scholarly journals A LaeA- and BrlA-dependent cellular network governs tissue-specific secondary metabolism in the human pathogen Aspergillus fumigatus

2017 ◽  
Author(s):  
Abigail L. Lind ◽  
Fang Yun Lim ◽  
Alexandra A. Soukup ◽  
Nancy P. Keller ◽  
Antonis Rokas
Keyword(s):  
Secondary Metabolites ◽  
Aspergillus Fumigatus ◽  
Cellular Network ◽  
Transcriptional Regulators ◽  
Asexual Development ◽  
Metabolic Profiles ◽  
Human Pathogen ◽  
Wild Type ◽  
Cellular Processes ◽  
Type Strains

AbstractBiosynthesis of many ecologically important secondary metabolites (SMs) in filamentous fungi is controlled by several global transcriptional regulators, like the chromatin modifier LaeA, and tied to both development and vegetative growth. In Aspergillus molds, asexual development is regulated by the BrlA>AbaA>WetA transcriptional cascade. To elucidate BrlA pathway involvement in SM regulation, we examined the transcriptional and metabolic profiles of ΔbrlA, ΔabaA, ΔwetA and wild-type strains of the human pathogen Aspergillus fumigatus. We find that BrlA, in addition to regulating production of developmental SMs, regulates vegetative SMs and the SrbA-regulated hypoxia stress response in a concordant fashion to LaeA. We further show that the transcriptional and metabolic equivalence of ΔbrlA and ΔlaeA is mediated by a LaeA requirement preventing heterochromatic marks in the brlA promoter. These results provide a framework for the cellular network regulating not only fungal SMs but diverse cellular processes linked to virulence of this pathogen.

scholarly journals An LaeA- and BrlA-Dependent Cellular Network Governs Tissue-Specific Secondary Metabolism in the Human PathogenAspergillus fumigatus

mSphere ◽  
2018 ◽  
Vol 3 (2) ◽  
Author(s):  
Abigail L. Lind ◽  
Fang Yun Lim ◽  
Alexandra A. Soukup ◽  
Nancy P. Keller ◽  
Antonis Rokas
Keyword(s):  
Aspergillus Fumigatus ◽  
Secondary Metabolism ◽  
Filamentous Fungi ◽  
Vegetative Growth ◽  
Cellular Network ◽  
Asexual Development ◽  
Human Pathogen ◽  
Wild Type ◽  
Cellular Processes ◽  
Type Strains

ABSTRACTBiosynthesis of many ecologically important secondary metabolites (SMs) in filamentous fungi is controlled by several global transcriptional regulators, like the chromatin modifier LaeA, and tied to both development and vegetative growth. InAspergillusmolds, asexual development is regulated by the BrlA > AbaA > WetA transcriptional cascade. To elucidate BrlA pathway involvement in SM regulation, we examined the transcriptional and metabolic profiles of ΔbrlA, ΔabaA, and ΔwetAmutant and wild-type strains of the human pathogenAspergillus fumigatus. We find that BrlA, in addition to regulating production of developmental SMs, regulates vegetative SMs and the SrbA-regulated hypoxia stress response in a concordant fashion to LaeA. We further show that the transcriptional and metabolic equivalence of the ΔbrlAand ΔlaeAmutations is mediated by an LaeA requirement preventing heterochromatic marks in thebrlApromoter. These results provide a framework for the cellular network regulating not only fungal SMs but diverse cellular processes linked to virulence of this pathogen.IMPORTANCEFilamentous fungi produce a spectacular variety of small molecules, commonly known as secondary or specialized metabolites (SMs), which are critical to their ecologies and lifestyles (e.g., penicillin, cyclosporine, and aflatoxin). Elucidation of the regulatory network that governs SM production is a major question of both fundamental and applied research relevance. To shed light on the relationship between regulation of development and regulation of secondary metabolism in filamentous fungi, we performed global transcriptomic and metabolomic analyses on mutant and wild-type strains of the human pathogenAspergillus fumigatusunder conditions previously shown to induce the production of both vegetative growth-specific and asexual development-specific SMs. We find that the genebrlA, previously known as a master regulator of asexual development, is also a master regulator of secondary metabolism and other cellular processes. We further show thatbrlAregulation of SM is mediated bylaeA, one of the master regulators of SM, providing a framework for the cellular network regulating not only fungal SMs but diverse cellular processes linked to virulence of this pathogen.

