Hyphal growth is essential for host colonization during Aspergillus infection. The transcription factor ZfpA regulates A. fumigatus hyphal development including branching, septation, and cell wall ...composition. However, how ZfpA affects fungal growth and susceptibility to host immunity during infection has not been investigated. Here, we use the larval zebrafish-Aspergillus infection model and primary human neutrophils to probe how ZfpA affects A. fumigatus pathogenesis and response to antifungal drugs in vivo. ZfpA deletion promotes fungal clearance and attenuates virulence in wild-type hosts and this virulence defect is abrogated in neutrophil-deficient zebrafish. ZfpA deletion also increases susceptibility to human neutrophils ex vivo while overexpression impairs fungal killing. Overexpression of ZfpA confers protection against the antifungal caspofungin by increasing chitin synthesis during hyphal development, while ZfpA deletion reduces cell wall chitin and increases caspofungin susceptibility in neutrophil-deficient zebrafish. These findings suggest a protective role for ZfpA activity in resistance to the innate immune response and antifungal treatment during A. fumigatus infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
12.
On the origins of GEMS grains Keller, Lindsay P.; Messenger, Scott
Geochimica et cosmochimica acta,
09/2011, Letnik:
75, Številka:
18
Journal Article
Recenzirano
From their birth as condensates in the outflows of oxygen-rich evolved stars, processing in interstellar space, and incorporation into disks around new stars, amorphous silicates predominate in most ...astrophysical environments. Amorphous silicates were a major building block of our Solar System and are prominent in infrared spectra of comets. Anhydrous interplanetary dust particles (IDPs) thought to derive from comets contain abundant amorphous silicates known as GEMS (glass with embedded metal and sulfides) grains. GEMS grains have been proposed to be isotopically and chemically homogenized interstellar amorphous silicate dust. We evaluated this hypothesis through coordinated chemical and isotopic analyses of GEMS grains in a suite of IDPs to constrain their origins. GEMS grains show order of magnitude variations in Mg, Fe, Ca, and S abundances. GEMS grains do not match the average element abundances inferred for ISM dust containing on average, too little Mg, Fe, and Ca, and too much S. GEMS grains have complementary compositions to the crystalline components in IDPs suggesting that they formed from the same reservoir. We did not observe any unequivocal microstructural or chemical evidence that GEMS grains experienced prolonged exposure to radiation.
We identified four GEMS grains having O isotopic compositions that point to origins in red giant branch or asymptotic giant branch stars and supernovae. Based on their O isotopic compositions, we estimate that 1–6% of GEMS grains are surviving circumstellar grains. The remaining 94–99% of GEMS grains have O isotopic compositions that are indistinguishable from terrestrial materials and carbonaceous chondrites. These isotopically solar GEMS grains either formed in the Solar System or were completely homogenized in the interstellar medium (ISM). However, the chemical compositions of GEMS grains are extremely heterogeneous and seem to rule out this possibility. Based on their solar isotopic compositions and their non-solar elemental compositions we propose that most GEMS grains formed in the nebula as late-stage non-equilibrium condensates.
Covering: 2010 to 2021
Organisms in nature have evolved into proficient synthetic chemists, utilizing specialized enzymatic machinery to biosynthesize an inspiring diversity of secondary metabolites. ...Often serving to boost competitive advantage for their producers, these secondary metabolites have widespread human impacts as antibiotics, anti-inflammatories, and antifungal drugs. The natural products discovery field has begun a shift away from traditional activity-guided approaches and is beginning to take advantage of increasingly available metabolomics and genomics datasets to explore undiscovered chemical space. Major strides have been made and now enable -omics-informed prioritization of chemical structures for discovery, including the prospect of confidently linking metabolites to their biosynthetic pathways. Over the last decade, more integrated strategies now provide researchers with pipelines for simultaneous identification of expressed secondary metabolites and their biosynthetic machinery. However, continuous collaboration by the natural products community will be required to optimize strategies for effective evaluation of natural product biosynthetic gene clusters to accelerate discovery efforts. Here, we provide an evaluative guide to scientific literature as it relates to studying natural product biosynthesis using genomics, metabolomics, and their integrated datasets. Particular emphasis is placed on the unique insights that can be gained from large-scale integrated strategies, and we provide source organism-specific considerations to evaluate the gaps in our current knowledge.
Here we provide a comprehensive guide for studying natural product biosynthesis using genomics, metabolomics, and their integrated datasets. We emphasize integrated strategies and provide a critical outlook on remaining challenges in the field.
Much of natural product chemistry concerns a group of compounds known as secondary metabolites. These low-molecular-weight metabolites often have potent physiological activities. Digitalis, morphine ...and quinine are plant secondary metabolites, whereas penicillin, cephalosporin, ergotrate and the statins are equally well known fungal secondary metabolites. Although chemically diverse, all secondary metabolites are produced by a few common biosynthetic pathways, often in conjunction with morphological development. Recent advances in molecular biology, bioinformatics and comparative genomics have revealed that the genes encoding specific fungal secondary metabolites are clustered and often located near telomeres. In this review, we address some important questions, including which evolutionary pressures led to gene clustering, why closely related species produce different profiles of secondary metabolites, and whether fungal genomics will accelerate the discovery of new pharmacologically active natural products.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
is a ubiquitous environmental mold and the leading cause of diverse human diseases ranging from allergenic bronchopulmonary aspergillosis (ABPA) to invasive pulmonary aspergillosis (IPA). ...Experimental investigations of the biology and virulence of this opportunistic pathogen have historically used a few type strains; however, it is increasingly observed with this fungus that heterogeneity among isolates potentially confounds the use of these reference isolates. Illustrating this point, Kowalski et al. (mBio 7:e01515-16, 2016, https://doi.org/10.1128/mBio.01515-16) demonstrated that variation in 16 environmental and clinical isolates of
correlated virulence with fitness in low oxygen, whereas Fuller et al. (mBio 7:e01517-16, 2016, https://doi.org/10.1128/mBio.01517-16) showed wide variation in light responses at a physiological and protein functionality level in 15
isolates. In both studies, two commonly used type strains, Af293 and CEA10, displayed significant differences in physiological responses to abiotic stimuli and virulence in a murine model of IPA.
