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
Abstract:
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.
Cara L. Buck; Jonathan D. Cohen; Field, Brent; Daniel Kahneman; Samuel M. McClure; Leigh E. Nystrom
Abstract:
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
Abstract:
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.
Martin, Nicholas R; Blackman, Edith; Bratton, Benjamin P; Chase, Katelyn J; Bartlett, Thomas M; Gitai, Zemer
Abstract:
Bacterial species have diverse cell shapes that enable motility, colonization, and virulence. The cell wall defines bacterial shape and is primarily built by two cytoskeleton-guided synthesis machines, the elongasome and the divisome. However, the mechanisms producing complex shapes, like the curved-rod shape of Vibrio cholerae, are incompletely defined. Previous studies have reported that species-specific regulation of cytoskeleton-guided machines enables formation of complex bacterial shapes such as cell curvature and cellular appendages. In contrast, we report that CrvA and CrvB are sufficient to induce complex cell shape autonomously of the cytoskeleton in V. cholerae. The autonomy of the CrvAB module also enables it to induce curvature in the Gram-negative species Escherichia coli, Pseudomonas aeruginosa, Caulobacter crescentus, and Agrobacterium tumefaciens. Using inducible gene expression, quantitative microscopy, and biochemistry we show that CrvA and CrvB circumvent the need for patterning via cytoskeletal elements by regulating each other to form an asymmetrically-localized, periplasmic structure that directly binds to the cell wall. The assembly and disassembly of this periplasmic structure enables dynamic changes in cell shape. Bioinformatics indicate that CrvA and CrvB may have diverged from a single ancestral hybrid protein. Using fusion experiments in V. cholerae, we find that a synthetic CrvA/B hybrid protein is sufficient to induce curvature on its own, but that expression of two distinct proteins, CrvA and CrvB, promotes more rapid curvature induction. We conclude that morphological complexity can arise independently of cell shape specification by the core cytoskeleton-guided synthesis machines.
Physical and biogeochemical variables from the NOAA-GFDL Earth System Model 2M experiments (pre-processed), previously published observation-based datasets, and code to reproduce figures from these datasets, used for the study 'Hydrological cycle amplification reshapes warming-driven oxygen loss in Atlantic Ocean'.
Microscopy images are part of a paper entitled "Structured foraging of soil predators unveils functional responses to bacterial defenses" by Fernando Rossine, Gabriel Vercelli, Corina Tarnita, and Thomas Gregor. For detailed acquisition methods see the paper. Experiments were performed between 2019 and 2020 at Princeton University. Two types of images are provided, macroscopic and microscopic widefiled Images. Macroscopic images all show Petri dishes covered in fluorescent bacteria being consumed by amoebae. Images are shown for D. discoideum, P. violaceum, and A. castellanii. Images depicting drug treatments (Nystatin and Fluorouracil) were obtained using D. discoideum. Images used for the creation of a profile were all taken within 30 minutes of each other. Within each directory numbered images are independent replicates. The raw video directory contains time series for dishes under drug treatments. Each numbered folder is a sequence of photos (taken 30 minutes apart of each other) of a single dish. Microscopic images all show amoebae consuming bacteria on a petri dish. The 45 minute videos show either edge cells (located at the edge of amoebae colonies), or inner cells (located 2.5 millimeters towards the center of the colony, from the edge). Videos are confocal stacks, with bacteria showing in green and amoebae appearing as black holes within the bacterial lawn. As was for the macroscopic images, images are shown for D. discoideum, P. violaceum, and A. castellanii. Images depicting drug treatments (Nystatin and Fluorouracil) were obtained using D. discoideum.
