ZBP1 promotes fungi-induced inflammasome activation and pyroptosis,apoptosis, and necroptosis (PANoptosis)

Candida albicans and Aspergillus fumigatus are dangerous fungal pathogens with high morbidity and mortality, particularly in immunocompromised patients. Innate immune-mediated programmed cell death (pyroptosis, apoptosis, necroptosis) is an integral part of host defense against pathogens. Inflammasomes, which are canonically formed upstream of pyroptosis, have been characterized as key mediators of fungal sensing and drivers of proinflammatory responses. However, the specific cell death pathways and key upstream sensors activated in the context of Candida and Aspergillus infections are unknown. Here, we report that C. albicans and A. fumigatus infection induced inflammatory programmed cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). Further, we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as the apical sensor of fungal infection responsible for activating the inflammasome/pyroptosis, apoptosis, and necroptosis. The Zα2 domain of ZBP1 was required to promote this inflammasome activation and PANoptosis. Overall, our results demonstrate that C. albicans and A. fumigatus induce PANoptosis and that ZBP1 plays a vital role in inflammasome activation and PANoptosis in response to fungal pathogens.     

Disease swamps molecular signatures of genetic-environmental associations to abiotic factors in Tasmanian devil (Sarcophilus harrisii) populations

Landscape genomics studies focus on identifying candidate genes under selection via spatial variation in abiotic environmental variables, but rarely by biotic factors (i.e., disease). The Tasmanian devil (Sarcophilus harrisii) is found only on the environmentally heterogeneous island of Tasmania and is threatened with extinction by a transmissible cancer, devil facial tumor disease (DFTD). Devils persist in regions of long-term infection despite epidemiological model predictions of species’ extinction, suggesting possible adaptation to DFTD. Here, we test the extent to which spatial variation and genetic diversity are associated with the abiotic environment (i.e., climatic variables, elevation, vegetation cover) and/or DFTD. We employ genetic-environment association analyses using 6886 SNPs from 3287 individuals sampled pre- and post-disease arrival across the devil's geographic range. Pre-disease, we find significant correlations of allele frequencies with environmental variables, including 365 unique loci linked to 71 genes, suggesting local adaptation to abiotic environment. The majority of candidate loci detected pre-DFTD are not detected post-DFTD arrival. Several post-DFTD candidate loci are associated with disease prevalence and were in linkage disequilibrium with genes involved in tumor suppression and immune response. Loss of apparent signal of abiotic local adaptation post-disease suggests swamping by strong selection resulting from the rapid onset of DFTD.     

Anxiolytic Properties of New Chemical Entity, 5TIO1

2-[(2,6-dichlorobenzylidene)amino]-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile), 5TIO1, is a new 2-aminothiophene derivative with a promising pharmacological activity. The aim of this work was to evaluate the potential anxiolytic effect of 5TIO1 in animal models. In the elevated plus-maze test, 5TIO1 (0.1, 1.0 and 10.0 mg/kg, i.p) increased the time of permanence and the number of entries in the open arms. In the light/dark box test, 5TIO1 at dose of 0.1 mg/kg (i.p) also showed anxiolytic-like effect indicated by an increase in the time spent in the light box, similar to diazepam 2.0 mg/kg (i.p). 5TIO1 groups did not change locomotor and coordination activities in open field and rotarod tests, respectively, when compared to vehicle. Dose dependent process was not observed and the anxiolytic effects demonstrated were not completely reversed by flumazenil 25 mg/kg (i.p). Our results suggest that 5TIO1 can bind with other receptors, besides the benzodiazepine site of the GABA receptor in mouse brain.     

Conservation status of New Zealand frogs, 2009

Abstract

A reappraisal of the conservation status of the New Zealand frog fauna is presented using the 2008 version of the New Zealand Threat Classification System. Of New Zealand's four extant endemic species, three are judged to be ‘Threatened’ (Leiopelma hamiltoni being ‘Nationally Critical’, and L. pakeka and L. archeyi being ‘Nationally Vulnerable’) and one ‘At Risk’ (L. hochstetteri ‘Declining’). Three Leiopelma species are listed as extinct—they are known from bone deposits in caves throughout the country until some time in the last 1000 years. Three introduced and naturalised Litoria species are abundant in New Zealand although two (L. aurea and L. raniformis) are threatened in their country of origin (Australia). An additional unidentified frog taxon from northern Great Barrier Island is listed as ‘Data Deficient’.     