In immunocompromised individuals, Aspergillus fumigatus causes invasive fungal disease that is often difficult to treat. Exactly how immune mechanisms control A. fumigatus in immunocompetent ...individuals remains unclear. Here, we use transparent zebrafish larvae to visualize and quantify neutrophil and macrophage behaviors in response to different A. fumigatus strains. We find that macrophages form dense clusters around spores, establishing a protective niche for fungal survival. Macrophages exert these protective effects by inhibiting fungal germination, thereby inhibiting subsequent neutrophil recruitment and neutrophil-mediated killing. Germination directly drives fungal clearance as faster-growing CEA10-derived strains are killed better in vivo than slower-growing Af293-derived strains. Additionally, a CEA10 pyrG-deficient strain with impaired germination is cleared less effectively by neutrophils. Host inflammatory activation through Myd88 is required for killing of a CEA10-derived strain but not sufficient for killing of an Af293-derived strain, further demonstrating the role of fungal-intrinsic differences in the ability of a host to clear an infection. Altogether, we describe a new role for macrophages in the persistence of A. fumigatus and highlight the ability of different A. fumigatus strains to adopt diverse modes of virulence.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The dysregulation of energy homeostasis in obesity involves multihormone resistance. Although leptin and insulin resistance have been well characterized, catecholamine resistance remains largely ...unexplored. Murine β3-adrenergic receptor expression in adipocytes is orders of magnitude higher compared with that of other isoforms. While resistant to classical desensitization pathways, its mRNA (Adrb3) and protein expression are dramatically downregulated after ligand exposure (homologous desensitization). β3-Adrenergic receptor downregulation also occurs after high-fat diet feeding, concurrent with catecholamine resistance and elevated inflammation. This downregulation is recapitulated in vitro by TNF-α treatment (heterologous desensitization). Both homologous and heterologous desensitization of Adrb3 were triggered by induction of the pseudokinase TRIB1 downstream of the EPAC/RAP2A/PI-PLC pathway. TRIB1 in turn degraded the primary transcriptional activator of Adrb3, CEBPα. EPAC/RAP inhibition enhanced catecholamine-stimulated lipolysis and energy expenditure in obese mice. Moreover, adipose tissue expression of genes in this pathway correlated with body weight extremes in a cohort of genetically diverse mice and with BMI in 2 independent cohorts of humans. These data implicate a signaling axis that may explain reduced hormone-stimulated lipolysis in obesity and resistance to therapeutic interventions with β3-adrenergic receptor agonists.
Transmission electron microscope (TEM) imaging techniques combined with focused ion beam sample preparation were used to calibrate the solar energetic particle track production rate in lunar samples. ...Track density measurements by TEM as a function of depth were obtained from lunar rock 64455 that has a well‐constrained exposure age of 2 Myr giving a track production rate of 4.4 ± 0.4 × 104 tracks cm−2 yr−1 for a 2π exposure at 1 AU. The typical space weathering effects in mature lunar soils (both vapor‐deposited rims and solar wind‐damaged rims) accumulate in ˜106 yr based on the new calibration applied to track densities in individual grains. Solar wind‐damaged rim widths in anorthite and olivine follow a power law relationship with track density and achieve steady‐state widths in a few Myr. Vapor‐deposited rim widths show no correlation with exposure age suggesting that their formation is episodic with the full width of vapor‐deposited rims accumulating in a single or a few rare impact events. Solar wind‐damaged rim development was modeled using the stopping range of ions in matter code. Modeling shows that the solar wind‐damaged rims develop rapidly and approach steady‐state values in 105–106 yr. Anorthite and olivine record similar track densities for similar exposure ages, but their structural response to solar wind irradiation differs significantly. Solar wind‐damaged rims on olivine are not amorphous in contrast to modeling and high flux laboratory experiments and a model is proposed to account for their different response to solar wind irradiation.
Sortilin is a post-Golgi trafficking receptor homologous to the yeast vacuolar protein sorting receptor 10 (VPS10). The VPS10 motif on sortilin is a 10-bladed β-propeller structure capable of binding ...more than 50 proteins, covering a wide range of biological functions including lipid and lipoprotein metabolism, neuronal growth and death, inflammation, and lysosomal degradation. Sortilin has a complex cellular trafficking itinerary, where it functions as a receptor in the trans-Golgi network, endosomes, secretory vesicles, multivesicular bodies, and at the cell surface. In addition, sortilin is associated with hypercholesterolemia, Alzheimer’s disease, prion diseases, Parkinson’s disease, and inflammation syndromes. The 1p13.3 locus containing SORT1, the gene encoding sortilin, carries the strongest association with LDL-C of all loci in human genome-wide association studies. However, the mechanism by which sortilin influences LDL-C is unclear. Here, we review the role sortilin plays in cardiovascular and metabolic diseases and describe in detail the large and often contradictory literature on the role of sortilin in the regulation of LDL-C levels.
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