Cellular responses of Candida albicans to phagocytosis and the extracellular activities of neutrophils are critical to counteract carbohydrate starvation, oxidative and nitrosative stress

Acknowledgments We thank Alexander Johnson (yhb1D/D), Karl Kuchler (sodD/D mutants), Janet Quinn (hog1D/D, hog1/cap1D/D, trx1D/D) and Peter Staib (ssu1D/D) for providing mutant strains. We acknowledge helpful discussions with our colleagues from the Microbial Pathogenicity Mechanisms Department, Fungal Septomics and the Microbial Biochemistry and Physiology Research Group at the Hans Kno¨ll Institute (HKI), specially Ilse D. Jacobsen, Duncan Wilson, Sascha Brunke, Lydia Kasper, Franziska Gerwien, Sea´na Duggan, Katrin Haupt, Kerstin Hu¨nniger, and Matthias Brock, as well as from our partners in the FINSysB Network. Author Contributions Conceived and designed the experiments: PM HW IMB AJPB OK BH. Performed the experiments: PM CD HW. Analyzed the data: PM HW IMB AJPB OK BH. Wrote the paper: PM HW OK AJPB BH.Peer reviewedPublisher PD

Small but crucial : the novel small heat shock protein Hsp21 mediates stress adaptation and virulence in Candida albicans

Peer reviewedPublisher PD

CD98hc facilitates B cell proliferation and adaptive humoral immunity.

The proliferation of antigen-specific lymphocytes and resulting clonal expansion are essential for adaptive immunity. We report here that B cell-specific deletion of the heavy chain of CD98 (CD98hc) resulted in lower antibody responses due to total suppression of B cell proliferation and subsequent plasma cell formation. Deletion of CD98hc did not impair early B cell activation but did inhibit later activation of the mitogen-activated protein kinase Erk1/2 and downregulation of the cell cycle inhibitor p27. Reconstitution of CD98hc-deficient B cells with CD98hc mutants showed that the integrin-binding domain of CD98hc was required for B cell proliferation but that the amino acid-transport function of CD98hc was dispensable for this. Thus, CD98hc supports integrin-dependent rapid proliferation of B cells. We propose that the advantage of adaptive immunity favored the appearance of CD98hc in vertebrates

Hsp90 orchestrates transcriptional regulation by Hsf1 and cell wall remodelling by MAPK signalling during thermal adaptation in a pathogenic yeast

Acknowledgments We thank Rebecca Shapiro for creating CaLC1819, CaLC1855 and CaLC1875, Gillian Milne for help with EM, Aaron Mitchell for generously providing the transposon insertion mutant library, Jesus Pla for generously providing the hog1 hst7 mutant, and Cathy Collins for technical assistance.Peer reviewedPublisher PD

Comparative cytogenetic analysis of two grasshopper species of the tribe Abracrini (Ommatolampinae, Acrididae)

The grasshopper species Orthoscapheus rufipes and Eujivarus fusiformis were analyzed using several cytogenetic techniques. The karyotype of O. rufipes, described here for the first time, had a diploid number of 2n = 23, whereas E. fusiformis had a karyotype with 2n = 21. The two species showed the same mechanism of sex determination (XO type) but differed in chromosome morphology. Pericentromeric blocks of constitutive heterochromatin (CH) were detected in the chromosome complement of both species. CMA3/DA/DAPI staining revealed CMA3-positive blocks in CH regions in four autosomal bivalents of O. rufipes and in two of E. fusiformis. The location of active NORs differed between the two species, occurring in bivalents M6 and S9 of O. rufipes and M6 and M7 of E. fusiformsi. The rDNA sites revealed by FISH coincided with the number and position of the active NORs detected by AgNO3 staining. The variability in chromosomal markers accounted for the karyotype differentiation observed in the tribe Abracrini

Identification and Characterization of Antifungal Compounds Using a Saccharomyces cerevisiae Reporter Bioassay

New antifungal drugs are urgently needed due to the currently limited selection, the emergence of drug resistance, and the toxicity of several commonly used drugs. To identify drug leads, we screened small molecules using a Saccharomyces cerevisiae reporter bioassay in which S. cerevisiae heterologously expresses Hik1, a group III hybrid histidine kinase (HHK) from Magnaporthe grisea. Group III HHKs are integral in fungal cell physiology, and highly conserved throughout this kingdom; they are absent in mammals, making them an attractive drug target. Our screen identified compounds 13 and 33, which showed robust activity against numerous fungal genera including Candida spp., Cryptococcus spp. and molds such as Aspergillus fumigatus and Rhizopus oryzae. Drug-resistant Candida albicans from patients were also highly susceptible to compounds 13 and 33. While the compounds do not act directly on HHKs, microarray analysis showed that compound 13 induced transcripts associated with oxidative stress, and compound 33, transcripts linked with heavy metal stress. Both compounds were highly active against C. albicans biofilm, in vitro and in vivo, and exerted synergy with fluconazole, which was inactive alone. Thus, we identified potent, broad-spectrum antifungal drug leads from a small molecule screen using a high-throughput, S. cerevisiae reporter bioassay

Fabrication and Properties of Porphyrin Nano- and Micro-particles with Novel Morphology

