Martin, James K; Sheehan, Joseph P; Bratton, Benjamin P; Moore, Gabriel M; Mateus, André; Li, Sophia Hsin-Jung; Kim, Hahn; Rabinowitz, Joshua D; Typas, Athanasios; Savitski, Mikhail M; Wilson, Maxwell Z; Gitai, Zemer
The rise of antibiotic resistance and declining discovery of new antibiotics have created a global health crisis. Of particular concern, no new antibiotic classes have been approved for treating Gram-negative pathogens in decades. Here, we characterize a compound, SCH-79797, that kills both Gram-negative and Gram-positive bacteria through a unique dual-targeting mechanism of action (MoA) with undetectably-low resistance frequencies. To characterize its MoA, we combined quantitative imaging, proteomic, genetic, metabolomic, and cell-based assays. This pipeline demonstrates that SCH-79797 has two independent cellular targets, folate metabolism and bacterial membrane integrity, and outperforms combination treatments in killing MRSA persisters. Building on the molecular core of SCH-79797, we developed a derivative, Irresistin-16, with increased potency and showed its efficacy against Neisseria gonorrheae in a mouse vaginal infection model. This promising antibiotic lead suggests that combining multiple MoAs onto a single chemical scaffold may be an underappreciated approach to targeting challenging bacterial pathogens.
It is well known that formation of new episodic memories depends on hippocampus, but in real-life settings (e.g., conversation), hippocampal amnesics can utilize information from several minutes earlier. What neural systems outside hippocampus might support this minutes-long retention? In this study, subjects viewed an audiovisual movie continuously for 25 min; another group viewed the movie in 2 parts separated by a 1-day delay. Understanding Part 2 depended on retrieving information from Part 1, and thus hippocampus was required in the day-delay condition. But is hippocampus equally recruited to access the same information from minutes earlier? We show that accessing memories from a few minutes prior elicited less interaction between hippocampus and default mode network (DMN) cortical regions than accessing day-old memories of identical events, suggesting that recent information was available with less reliance on hippocampal retrieval. Moreover, the 2 groups evinced
reliable but distinct DMN activity timecourses, reflecting differences in information carried in these regions when Part 1 was recent versus distant. The timecourses converged after 4 min, suggesting a time frame over which the continuous-viewing group may have relied less on hippocampal retrieval. We propose that cortical default mode regions can intrinsically retain real-life episodic information for several minutes.
Small changes in word choice can lead to dramatically different interpretations of narratives. How does the brain accumulate and integrate such local changes to construct unique neural representations for different stories? In this study we created two distinct narratives by changing only a few words in each sentence (e.g. “he” to “she” or “sobbing” to “laughing”) while preserving the grammatical structure across stories. We then measured changes in neural responses between the two stories. We found that the differences in neural responses between the two stories gradually increased along the hierarchy of processing timescales. For areas with short integration windows, such as early auditory cortex, the differences in neural responses between the two stories were relatively small. In contrast, in areas with the longest integration windows at the top of the hierarchy, such as the precuneus, temporal parietal junction, and medial frontal cortices, there were large differences in neural responses between stories. Furthermore, this gradual increase in neural difference between the stories was highly correlated with an area’s ability to integrate information over time. Amplification of neural differences did not occur when changes in words did not alter the interpretation of the story (e.g. “sobbing” to “crying”). Our results demonstrate how subtle differences in words are gradually accumulated and amplified along the cortical hierarchy as the brain constructs a narrative over time.
The Magnetospheric Multiscale (MMS) mission has given us unprecedented access to high cadence particle and field data of magnetic reconnection at Earth's magnetopause. MMS first passed very near an X-line on 16 October 2015, the Burch event, and has since observed multiple X-line crossings. Subsequent 3D particle-in-cell (PIC) modeling efforts of and comparison with the Burch event have revealed a host of novel physical insights concerning magnetic reconnection, turbulence induced particle mixing, and secondary instabilities. In this study, we employ the Gkeyll simulation framework to study the Burch event with different classes of extended, multi-fluid magnetohydrodynamics (MHD), including models that incorporate important kinetic effects, such as the electron pressure tensor, with physics-based closure relations designed to capture linear Landau damping. Such fluid modeling approaches are able to capture different levels of kinetic physics in global simulations and are generally less costly than fully kinetic PIC. We focus on the additional physics one can capture with increasing levels of fluid closure refinement via comparison with MMS data and existing PIC simulations. In particular, we find that the ten-moment model well captures the agyrotropic structure of the pressure tensor in the vicinity of the X-line and the magnitude of anisotropic electron heating observed in MMS and PIC simulations. However, the ten-moment model has difficulty resolving the lower hybrid drift instability, which has been observed to plays a fundamental role in heating and mixing electrons in the current layer.