scholarly journals Pharmacodynamics of Itraconazole against Aspergillus fumigatus in anIn VitroModel of the Human Alveolus: Perspectives on the Treatment of Triazole-Resistant Infection and Utility of Airway Administration

2012 ◽  
Vol 56 (8) ◽  
pp. 4146-4153 ◽  
Author(s):  
Zaid Al-Nakeeb ◽  
Ajay Sudan ◽  
Adam R. Jeans ◽  
Lea Gregson ◽  
Joanne Goodwin ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Therapeutic Strategies ◽  
Wild Type ◽  
Content Type ◽  
Exposure Response ◽  
Prevention And Treatment ◽  
Resistant Infection ◽  
Resistant Strains ◽  
Type Strains

ABSTRACTItraconazole is used for the prevention and treatment of infections caused byAspergillus fumigatus. An understanding of the pharmacodynamics of itraconazole against wild-type and triazole-resistant strains provides a basis for innovative therapeutic strategies for treatment of infections. Anin vitromodel of the human alveolus was used to define the pharmacodynamics of itraconazole. Galactomannan was used as a biomarker. The effect of systemic and airway administration of itraconazole was assessed, as was a combination of itraconazole administered to the airway and systemically administered 5FC. Systemically administered itraconazole against the wild type induced a concentration-dependent decline in galactomannan in the alveolar and endothelial compartments. No exposure-response relationships were apparent for the L98H, M220T, or G138C mutant. The administration of itraconazole to the airway resulted in comparable exposure-response relationships to those observed with systemic therapy. This was achieved without detectable concentrations of drug within the endothelial compartment. The airway administration of itraconazole resulted in a definite but submaximal effect in the endothelial compartment against the L98H mutant. The administration of 5FC resulted in a concentration-dependent decline in galactomannan in both the alveolar and endothelial compartments. The combination of airway administration of itraconazole and systemically administered 5FC was additive. Systemic administration of itraconazole is ineffective against Cyp51 mutants. The airway administration of itraconazole is effective for the treatment of wild-type strains and appears to have some activity against the L98H mutants. Combination with other agents, such as 5FC, may enable the attainment of near-maximal antifungal activity.

Characterization of the Role of the FluG Protein in Asexual Development of Aspergillus nidulans

Genetics ◽  
2001 ◽  
Vol 158 (3) ◽  
pp. 1027-1036 ◽  
Author(s):  
Cletus A D'Souza ◽  
Bee Na Lee ◽  
Thomas H Adams
Keyword(s):  
Aspergillus Nidulans ◽  
Negative Influence ◽  
Asexual Development ◽  
Wild Type ◽  
Significant Similarity ◽  
Developmental Defects ◽  
Asexual Sporulation ◽  
Type Strains

Abstract We showed previously that a ΔfluG mutation results in a block in Aspergillus nidulans asexual sporulation and that overexpression of fluG activates sporulation in liquid-submerged culture, a condition that does not normally support sporulation of wild-type strains. Here we demonstrate that the entire N-terminal region of FluG (∼400 amino acids) can be deleted without affecting sporulation, indicating that FluG activity resides in the C-terminal half of the protein, which bears significant similarity with GSI-type glutamine synthetases. While FluG has no apparent role in glutamine biosynthesis, we propose that it has an enzymatic role in sporulation factor production. We also describe the isolation of dominant suppressors of ΔfluG(dsg) that should identify components acting downstream of FluG and thereby define the function of FluG in sporulation. The dsgA1 mutation also suppresses the developmental defects resulting from ΔflbA and dominant activating fadA mutations, which both cause constitutive induction of the mycelial proliferation pathway. However, dsgA1 does not suppress the negative influence of these mutations on production of the aflatoxin precursor, sterigmatocystin, indicating that dsgA1 is specific for asexual development. Taken together, our studies define dsgA as a novel component of the asexual sporulation pathway.

