The predictors of outcome in immunocompetent patients with hematogenous candidasis

AbstractObjective: Clinical parameters that predict outcome in non-immunosuppressed candidemic patients are not fully understood.Methods: Eighty-one consecutive episodes of candidemia were retrospectively evaluated in 75 patients during 1998–2000.Results: Infection due to Candida albicans was common (n=30; 37%) followed by Candida glabrata (n=25; 31%), Candida parapsilosis (n=14; 17%), Candida tropicalis (n=6; 7%), Candida krusei (n=5; 6%), and Candida lusitaniae (n=1; 1%). Among 70 evaluable patients, 31 (44%) had fungemia-associated mortality; advanced age (P<0.004), underlying malignancy (P<0.025), coronary artery disease (P<0.01), and concurrent non-Candida species fungal infection (P<0.047) were significant prognosticators of compromised short-term survival by multivariate analysis. Mortality was higher in patients with Candida glabrata (60%) and C. tropicalis (75%) infection compared to 44% deaths in individuals with C. albicans infection (P>0.1). 11/25 (44%) of non-immunocompromised individuals died and 20/45 (44%) immunosuppressed patients succumbed to fungemia: persistent vs. non-persistent (<3 days) Candida bloodstream invasion, neutropenia, diabetes mellitus, renal insufficiency, prior antimicrobial therapy, cirrhosis of liver, abdomino-pelvis surgery, and critical-care-unit vs. non critical-care-unit admission did not significantly impact outcome in either group. All 11 infants, including nine with prematurity survived Candida species bloodstream infection (P<0.025).Conclusions: Short-term mortality in candidemic non-immunocompromised patients was comparable to fungemia-associated deaths in immunosuppressed patients. Ischemic heart disease has appeared as a new predictor of unfavorable outcome in patients with hematogenous candidiasis

Arguments for an additional long-lived intermediate in the photocycle of the full-length aureochrome 1c receptor: A time-resolved small-angle X-ray scattering study

Bannister S, Böhm E, Zinn T, Hellweg T, Kottke T. Arguments for an additional long-lived intermediate in the photocycle of the full-length aureochrome 1c receptor: A time-resolved small-angle X-ray scattering study. Structural Dynamics. 2019;6(3): 34701.Aureochromes (AUREO) act as blue-light photoreceptors in algae. They consist of a light-, oxygen-, voltage-sensitive (LOV) domain and a DNA-binding basic region/leucine zipper. Illumination of the flavin cofactor in LOV leads to the formation of an adduct, followed by global structural changes. Here, we first applied UV/vis spectroscopy to characterize the photocycle of full-length aureochrome 1c (PtAUREO1c) from the diatom Phaeodactylum tricornutum. With a time constant of 850 s and a quantum yield of 23%, PtAUREO1c reveals a faster recovery time and a much lower sensitivity toward light than PtAUREO1a, pointing to its role as a high light sensor in vivo. UV/vis spectroscopy offers details on the local recovery of the flavin chromophore. However, kinetic information on the global structural recovery of full-length AUREO or any other multidomain LOV protein is missing. This information is essential not least for the photoreceptors' applications as optogenetic devices. Therefore, we established a procedure to apply small-angle X-ray scattering on PtAUREO1c in a time-resolved manner employing an in-house setup. In combination with UV/vis spectroscopy under similar conditions, we revealed a discrepancy between the recovery of the global protein structure and the adduct lifetime. Accordingly, we propose to supplement the photocycle by an intermediate state (I447), which decays with a time constant of about 800 s and prolongs the lifetime of the signaling state

The Geologic Remote Sensing Field Experiment (GRSFE)

Field measurements for the Geologic Remote Sensing Field Experiment (GRSFE) were concentrated in the Lunar Lake area of Nevada. The GRSFE data are meant to be used in a variety of investigations, including tests of multispectral radiative transfer models for scattering and emission from planetary surfaces in support of the Earth Observing System (EOS), Mars Observer, and Magellan Missions. Studies will also be pursued to establish the neotectonic and paleoclimatic history of the arid southwestern United States. The data will also be used to support Mars Rover Sample Return (MRSR) simulation studies

Induction, characterization, and cell transfer of autoimmune tubulointerstitial nephritis