Wilterson, Andrew; Nastase, Samuel; Bio, Branden; Guterstam, Arvid; Graziano, Michael
The attention schema theory (AST) posits a specific relationship between subjective awareness and attention, in which awareness is the control model that the brain uses to aid in the endogenous control of attention. We proposed that the right temporoparietal junction (TPJ) is involved in that interaction between awareness and attention. In previous experiments, we developed a behavioral paradigm in human subjects to manipulate awareness and attention. The paradigm involved a visual cue that could be used to guide a shift of attention to a target stimulus. In task 1, subjects were aware of the visual cue, and their endogenous control mechanism was able to use the cue to help control attention. In task 2, subjects were unaware of the visual cue, and their endogenous control mechanism was no longer able to use it to control attention, even though the cue still had a measurable effect on other aspects of behavior. Here we tested the two tasks while scanning brain activity in human volunteers. We predicted that the right TPJ would be active in relation to the cue in task 1, but not in task 2. This prediction was confirmed. The right TPJ was active in relation to the cue in task 1; it was not measurably active in task 2; the difference was significant. In our interpretation, the right TPJ is involved in a complex interaction in which awareness aids in the control of attention.
Cara L. Buck; Jonathan D. Cohen; Field, Brent; Daniel Kahneman; Samuel M. McClure; Leigh E. Nystrom
Studies of subjective well-being have conventionally relied upon self-report, which directs subjects’ attention to their emotional experiences. This method presumes that attention itself does not influence emotional processes, which could bias sampling. We tested whether attention influences experienced utility (the moment-by-moment experience of pleasure) by using functional magnetic resonance imaging (fMRI) to measure the activity of brain systems thought to represent hedonic value while manipulating attentional load. Subjects received appetitive or aversive solutions orally while alternatively executing a low or high attentional load task. Brain regions associated with hedonic processing, including the ventral striatum, showed a response to both juice and quinine. This response decreased during the high-load task relative to the low-load task. Thus, attentional allocation may influence experienced utility by modulating (either directly or indirectly) the activity of brain mechanisms thought to represent hedonic value.
Mondal, Shanka Subhra; Webb, Taylor; Cohen, Jonathan
A dataset of Raven’s Progressive Matrices (RPM)-like problems using realistically rendered
3D shapes, based on source code from CLEVR (a popular visual-question-answering dataset) (Johnson, J., Hariharan, B., Van Der Maaten, L., Fei-Fei, L., Lawrence Zitnick, C., & Girshick, R. (2017). Clevr: A diagnostic dataset for compositional language and elementary visual reasoning. In Proceedings of the IEEE conference on computer vision and pattern recognition (pp. 2901-2910)).
Explosive volcanic eruptions have large climate impacts, and can serve as observable tests of the climatic response to radiative forcing. Using a high resolution climate model, we contrast the climate responses to Pinatubo, with symmetric forcing, and those to Santa Maria and Agung, which had meridionally asymmetric forcing. Although Pinatubo had larger global-mean forcing, asymmetric forcing strongly shifts the latitude of tropical rainfall features, leading to larger local precipitation/TC changes. For example, North Atlantic TC activity over is enhanced/reduced by SH-forcing (Agung)/NH-forcing (Santa Maria), but changes little in response to the Pinatubo forcing. Moreover, the transient climate sensitivity estimated from the response to Santa Maria is 20% larger than that from Pinatubo or Agung. This spread in climatic impacts of volcanoes needs to be considered when evaluating the role of volcanoes in global and regional climate, and serves to contextualize the well-observed response to Pinatubo.
Severe acute respiratory coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, is of zoonotic origin. Evolutionary analyses assessing whether coronaviruses similar to SARS-CoV-2 infected ancestral species of modern-day animal hosts could be useful in identifying additional reservoirs of potentially dangerous coronaviruses. We reasoned that if a clade of species has been repeatedly exposed to a virus, then their proteins relevant for viral entry may exhibit adaptations that affect host susceptibility or response. We perform comparative analyses across the mammalian phylogeny of angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2, in order to uncover evidence for selection acting at its binding interface with the SARS-CoV-2 spike protein. We uncover that in rodents there is evidence for adaptive amino acid substitutions at positions comprising the ACE2-spike interaction interface, whereas the variation within ACE2 proteins in primates and some other mammalian clades is not consistent with evolutionary adaptations. We also analyze aminopeptidase N (APN), the receptor for the human coronavirus 229E, a virus that causes the common cold, and find evidence for adaptation in primates. Altogether, our results suggest that the rodent and primate lineages may have had ancient exposures to viruses similar to SARS-CoV-2 and HCoV-229E, respectively. Included in this repository are the instructions and corresponding code required to build the dataset and run the analysis in the manuscript.