here, we investigated the interplay between physical and biological timescales using a model of adaptation and an eddy-resolving ocean circulation climate model. Two criteria were identified that relate the timing and nature of adaptation to the ratio of physical to biological timescales. Genetic adaptation was impeded in highly variable regimes by nongenetic modifications but was promoted in more stable environments. An evolutionary trade-off emerged where greater short-term nongenetic transgenerational effects (low-γ strategy) enabled rapid responses to environmental fluctuations but delayed genetic adaptation, while fewer short-term transgenerational effects (high-γ strategy) allowed faster genetic adaptation but inhibited short-term responses. Our results demonstrate that the selective pressures for organisms within a single water mass vary based on differences in generation timescales resulting in different evolutionary strategies being favored. Organisms that experience more variable environments should favor a low-γ strategy. Furthermore, faster cell division rates should be a key factor in genetic adaptation in a changing ocean. Understanding and quantifying the relationship between evolutionary and physical timescales is critical for robust predictions of future microbial dynamics. Copyright © 2020 the Author(s). Published by PNAS.Endogenous retroviruses and long terminal repeat (LTR) retrotransposons are mobile genetic elements that are closely related to retroviruses. Desilenced endogenous retroviruses are associated with human autoimmune disorders and neurodegenerative diseases. Caenorhabditis elegans and related Caenorhabditis spp. contain LTR retrotransposons and, as described here, numerous integrated viral genes including viral envelope genes that are part of LTR retrotransposons. We found that both LTR retrotransposons and endogenous viral elements are silenced by ADARs [adenosine deaminases acting on double-stranded RNA (dsRNA)] together with the endogenous RNA interference (RNAi) factor ERI-6/7, a homolog of MOV10 helicase, a retrotransposon and retrovirus restriction factor in human. siRNAs corresponding to integrated viral genes and LTR retrotransposons, but not to DNA transposons, are dependent on the ADARs and ERI-6/7. siRNAs corresponding to palindromic repeats are independent of the ADARs and ERI-6/7, and are in fact increased in adar- and eri-6/7-defective mutants because of an antiviral RNAi response to dsRNA. Silencing of LTR retrotransposons is dependent on downstream RNAi factors and P granule components but is independent of the viral sensor DRH-1/RIG-I and the nuclear Argonaute NRDE-3. The activation of retrotransposons in the ADAR- and ERI-6/7/MOV10-defective mutant is associated with the induction of the unfolded protein response (UPR), a common response to viral infection. The overlap between genes induced upon viral infection and infection with intracellular pathogens and genes coexpressed with retrotransposons suggests that there is a common response to different types of foreign elements that includes a response to proteotoxicity presumably caused by the burden of replicating pathogens and expressed retrotransposons. Copyright © 2020 the Author(s). Published by PNAS.Vibrational modes in mechanical resonators provide a promising candidate to interface and manipulate classical and quantum information. The observation of coherent dynamics between distant mechanical resonators can be a key step toward scalable phonon-based applications. Here we report tunable coherent phonon dynamics with an architecture comprising three graphene mechanical resonators coupled in series, where all resonators can be manipulated by electrical signals on control gates. We demonstrate coherent Rabi oscillations between spatially separated resonators indirectly coupled via an intermediate resonator serving as a phonon cavity. The Rabi frequency fits well with the microwave burst power on the control gate. We also observe Ramsey interference, where the oscillation frequency corresponds to the indirect coupling strength between these resonators. https://www.selleckchem.com/ Such coherent processes indicate that information encoded in vibrational modes can be transferred and stored between spatially separated resonators, which can open the venue of on-demand phonon-based information processing.The ability to recall a detailed event from a simple reminder is supported by pattern completion, a cognitive operation performed by the hippocampus wherein existing mnemonic representations are retrieved from incomplete input. In behavioral studies, pattern completion is often inferred through the false endorsement of lure (i.e., similar) items as old. However, evidence that such a response is due to the specific retrieval of a similar, previously encoded item is severely lacking. We used eye movement (EM) monitoring during a partial-cue recognition memory task to index reinstatement of