ing of skeletal muscle regeneration through the identification of Fbxl2 as both a critical regulator of myogenic proliferative processes and a susceptible gene target during inflammatory stimulation by TNFα in skeletal muscle. Modulation of Fbxl2 activity may have relevance to disorders of muscle wasting associated with sustained pro-inflammatory signaling. Copyright © 2020 American Society for Microbiology.Defects in the spindle assembly checkpoint (SAC) can lead to aneuploidy and cancer. Sphingolipids have important roles in many cellular functions including cell cycle regulation and apoptosis. However, defining specific mechanisms and functions of sphingolipids in cell cycle regulation is missing. Using analysis of concordance for synthetic lethality for the yeast sphingolipid phospholipase ISC1, we identified two groups of genes The first comprises genes involved in chromosome segregation and stability (CSM3, CTF4, YKE2, DCC1, GIM4) as synthetically lethal with ISC1 The second group, to which ISC1 belongs, comprises genes involved in the spindle checkpoint (BUB1, MAD1, BIM1, KAR3), and they all share the same synthetic lethality with the first group. We demonstrate that spindle checkpoint genes act upstream of Isc1, and their deletion phenocopies that of ISC1. Reciprocally, ISC1 deletion mutants were sensitive to Benomyl, indicating a SAC defect. Similar to BUB1 deletion, ISC1 deletion prevents spindle elongation in hydroxyurea treated cells. Mechanistically, PP2A-Cdc55 ceramide-activated phosphatase was found to act downstream of Isc1, thus, coupling the spindle checkpoint genes and Isc1 to CDC55-mediated nuclear functions. Copyright © 2020 American Society for Microbiology.Maintenance of protein homeostasis in eukaryotes during normal growth and stress conditions requires the functions of Hsp70 chaperones and associated co-chaperones. Here we investigate an evolutionarily-conserved serine phosphorylation that occurs at the site of communication between the nucleotide-binding and substrate-binding domains of Hsp70. Ser151 phosphorylation in yeast Hsp70 (Ssa1) is promoted by cyclin-dependent kinase (Cdk1) during normal growth. Phospho-mimic substitutions at this site (S151D) dramatically down-regulate heat shock responses, a result conserved with HSC70 S153 in human cells. Phospho-mimic forms of Ssa1 also fail to relocalize in response to starvation conditions, do not associate in vivo with Hsp40 co-chaperones, Ydj1 and Sis1, and do not catalyze refolding of denatured proteins in vitro in cooperation with Ydj1 and Hsp104. Despite these negative effects on HSC70/HSP70 function, the S151D phospho-mimic allele promotes survival of heavy metal exposure and suppresses the Sup35-dependent [PSI+ ] prion phenotype, consistent with proposed roles for Ssa1 and Hsp104 in generating self-nucleating seeds of misfolded proteins. Taken together, these results suggest that Cdk1 can downregulate Hsp70 function through phosphorylation of this site, with potential costs to overall chaperone efficiency but also advantages with respect to reduction of metal-induced and prion-dependent protein aggregate production. Copyright © 2020 American Society for Microbiology.Sepsis remains to be medically challenging with high morbidities and mortalities. A novel intervention is urgently needed in the absence of specific, targeted therapy. Neutrophils act as double-edged swords in sepsis; they can help to eradicate microbes, while contributing to tissue injury. β2 integrins are critical adhesion molecules regulating a number of neutrophil functions. β2 integrins consist of four members αLβ2, αMβ2, αXβ2 and αDβ2. Here we review the role of each β2 integrin in neutrophils and sepsis and consider future direction for therapeutic intervention. Copyright © 2020 American Society for Microbiology.Clostridioides difficile infection (CDI) is associated with increasing morbidity and mortality posing an urgent threat to public health. Recurrence of CDI after successful treatment with antibiotics is high, thus necessitating discovery of novel therapeutics against this enteric pathogen. Administration of the secondary bile acid ursodeoxycholic acid (UDCA, ursodiol) inhibits the life cycle of various strains of C. difficile in vitro, suggesting the FDA approved formulation of UDCA, known as ursodiol, may be able to restore colonization resistance against C. difficile in vivo However, the mechanism(s) by which ursodiol is able to restore colonization resistance against C. difficile remains unknown. Here, we confirmed that ursodiol inhibits C. difficile R20291 spore germination and outgrowth, growth, and toxin activity in a dose dependent manner in vitro In a murine model of CDI, exogenous administration of ursodiol resulted in significant alterations in the bile acid metabolome with little to no changes in gut microbial community structure. Ursodiol pretreatment resulted in attenuation of CDI pathogenesis early in the course of disease, which coincided with alterations in the cecal and colonic inflammatory transcriptome, bile acid activated receptors nuclear farnesoid X receptor (FXR), and transmembrane G protein-coupled membrane receptor 5 (TGR5), which are able to modulate the innate immune response through signaling pathways such as NF-κB. Although ursodiol pretreatment did not result in a consistent decrease in the C. difficile life cycle in vivo, it was able to attenuate an overly robust inflammatory response that is detrimental to the host during CDI. Ursodiol remains a viable non-antibiotic treatment and/or prevention strategy against CDI. Likewise, modulation of the host innate immune response via bile acid activated receptors, FXR and TGR5, represents a new potential treatment strategy for patients with CDI. Copyright © 2020 American Society for Microbiology.The zoonotic bacterial pathogen Coxiella burnetii is the causative agent of Q fever, a febrile illness which can cause a serious chronic infection. C. burnetii is a unique intracellular bacterium which replicates within host lysosome-derived vacuoles.  https://www.selleckchem.com/products/ve-822.html  The ability of C. burnetii to replicate within this normally hostile compartment is dependent on the activity of the Dot/Icm type 4B secretion system. In a previous study, a transposon mutagenesis screen suggested that disruption of the gene encoding the novel protein CBU2072 rendered C. burnetii incapable of intracellular replication. This protein, subsequently named EirA (Essential for intracellular replication A), is indispensable for intracellular replication and virulence, as demonstrated by infection of human cell lines, and in vivo infection of Galleria mellonella The putative N-terminal signal peptide is essential for protein function but is not required for localization of EirA to the bacterial inner membrane compartment and axenic culture supernatant. In the absence of EirA, C.