Biodistribution of sodium borocaptate (BSH) for boron neutron capture therapy (BNCT) in an oral cancer model

Boron neutron capture therapy (BNCT) is based on selective accumulation of ¹⁰B carriers in tumor followed by neutron irradiation. We previously proved the therapeutic success of BNCT mediated by the boron compounds boronophenylalanine and sodium decahydrodecaborate (GB-10) in the hamster cheek pouch oral cancer model. Based on the clinical relevance of the boron carrier sodium borocaptate (BSH) and the knowledge that the most effective way to optimize BNCT is to improve tumor boron targeting, the specific aim of this study was to perform biodistribution studies of BSH in the hamster cheek pouch oral cancer model and evaluate the feasibility of BNCT mediated by BSH at nuclear reactor RA-3. The general aim of these studies is to contribute to the knowledge of BNCT radiobiology and optimize BNCT for head and neck cancer. Sodium borocaptate (50 mg ¹⁰B/kg) was administered to tumor-bearing hamsters. Groups of 3–5 animals were killed humanely at nine time-points, 3–12 h post-administration. Samples of blood, tumor, precancerous pouch tissue, normal pouch tissue and other clinically relevant normal tissues were processed for boron measurement by optic emission spectroscopy. Tumor boron concentration peaked to therapeutically useful boron concentration values of 24–35 ppm. The boron concentration ratio tumor/normal pouch tissue ranged from 1.1 to 1.8. Pharmacokinetic curves showed that the optimum interval between BSH administration and neutron irradiation was 7–11 h. It is concluded that BNCT mediated by BSH at nuclear reactor RA-3 would be feasible.     

Computational study of conformational changes in human 3-hydroxy-3-methylglutaryl coenzyme reductase induced by substrate binding

Abstract

The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is mainly involved in the regulation of cholesterol biosynthesis. HMGR catalyses the reduction of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate at the expense of two NADPH molecules in a two-step reversible reaction. In the present study, we constructed a model of human HMGR (hHMGR) to explore the conformational changes of HMGR in complex with HMG-CoA and NADPH. In addition, we analysed the complete sequence of the Flap domain using molecular dynamics (MD) simulations and principal component analysis (PCA). The simulations revealed that the Flap domain plays an important role in catalytic site activation and substrate binding. The apo form of hHMGR remained in an open state, while a substrate-induced closure of the Flap domain was observed for holo hHMGR. Our study also demonstrated that the phosphorylation of Ser872 induces significant conformational changes in the Flap domain that lead to a complete closure of the active site, suggesting three principal conformations for the first stage of hHMGR catalysis. Our results were consistent with previous proposed models for the catalytic mechanism of hHMGR.

Communicated by Ramaswamy H. Sarma     

Strigolactones fine-tune the root system

Strigolactones were originally discovered to be involved in parasitic weed germination, in mycorrhizal association and in the control of shoot architecture. Despite their clear role in rhizosphere signaling, comparatively less attention has been given to the belowground function of strigolactones on plant development. However, research has revealed that strigolactones play a key role in the regulation of the root system including adventitious roots, primary root length, lateral roots, root hairs and nodulation. Here, we review the recent progress regarding strigolactone regulation of the root system and the antagonism and interplay with other hormones.     

Geographic variation in feeding preference of a generalist herbivore: the importance of seaweed chemical defenses

The ecological impacts of generalist herbivores depend on feeding preferences, which can vary across and within herbivore species. Among mesoherbivores, geographic variation in host use can occur because host plants have a more restricted geographic distribution than does the herbivore, or there is local evolution in host preference, or both. We tested the role of local evolution using the marine amphipod Ampithoe longimana by rearing multiple amphipod populations from three regions (subtropical Florida, warm-temperate North Carolina and cold-temperate New England) and assaying their feeding preferences toward ten seaweeds that occur in some but not all regions. Six of the ten seaweeds produce anti-herbivore secondary metabolites, and we detected geographic variation in feeding preference toward five (Dictyota menstrualis, Dictyota ciliolata, Fucus distichus, Chondrus crispus and Padina gymnospora, but not Caulerpa sertularioides). Amphipod populations that co-occur with a chemically-rich seaweed tended to have stronger feeding preferences for that seaweed, relative to populations that do not co-occur with the seaweed. A direct test indicated that geographic variation in feeding preference toward one seaweed (D. ciliolata) is mediated by feeding tolerance for lipophilic secondary metabolites. Among the four seaweeds that produce no known secondary metabolites (Acanthophora, Ectocarpus, Gracilaria and Hincksia/Feldmannia spp.), we detected no geographic variation in feeding preference. Thus, populations are more likely to evolve greater feeding preferences for local hosts when those hosts produce secondary metabolites. Microevolution of feeding behaviors of generalist marine consumers likely depends on the availability and identity of local hosts and the strength of their chemical defenses.