scholarly journals Two α(1-3) Glucan Synthases with Different Functions in Aspergillus fumigatus

2005 ◽  
Vol 71 (3) ◽  
pp. 1531-1538 ◽  
Author(s):  
A. Beauvais ◽  
D. Maubon ◽  
S. Park ◽  
W. Morelle ◽  
M. Tanguy ◽  
...  
Keyword(s):  
Cell Wall ◽  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Molecular Mass ◽  
Mixed Infection ◽  
Cellular Localization ◽  
Amorphous Polymer ◽  
Wild Type ◽  
Main Component ◽  
Type Strains

ABSTRACT α(1-3) glucan is a main component of the Aspergillus fumigatus cell wall. In spite of its importance, synthesis of this amorphous polymer has not been investigated to date. Two genes in A. fumigatus, AGS1 and AGS2, are highly homologous to the AGS genes of Schizosaccharomyces pombe, which encode putative α(1-3) glucan synthases. The predicted Ags proteins of A. fumigatus have an estimated molecular mass of 270 kDa. AGS1 and AGS2 were disrupted in A. fumigatus. Both Δags mutants have similar altered hyphal morphologies and reduced conidiation levels. Only Δags1 presented a reduction in the α(1-3) glucan content of the cell wall. These results showed that Ags1p and Ags2p were functionally different. The cellular localization of the two proteins was in agreement with their different functions: Ags1p was localized at the periphery of the cell in connection with the cell wall, whereas Ags2p was intracellularly located. An original experimental model of invasive aspergillosis based on mixed infection and quantitative PCR was developed to analyze the virulence of A. fumigatus mutant and wild-type strains. Using this model, it was shown that the cell wall and morphogenesis defects of Δags1 and Δags2 were not associated with a reduction in virulence in either mutant. This result showed that a 50% reduction in the content of the cell wall α(1-3) glucan does not play a significant role in A. fumigatus pathogenicity.

scholarly journals Upstream and Downstream Regulation of Asexual Development in Aspergillus fumigatus

2006 ◽  
Vol 5 (10) ◽  
pp. 1585-1595 ◽  
Author(s):  
Jae-Hyung Mah ◽  
Jae-Hyuk Yu
Keyword(s):  
Aspergillus Fumigatus ◽  
G Proteins ◽  
Asexual Development ◽  
Human Pathogen ◽  
Loss Of Function ◽  
Primary Target ◽  
Asexual Sporulation ◽  
Opportunistic Human Pathogen ◽  
Upstream Regulators ◽  
Primary Agent

ABSTRACT The opportunistic human pathogen Aspergillus fumigatus produces a large quantity of asexual spores (conidia), which are the primary agent causing invasive aspergillosis in immunocompromised patients. We investigated the mechanisms controlling asexual sporulation (conidiation) in A. fumigatus via examining functions of four key regulators, GpaA (Gα), AfFlbA (RGS), AfFluG, and AfBrlA, previously studied in Aspergillus nidulans. Expression analyses of gpaA, AfflbA, AffluG, AfbrlA, and AfwetA throughout the life cycle of A. fumigatus revealed that, while transcripts of AfflbA and AffluG accumulate constantly, the latter two downstream developmental regulators are specifically expressed during conidiation. Both loss-of-function AfflbA and dominant activating GpaAQ204L mutations resulted in reduced conidiation with increased hyphal proliferation, indicating that GpaA signaling activates vegetative growth while inhibiting conidiation. As GpaA is the primary target of AfFlbA, the dominant interfering GpaAG203R mutation suppressed reduced conidiation caused by loss of AfflbA function. These results corroborate the hypothesis that functions of G proteins and RGSs are conserved in aspergilli. We then examined functions of the two major developmental activators AfFluG and AfBrlA. While deletion of AfbrlA eliminated conidiation completely, null mutation of AffluG did not cause severe alterations in A. fumigatus sporulation in air-exposed culture, implying that, whereas the two aspergilli may have a common key downstream developmental activator, upstream mechanisms activating brlA may be distinct. Finally, both AffluG and AfflbA mutants showed reduced conidiation and delayed expression of AfbrlA in synchronized developmental induction, indicating that these upstream regulators contribute to the proper progression of conidiation.