New types of porphyrin nano- and micro-particles composed of J- and H-heteroaggregates were prepared by electrostatic self-assembly of two oppositely charged porphyrins, tetrakis(4-trimethylammoniophenyl)porphyrin (H2TAPP4+) and tetrakis(4-sulfonatophenyl)porphyrin cobalt(II) (CoTPPS4−), in aqueous solutions. Transmission electron microscopy (TEM) images showed novel morphology and size distribution of porphyrin particles fabricated under different experimental conditions. The assembly process of the nano- and micro-particles was monitored by UV–Vis spectra. Fluorescence spectra and UV–Vis spectra provided optical information on the formation of the nano- and micro-particles. Cyclic voltammograms of the porphyrin particles indicated that the electron gain and loss of the H2TAPP4+ion were restrained, and the electron transfer of the CoTPPS4−ion was promoted in the J- and H-type porphyrin heteroaggregates within the particles. The stability and constitution of the nano- and micro-particles were confirmed by UV-light irradiation, heat-treatment, and pH and ionic strength changes. Photoelectrochemical measurements showed that the photoelectron transfer of TiO2modified with the particles was more efficient than that of TiO2sensitized by either monomers. The photoelectronic and photocatalytic properties of the products indicated that the pyramidal or spherical configuration of the nano- and micro-particles was favorable for the absorption and transfer of the energy. It can be found that TiO2sensitized by the porphyrin nano- and micro-particles exhibits significant improvement in energy conversion and photocatalytic activity with reference to pure TiO2

Neural Correlates of Appetite and Hunger-Related Evaluative Judgments

How much we desire a meal depends on both the constituent foods and how hungry we are, though not every meal becomes more desirable with increasing hunger. The brain therefore needs to be able to integrate hunger and meal properties to compute the correct incentive value of a meal. The present study investigated the functional role of the amygdala and the orbitofrontal cortex in mediating hunger and dish attractiveness. Furthermore, it explored neural responses to dish descriptions particularly susceptible to value-increase following fasting. We instructed participants to rate how much they wanted food menu items while they were either hungry or sated, and compared the rating differences in these states. Our results point to the representation of food value in the amygdala, and to an integration of attractiveness with hunger level in the orbitofrontal cortex. Dishes particularly desirable during hunger activated the thalamus and the insula. Our results specify the functions of evaluative structures in the context of food attractiveness, and point to a complex neural representation of dish qualities which contribute to state-dependent value

Short-term consumption of a high-fat diet increases host susceptibility to Listeria monocytogenes infection

peer-reviewedBackground A westernized diet comprising a high caloric intake from animal fats is known to influence the development of pathological inflammatory conditions. However, there has been relatively little focus upon the implications of such diets for the progression of infectious disease. Here, we investigated the influence of a high-fat (HF) diet upon parameters that influence Listeria monocytogenes infection in mice. Results We determined that short-term administration of a HF diet increases the number of goblet cells, a known binding site for the pathogen, in the gut and also induces profound changes to the microbiota and promotes a pro-inflammatory gene expression profile in the host. Host physiological changes were concordant with significantly increased susceptibility to oral L. monocytogenes infection in mice fed a HF diet relative to low fat (LF)- or chow-fed animals. Prior to Listeria infection, short-term consumption of HF diet elevated levels of Firmicutes including Coprococcus, Butyricicoccus, Turicibacter and Clostridium XIVa species. During active infection with L. monocytogenes, microbiota changes were further exaggerated but host inflammatory responses were significantly downregulated relative to Listeria-infected LF- or chow-fed groups, suggestive of a profound tempering of the host response influenced by infection in the context of a HF diet. The effects of diet were seen beyond the gut, as a HF diet also increased the sensitivity of mice to systemic infection and altered gene expression profiles in the liver. Conclusions We adopted a systems approach to identify the effects of HF diet upon L. monocytogenes infection through analysis of host responses and microbiota changes (both pre- and post-infection). Overall, the results indicate that short-term consumption of a westernized diet has the capacity to significantly alter host susceptibility to L. monocytogenes infection concomitant with changes to the host physiological landscape. The findings suggest that diet should be a consideration when developing models that reflect human infectious disease.This research was funded by the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie grant agreement No. 641984, through funding of the List_MAPS consortium. We also acknowledge funding and support from Science Foundation Ireland (SFI) in the form of a center grant (APC Microbiome Ireland grant SFI/12/RC/2273)

Mathematical Model of Plasmid-Mediated Resistance to Ceftiofur in Commensal Enteric Escherichia coli of Cattle

Antimicrobial use in food animals may contribute to antimicrobial resistance in bacteria of animals and humans. Commensal bacteria of animal intestine may serve as a reservoir of resistance-genes. To understand the dynamics of plasmid-mediated resistance to cephalosporin ceftiofur in enteric commensals of cattle, we developed a deterministic mathematical model of the dynamics of ceftiofur-sensitive and resistant commensal enteric Escherichia coli (E. coli) in the absence of and during parenteral therapy with ceftiofur. The most common treatment scenarios including those using a sustained-release drug formulation were simulated; the model outputs were in agreement with the available experimental data. The model indicated that a low but stable fraction of resistant enteric E. coli could persist in the absence of immediate ceftiofur pressure, being sustained by horizontal and vertical transfers of plasmids carrying resistance-genes, and ingestion of resistant E. coli. During parenteral therapy with ceftiofur, resistant enteric E. coli expanded in absolute number and relative frequency. This expansion was most influenced by parameters of antimicrobial action of ceftiofur against E. coli. After treatment (>5 weeks from start of therapy) the fraction of ceftiofur-resistant cells among enteric E. coli, similar to that in the absence of treatment, was most influenced by the parameters of ecology of enteric E. coli, such as the frequency of transfer of plasmids carrying resistance-genes, the rate of replacement of enteric E. coli by ingested E. coli, and the frequency of ceftiofur resistance in the latter