OConnor, A. M. | Search bioRxiv

bioRxiv2020

Intestinal progenitor P-bodies maintain stem cell identity by suppressing pro-differentiation factors.

The role of Processing bodies (P-bodies), key sites of post-transcriptional control, in adult stem cells remains poorly understood. Here, we report that adult Drosophila intestinal stem cells, but not surrounding differentiated cells such as absorptive Enterocytes (ECs), harbor P-bodies that contain Drosophila orthologs of mammalian P-body components DDX6, EDC3, EDC4 and LSM14A/B. A targeted RNAi screen in intestinal progenitor cells identified 39 previously known and 64 novel P-body regulators, including Patr-1, a gene necessary for P-body assembly. Loss of Patr-1-dependent P-bodies leads to a loss of stem cells that is associated with inappropriate translation and expression of EC-fate gene nubbin. Transcriptomic analysis of progenitor cells identifies a cadre of such weakly transcribed pro-differentiation transcripts that are elevated after P-body loss. Altogether, this study identifies a coordinated P-body dependent, translational and transcriptional repression program that maintains a defined set of in vivo stem cells in a state primed for differentiation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/175398v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@d57273org.highwire.dtl.DTLVardef@14d057aorg.highwire.dtl.DTLVardef@1a2c4a5org.highwire.dtl.DTLVardef@11c5ba3_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDrosophila intestinal progenitor cells contain constitutive and ultrastructurally organized P-bodies. C_LIO_LIA P-body regulator Patr-1 is required for intestinal progenitor cell maintenance. C_LIO_LIEnterocyte (EC) genes such as nubbin are weakly transcribed but not translated in intestinal progenitors. C_LIO_LIP-bodies repress EC gene translation to promote stem cell maintenance. C_LI

cell biology↗

bioRxiv2019

Switching between bacteriostatic and bactericidal antimicrobials for retreatment of bovine respiratory disease (BRD) relapses is associated with an increased frequency of resistant pathogen isolation from veterinary diagnostic laboratory submissions

Although 90% of BRD relapses are reported to receive retreatment with a different class of antimicrobial, studies examining the impact of antimicrobial selection (i.e. bactericidal or bacteriostatic) on retreatment outcomes and the emergence of antimicrobial resistance (AMR) are deficient in the published literature. A survey was conducted to determine the association between antimicrobial class selection for retreatment of BRD relapses on antimicrobial susceptibility of Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni. Pathogens were isolated from samples submitted to the Iowa State University Veterinary Diagnostic Laboratory from January 2013 to December 2015. A total of 781 isolates with corresponding animal case histories, including treatment protocols, were included in the analysis. Original susceptibility testing of these isolates for ceftiofur, danofloxacin, enrofloxacin, florfenicol, oxytetracycline, spectinomycin, tilmicosin, and tulathromycin was performed using Clinical and Laboratory Standards Institute guidelines. Data were analyzed using a Bayesian approach to evaluate whether retreatment with antimicrobials of different mechanistic classes (bactericidal or bacteriostatic) increased the probability of resistant BRD pathogen isolation in calves. The posterior distribution we calculated suggests that an increased number of treatments is associated with a greater probability of isolates resistant to at least one antimicrobial. In addition, the frequency of resistant M. haemolytica isolates was greater with retreatment using antimicrobials of different mechanistic classes than retreatment with the same class. Specifically, treatment protocols using a bacteriostatic drug first followed by retreatment with a bactericidal drug was associated with a higher frequency of resistant BRD pathogen isolation. This effect was more profound with specific treatment combinations; tulathromycin (bacteriostatic) followed by ceftiofur (bactericidal) was associated with the highest probability of resistant isolates among all antimicrobial combinations. These findings suggest that the selection of antimicrobial mechanistic class for retreatment of BRD should be considered as part of an antimicrobial stewardship program.

microbiology↗