Early embryos of some metazoans polarize radially to facilitate critical patterning events such as gastrulation and asymmetric cell division; however, little is known about how radial polarity is established. C. elegans early embryos polarize radially when cell contacts restrict the polarity protein PAR-6 to contact-free cell surfaces, where PAR-6 regulates gastrulation movements. Here, we identify a Rho GTPase activating protein (RhoGAP), PAC-1, which mediates C. elegans radial polarity and gastrulation by excluding PAR-6 from contacted cell surfaces. We show that PAC-1 is recruited to cell contacts, and we suggest that PAC-1 controls radial polarity by restricting active CDC-42 to contact-free surfaces, where CDC-42 binds and recruits PAR-6. Thus, PAC-1 provides a dynamic molecular link between cell contacts and PAR proteins that polarizes embryos radially.
Many genes that affect axon pathfinding and cell migration have been identified. Mechanisms by which these genes and the molecules they encode interact with one another in pathways and networks to control developmental events are unclear. Rac GTPases, the cytoskeletal signaling molecule Enabled, and NIK kinase have all been implicated in regulating axon pathfinding and cell migration. Here we present evidence that, in Caenorhabditis elegans, three Rac GTPases, CED-10, RAC-2, and MIG-2, define three redundant pathways that each control axon pathfinding, and that the NIK kinase MIG-15 acts in each Rac pathway. Furthermore, we show that the Enabled molecule UNC-34 defines a fourth partially redundant pathway that acts in parallel to Rac/MIG-15 signaling in axon pathfinding. Enabled and the three Racs also act redundantly to mediate AQR and PQR neuronal cell migration. The Racs and UNC-34 Ena might all control the formation of actin-based protrusive structures (lamellipodia and filopodia) that mediate growth cone outgrowth and cell migration. MIG-15 does not act with the three Racs in execution of cell migration. Rather, MIG-15 affects direction of PQR neuronal migration, similar to UNC-40 and DPY-19, which control initial Q cell polarity, and Wnt signaling, which acts later to control Q cell-directed migration. MIG-2 Rac, which acts with CED-10 Rac, RAC-2 Rac, and UNC-34 Ena in axon pathfinding and cell migration, also acts with MIG-15 in PQR directional migration.
Antimicrobial peptides act as a host defense mechanism and regulate the commensal microbiome. To obtain a comprehensive view of genes contributing to long-term memory we performed mRNA sequencing from single Drosophila heads following behavioral training that produces long-lasting memory. Surprisingly, we found that Diptericin B, an immune peptide with antimicrobial activity, is upregulated following behavioral training. Deletion and knock down experiments revealed that Diptericin B and another immune peptide, Gram-Negative Bacteria Binding Protein like 3, regulate long-term but not short-term memory or instinctive behavior in Drosophila. Interestingly, removal of DptB in the head fat body and GNBP-like3 in neurons results in memory deficit. That putative antimicrobial peptides influence memory provides an example of how some immune peptides may have been repurposed to influence the function of nervous system.
Myriad experiences produce transient memory, yet, contingent on the internal state of the organism and the saliency of the experience, only some memories persist over time. How experience and internal state influence the duration of memory at the molecular level remains unknown. A self-assembled aggregated state of Drosophila Orb2A protein is required specifically for long-lasting memory. We report that in the adult fly brain the mRNA encoding Orb2A protein exists in an unspliced non-protein-coding form. The convergence of experience and internal drive transiently increases the spliced protein-coding Orb2A mRNA. A screen indentified pasilla, the fly orthologue of mammalian Nova-1/2, as a mediator of Orb2A mRNA processing. A single nucleotide substitution in the intronic region that reduces Pasilla binding and intron removal selectively impairs long-term memory. We posit that pasilla-mediated processing of unspliced Orb2A mRNA integrates experience and internal state to control Orb2A protein abundance and long-term memory formation.
Background:Infection by Pseudomonas aeruginosa is common in the Intensive Care Unit (ICU), leading to increased morbidity and mortality. The organism is classified into various phenotypes based on the drug resistance pattern, namely, drug-resistant (DR), multi-DR (MDR), extensively DR (XDR), and pan-DR (PDR). We aim to study the incidence of P. aeruginosa phenotypes in a tertiary level ICU.Materials and Methods:We conducted this prospective, observational study for 2 years (January 2014-December 2015) and collected appropriate clinical samples (blood, urine, wound discharge, etc.,) from all the patients admitted to ICU. We excluded patients with known septicemia and P. aeruginosa infection. Group 1 comprised a total 1915 patient samples and Group 2 comprised 100 active surveillance samples, collected from the medical staff and the hospital environment. The data were analyzed using appropriate statistical methods, and a P < 0.05 was considered statistically significant.Results:We isolated 597 pathogenic bacteria out of 1915 specimens, giving a culture positivity rate of 31.2%. Klebsiella (43%), Acinetobacter (22%), and P. aeruginosa (15%) were the top three isolated bacteria. None of the surveillance samples grew P. aeruginosa. Antibiotic resistance studies revealed that 47.7% of P. aeruginosa isolates were DR, 50% were MDR, and 2.3% were XDR phenotype. None of the strains showed PDR phenotype.Conclusion:Our data revealed a high prevalence of DR phenotypes of P. aeruginosa in the ICU. Judicious use of antibiotics and strict infection control measures are essential to reduce the prevalence of drug resistance.
