Propionic acid promotes the virulent phenotype of Crohn's disease-associated adherent-invasive Escherichia coli

Propionic acid (PA) is a bacterium-derived intestinal antimicrobial and immune modulator used widely in food production and agriculture. Passage of Crohn’s disease-associated adherent-invasive Escherichia coli (AIEC) through a murine model, in which intestinal PA levels are increased to mimic the human intestine, leads to the recovery of AIEC with significantly increased virulence. Similar phenotypic changes are observed outside the murine model when AIEC is grown in culture with PA as the sole carbon source; such PA exposure also results in AIEC that persists at 20-fold higher levels in vivo. RNA sequencing identifies an upregulation of genes involved in biofilm formation, stress response, metabolism, membrane integrity, and alternative carbon source utilization. PA exposure also increases virulence in a number of E. coli isolates from Crohn’s disease patients. Removal of PA is sufficient to reverse these phenotypic changes. Our data indicate that exposure to PA results in AIEC resistance and increased virulence in its presence

Propionic Acid Promotes the Virulent Phenotype of Crohn’s Disease-Associated Adherent-Invasive Escherichia coli

The short chain fatty acid propionic acid is a bacterium-derived human intestinal antimicrobial and immune modulator used widely in Western food production and agriculture. Here, Ormsby et al. demonstrate that exposure to propionic acid induces virulence-associated phenotypic changes in Crohn's disease-associated adherent-invasive Escherichia coli (AIEC)

Senior Thesis Proposal

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Mutual Entrainment Within the Human Body

How do pacemaker cells of the heart all fire action potentials simultaneously to produce a regular rhythm in the heartbeat? Why do neurons in the brain spontaneously begin to fire in the same period causing a dangerous malfunction? How does your body know what time of the day to feel hungry, tired, or sleepy? Synchronization, a phenomenon found in nearly all entities of the universe, across vastly varying orders of magnitude, governs many of the processes that allow for the existence of homeostasis. The phenomenon allows for individual parts in a system to operate in unison. When in sync, these individual parts are known as coupled oscillators, which are entities that repeat themselves in an automatic cycle at regular time intervals, influencing one another through a chemical or physical process. The syncing of two independent systems, specifically referring to the human body, is termed entrainment. This thesis explores how the phenomenon of synchronization plays a part in pacemaker cells, seizures, and the circadian rhythm

The SAS Gamma-Ray Spectrometer

A new type of compact high resolution high sensitivity gamma ray spectrometer for short pulse intense 250 keV to 50 MeV gamma rays has been developed by combining the principles of scintillators and attenuation spectrometers. The first prototype of this scintillator attenuation spectrometer or SAS was tested successfully in Trident laser experiments at LANL. Later versions have been used extensively in the Texas Petawatt laser experiments in Austin TX, and more recently in OMEGAEP laser experiments at LLE, Rochester, NY. The SAS is particularly useful for high repetition rate laser applications. Here we give a concise description of the design principles, capabilities and sample preliminary results of the SAS.Comment: Revised version of paper for submission to the Review of Scientific Instruments. New version has 13 pages and 12 figure

Evaluation of Candidate Theranostics for²²⁷Th/⁸⁹Zr Paired Radioimmunotherapy of Lymphoma