Induction, characterization, and cell transfer of autoimmune tubulointerstitial nephritis. Autoimmune tubulointerstitial nephritis (TIN) was induced in Lewis (LEW) rats by immunization with homologous Brown–Norway (BN) rat renal basement membrane (RBM), complete Freund's adjuvant and Bordetella pertussis vaccine. The BN strain has a tubular basement membrane (TBM) antigen (Ag+) detectable by immunofluorescence which is lacking in unmodified LEW rat TBM. Development of TIN in LEW rats correlated with TBM Ag+ immunogens from homologous and heterologous RBM preparations. By day 14 after immunization TIN developed characterized by elevated serum creatinine levels and by tubular destruction with focal, circumscribed lesions containing epithelioid cells, giant cells and mononuclear cell infiltrates. Approximately 60% of the mononuclear cells bore T cell antigens with most cells expressing la markers. Immunofluorescence and elution studies revealed no selective IgG fixation to TBM at day 14 despite high titers of circulating alloantibody reactive with the immunizing TBM. Intravenous transfer of LNC and/or splenic cells (3.5 to 7 × 108) to naive LEW rats resulted in less severe but histologically identical TIN in seven days with T cell subpopulations similar to those seen in the active model. This model strongly suggests an initiating role for cell–mediated immunity in TIN in the rat and may provide a parallel to human TIN

Fatigue performance of thermally cut bolt holes in structural steel S460M

Current fatigue codes only consider the fatigue performance of drilled and punched holes, limiting the use of thermal cutting processes to produce bolt holes. This paper studies the fatigue performance of structural steel S460M plates containing thermally cut bolt holes. The research covers three thermal cutting methods: the traditional one (oxy-fuel cutting) and two more modern processes (plasma and laser cutting). Specimen geometry is defined by a rectangular cross section with a cut hole in the middle. All the specimens were conducted to failure by applying fatigue cycles, the stress ratio (R) being 0.1. The corresponding S-N curve and fatigue limit were obtained for each cutting method. Fatigue results have been compared with previous researches on fatigue performance of drilled and punched holes, and with the predictions provided by current fatigue standards, analyzing the possibility to extrapolate their S-N curves, focused on drilled and punched holes, to thermally cut holes

Receptor antagonism/agonism can be uncoupled from pharmacoperone activity

Pharmacoperones rescue misrouted mutants of the vasopressin receptor type 2 (V2R) and enable them to traffic to the correct biological locus where they function. Previously, a library of nearly 645,000 structures was interrogated with a high throughput screen; pharmacoperones were identified for V2R mutants with a view toward correcting the underlying mutational defects in nephrogenic diabetes insipidus. In the present study, an orthologous assay was used to evaluate hits from the earlier study. We found no consistent relation between antagonism or agonism and pharmacoperone activity. Active pharmacoperones were identified which had minimal antagonistic activity. This increases the therapeutic reach of these drugs, since virtually all pharmacoperone drugs reported to date were selected from peptidomimetic antagonists. Such mixed-activity drugs have a complex pharmacology limiting their therapeutic utility and requiring their removal prior to stimulation of the receptor with agonist

Identification of an amino-terminus determinant critical for ryanodine receptor/Ca2+ release channel function

Aims The cardiac ryanodine receptor (RyR2), which mediates intracellular Ca2+ release to trigger cardiomyocyte contraction, participates in development of acquired and inherited arrhythmogenic cardiac disease. This study was undertaken to characterize the network of inter- and intra-subunit interactions regulating the activity of the RyR2 homotetramer. Methods and Results We use mutational investigations combined with biochemical assays to identify the peptide sequence bridging the β8 with β9 strand as the primary determinant mediating RyR2 N-terminus self-association. The negatively-charged side chains of two aspartate residues (D179 and D180) within the β8-β9 loop are crucial for the N-terminal inter-subunit interaction. We also show that the RyR2 N-terminus domain interacts with the C-terminal channel pore region in a Ca2+-independent manner. The β8-β9 loop is required for efficient RyR2 subunit oligomerization but it is dispensable for N-terminus interaction with C-terminus. Deletion of the β8-β9 sequence produces unstable tetrameric channels with subdued intracellular Ca2+ mobilization implicating a role for this domain in channel opening. The arrhythmia-linked R176Q mutation within the β8-β9 loop decreases N-terminus tetramerization but does not affect RyR2 subunit tetramerization or the N-terminus interaction with C-terminus. RyR2R176Q is a characteristic hypersensitive channel displaying enhanced intracellular Ca2+ mobilization suggesting an additional role for the β8-β9 domain in channel closing. Conclusions These results suggest that efficient N-terminus inter-subunit communication mediated by the β8-β9 loop may constitute a primary regulatory mechanism for both RyR2 channel activation and suppression. Translational Potential Our findings that the RyR2 β8-β9 loop is involved in both Ca2+ release channel opening and closing have important clinical implications. This RyR2 domain is a known “hot-spot” for mutations associated with arrhythmogenic cardiac disease, which could produce hypersensitive as well as hyposensitive channels. Therapeutic strategies currently focus on gain-of-function RyR2 channels to suppress sarcoplasmic reticulum Ca2+ release either indirectly with class I/II anti-arrhythmic drugs, or by directly targeting RyR2 to inhibit channel activity. These strategies may not only be ineffective, but they may exacerbate the malignant phenotype in the case of loss-of-function RyR2 mutations