Antimicrobial peptides act as a host defense mechanism and regulate the commensal microbiome.To obtain a comprehensive view of genes contributing to long-term memory we performed mRNA sequencing from single Drosophila heads following behavioral training that produces long-lasting memory. Surprisingly, we find that two immune peptides with antimicrobial activity, Diptericin B and Gram-Negative Bacteria Binding Protein like 3, regulate long-term but not short-term memory or instinctive behavior in Drosophila. The cellular requirement of these two peptides is distinct: head fat body for DptB, and neurons for GNBP-like3. That antimicrobial peptides influence memory provides a novel example of the emerging link between the immune and nervous systems and reveals that some immune peptides may have been repurposed in the nervous system. Author summaryIt is becoming evident that the nervous system and immune system share not only some of the same molecular logic but also the same components. Here, we report a novel and unanticipated example of how immune genes influence nervous system function. During exploring how Drosophila form longlasting memories of certain experiences, we have found that antimicrobial peptides that fight bacteria in the body, are expressed in the head, and control whether an animal would form long-term memory of a food source or a mating partner. Antimicrobial peptides are detected in the brain of many species and has often been associated with dysfunction of the nervous system. This and other recent works, provide an explanation to why antimicrobial peptides may be expressed in the brain: they regulate normal functions of the brain. Both eating, and mating engage the immune system in preparation of exposure to external agents including bacteria. We speculate antimicrobial peptides were upregulated in the body to deal with immune challenges and over evolutionary time some of them are co-adopted to convey specific information about food or mating to the brain.
Carbapenem‐resistant Enterobacteriaceae (CRE) are a group of Gram‐negative bacterial pathogens which carry resistance to a large proportion of available antibiotics and are a significant cause of nosocomial infection in the United States. Within this group, Klebsiella pneumoniae carrying the blaKPC carbapenemase gene (KPC+) are of particular concern in the hospital setting among immunocompromised patients, and strains of sequence type (ST) 258 are prevalent in the US, South America and Europe. Bacteriophages, bacterial viruses, have been proposed as a potential alternative form of treatment for infections caused by multidrug‐resistant pathogens, including KPC+ K. pneumoniae. Bacteriophage therapy has many appealing qualities including ease of isolation, specificity, and a low production cost. One limitation, however, is the quick appearance of bacteriophage resistant bacterial mutants. In this study, we examine the genetic modifications responsible for bacteriophage resistance in several ST 258 K. pneumoniae strains and investigate how bacteriophage resistance might be overcome in a model of tri‐bacteriophage combination therapy for K. pneumoniae. Identification, evaluation and characterization of candidate phages was based on in vitro virulence assays, whole genome sequencing, complementation, transmission electron microscopy and traditional plaque assays. Isolation of 27 bacteriophages from environmental sources resulted in 9 bacteriophages (primary phages) which infect the ST258 KPC+ K. pneumoniae model strain 39827. Further isolation of phages specific for “primary” phage resistant bacterial mutants yielded “secondary” phages and subsequent double phage resistant mutants. Whole genome sequencing, SNP and INDEL identification, and complementation of these in vitro generated bacteriophage resistant K. pneumoniae strains characterizes the bacterial capsule as a probable common primary phage receptor in ST258 KPC+ K. pneumoniae and mutational loss of this primary receptor exposes outer membrane proteins and lipopolysaccharide (LPS) as secondary phage receptors. A tri‐phage cocktail representing multiple receptor types was more effective at suppressing growth of the wild‐type KPC+ K. pneumoniae host strain than a single phage in vitro. Additionally, single and double phage resistant bacterial mutants exhibited growth defects, suggesting a loss of fitness associated with phage resistance mutations. In an in vivo murine model of GI decolonization the tri‐phage cocktail was able to lower bacterial K. pneumoniae concentrations in both fecal and cecal samples by 1–2 log units. These data indicate a promising treatment for K. pneumoniae using genomics to overcome bacteriophage resistance and increase the effectiveness of bacteriophage therapy. Support or Funding Information Funding for this project is generously provided by NIAID Project R33‐AI121689
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