International audienceTh is a promising radioisotope for targeted a-particle therapy. It produces 5 a-particles through its decay, with the clinically approved 223 Ra as its first daughter. There is an ample supply of 227 Th, allowing for clinical use; however, the chemical challenges of chelating this large tetravalent f-block cation are considerable. Using the CD20-targeting antibody ofatumumab, we evaluated chelation of 227 Th 41 for a-particle-emitting and radiotheranostic applications. Methods: We compared 4 bifunctional chelators for thorium radiopharmaceutical preparation: S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 2-(4-isothicyanatobenzyl)-1,2,7,10,13-hexaazacyclooctadecane-1,4,7,10,13,16-hexaacetic acid (p-SCN-Bn-HEHA), p-isothiacyanatophenyl-1-hydroxy-2-oxopiperidine-desferrioxamine (DFOcyclo*-p-Phe-NCS), and macrocyclic 1,2-HOPO N-hydroxysuccinimide (L804-NHS). Immunoconstructs were evaluated for yield, purity, and stability in vitro and in vivo. Tumor targeting of the lead 227 Thlabeled compound in vivo was performed in CD20-expressing models and compared with a companion 89 Zr-labeled PET agent. Results: 227 Th-labeled ofatumumab-chelator constructs were synthesized to a radiochemical purity of more than 95%, excepting HEHA. 227 Th-HEHAofatumumab showed moderate in vitro stability. 227 Th-DFOcyclo*-ofatumumab presented excellent 227 Th labeling efficiency; however, high liver and spleen uptake was revealed in vivo, indicative of aggregation. 227 Th-DOTA-ofatumumab labeled poorly, yielding no more than 5%, with low specific activity (0.08 GBq/g) and modest long-term in vitro stability (,80%). 227 Th-L804-ofatumumab coordinated 227 Th rapidly and efficiently at high yields, purity, and specific activity (8 GBq/g) and demonstrated extended stability. In vivo tumor targeting confirmed the utility of this chelator, and the diagnostic analog, 89 Zr-L804-ofatumumab, showed organ distribution matching that of 227 Th to delineate SU-DHL-6 tumors. Conclusion: Commercially available and novel chelators for 227 Th showed a range of performances. The L804 chelator can be used with potent radiotheranostic capabilities for 89 Zr/ 227 Th quantitative imaging and a-particle therapy

High Resolution Model Intercomparison Project phase 2 (HighResMIP2) towards CMIP7

Robust projections and predictions of climate variability and change, particularly at regional scales, rely on the driving processes being represented with fidelity in model simulations. Consequently, the role of enhanced horizontal resolution in improved process representation in all components of the climate system continues to be of great interest. Recent simulations suggest both the possibility of significant changes in large-scale aspects of the ocean and atmospheric circulations and the regional responses to climate change, as well as improvements in representations of small-scale processes and extremes, when resolution is enhanced. The first phase of HighResMIP (HighResMIP1) was successful in producing a baseline multi-model assessment of global simulations with model grid spacings of 25–50 km in the atmosphere and 10–25 km in the ocean, a significant increase when compared to models with standard resolutions of order 1-degree typically used as part of the Coupled Model Intercomparison Project (CMIP) experiments. In addition to over 250 peer-reviewed manuscripts using the published HighResMIP1 datasets, the results were widely cited in the Intergovernmental Panel on Climate Change report and were the basis for a variety of derived datasets, including tracked cyclones (both tropical and extratropical), river discharge, storm surge, and others that were used for impact studies. There were also suggestions from the few ocean eddy-rich coupled simulations that aspects of climate variability and change might be significantly influenced by improved process representation in such models. The compromises that HighResMIP1 made should now be revisited, given the recent major advances in modelling and computing resources. Aspects that will be reconsidered include experimental design and simulation length, complexity, and resolution. In addition, larger ensemble sizes and a wider range of future scenarios would enhance the applicability of HighResMIP. Therefore, we propose an updated HighResMIP2 to improve and extend the previous work, to address new science questions, and to further advance our understanding of the role of horizontal resolution (and hence process representation) in state-of-the-art climate simulations. With further increases in high-performance computing resources and modelling advances along with the ability to take full advantage of these computational resources, an enhanced investigation of the drivers and consequences of variability and change in both large- and synoptic-scale weather and climate is now made possible. With the arrival of global cloud-resolving models (currently run for relatively short timescales), there is also an opportunity to improve links between such models and more traditional CMIP models, with HighResMIP providing a bridge to link understanding between these domains. HighResMIP also aims to link to other CMIP projects and international efforts such as the World Climate Research Program lighthouse activities and various Digital Twin initiatives, as well as having the potential to be used as training and validation data for the fast evolving Machine Learning climate models