lure images behaviorally via the recapitulation of encoding-related EMs or gaze reinstatement. Participants reinstated encoding-related EMs following degraded retrieval cues and this reinstatement was negatively correlated with accuracy for lure images, suggesting that retrieval of existing representations (i.e., pattern completion) underlies lure false alarms. Our findings provide evidence linking gaze reinstatement and pattern completion and advance a functional role for EMs in memory retrieval.The nervous system evaluates environmental cues and adjusts motor output to ensure navigation toward a preferred environment. The nematode Caenorhabditis elegans navigates in the thermal environment and migrates toward its cultivation temperature by moving up or down thermal gradients depending not only on absolute temperature but on relative difference between current and previously experienced cultivation temperature. Although previous studies showed that such thermal context-dependent opposing migration is mediated by bias in frequency and direction of reorientation behavior, the complete neural pathways-from sensory to motor neurons-and their circuit logics underlying the opposing behavioral bias remain elusive. By conducting comprehensive cell ablation, high-resolution behavioral analyses, and computational modeling, we identified multiple neural pathways regulating behavioral components important for thermotaxis, and demonstrate that distinct sets of neurons are required for opposing bias of even single behavioral components. Furthermore, our imaging analyses show that the context-dependent operation is evident in sensory neurons, very early in the neural pathway, and manifested by bidirectional responses of a first-layer interneuron AIB under different thermal contexts. Our results suggest that the contextual differences are encoded among sensory neurons and a first-layer interneuron, processed among different downstream neurons, and lead to the flexible execution of context-dependent behavior. Copyright © 2020 the Author(s). Published by PNAS.Targeted degradation approaches such as proteolysis targeting chimeras (PROTACs) offer new ways to address disease through tackling challenging targets and with greater potency, efficacy, and specificity over traditional approaches. However, identification of high-affinity ligands to serve as PROTAC starting points remains challenging. As a complementary approach, we describe a class of molecules termed biological PROTACs (bioPROTACs)-engineered intracellular proteins consisting of a target-binding domain directly fused to an E3 ubiquitin ligase. Using GFP-tagged proteins as model substrates, we show that there is considerable flexibility in both the choice of substrate binders (binding positions, scaffold-class) and the E3 ligases. We then identified a highly effective bioPROTAC against an oncology target, proliferating cell nuclear antigen (PCNA) to elicit rapid and robust PCNA degradation and associated effects on DNA synthesis and cell cycle progression. Overall, bioPROTACs are powerful tools for interrogating degradation approaches, target biology, and potentially for making therapeutic impacts.The CRISPR-Cas9 nuclease has been widely repurposed as a molecular and cell biology tool for its ability to programmably target and cleave DNA. Cas9 recognizes its target site by unwinding the DNA double helix and hybridizing a 20-nucleotide section of its associated guide RNA to one DNA strand, forming an R-loop structure. A dynamic and mechanical description of R-loop formation is needed to understand the biophysics of target searching and develop rational approaches for mitigating off-target activity while accounting for the influence of torsional strain in the genome. Here we investigate the dynamics of Cas9 R-loop formation and collapse using rotor bead tracking (RBT), a single-molecule technique that can simultaneously monitor DNA unwinding with base-pair resolution and binding of fluorescently labeled macromolecules in real time. By measuring changes in torque upon unwinding of the double helix, we find that R-loop formation and collapse proceed via a transient discrete intermediate, consistent with DNARNA hybridization within an initial seed region. Using systematic measurements of target and off-target sequences under controlled mechanical perturbations, we characterize position-dependent effects of sequence mismatches and show how DNA supercoiling modulates the energy landscape of R-loop formation and dictates access to states competent for stable binding and cleavage. Consistent with this energy landscape model, in bulk experiments we observe promiscuous cleavage under physiological negative supercoiling. The detailed description of DNA interrogation presented here suggests strategies for improving the specificity and kinetics of Cas9 as a genome engineering tool and may inspire expanded applications that exploit sensitivity to DNA supercoiling.