Isoflavone Glycoside Formation in Transformed and Non-Transformed Suspension and Hairy Root Cultures of Lupinus polyphyllus and Lupinus hartwegii

1991 ◽  
Vol 46 (9-10) ◽  
pp. 725-734 ◽  
Author(s):  
J. Berlin ◽  
L. Fecker ◽  
C. Rügenhagen ◽  
C. Sator ◽  
D. Strack ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Cell Suspension ◽  
Hairy Root ◽  
Southern Analysis ◽  
Hairy Root Cultures ◽  
Root Cultures ◽  
Wild Type ◽  
Lupinus Polyphyllus ◽  
Isoflavone Glycoside ◽  
Type Strains

Abstract Transformed cell suspension and hairy root cultures were established by infecting seedlings of Lupinus polyphyllus and L. hartwegii with various wild type strains of Agrobacterium tume-faciens and A. rhizogenes. Transformation of the cultures was confirmed either by their phyto­hormone autotrophy, detection of opines or southern analysis. Glueosides of genistein and 2′-hydroxygenistein, were found to be the main secondary metabolites in normal and trans­formed suspension cultures as well as in hairy root cultures. Although some of the isoflavone glycosides of the cultures were apparently new constituents of Lupinus, they were afterwards also found in young seedlings.

scholarly journals Gliotoxin, a known virulence factor in the major human pathogen Aspergillus fumigatus, is also biosynthesized by the non-pathogenic relative A. fischeri

2019 ◽  
Author(s):  
Sonja L. Knowles ◽  
Matthew E. Mead ◽  
Lilian Pereira Silva ◽  
Huzefa A. Raja ◽  
Jacob L. Steenwyk ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Aspergillus Fumigatus ◽  
Secondary Metabolite ◽  
Virulence Factors ◽  
Secondary Metabolite Production ◽  
Close Relative ◽  
Human Pathogen ◽  
Metabolite Production ◽  
Similarities And Differences ◽  
Close Relatives

ABSTRACTAspergillus fumigatus is a major opportunistic human pathogen. Multiple traits contribute to A. fumigatus pathogenicity, including its ability to produce specific secondary metabolites, such as gliotoxin. Gliotoxin is known to inhibit the host immune response, and genetic mutants that inactivate gliotoxin biosynthesis (or secondary metabolism in general) attenuate A. fumigatus virulence. The genome of A. fischeri, a very close non-pathogenic relative of A. fumigatus, contains a biosynthetic gene cluster that exhibits high sequence similarity to the A. fumigatus gliotoxin cluster. However, A. fischeri is not known to produce gliotoxin. To gain further insight into the similarities and differences between the major pathogen A. fumigatus and the non-pathogen A. fischeri, we examined whether A. fischeri strain NRRL 181 biosynthesizes gliotoxin and whether its production, and of secondary metabolites more generally, influence its virulence profile. We found that A. fischeri biosynthesizes gliotoxin in the same conditions as A. fumigatus. However, whereas loss of laeA, a master regulator of secondary metabolite production, has been previously shown to reduce the virulence of A. fumigatus, we found that laeA loss (and loss of secondary metabolite production, including gliotoxin) in A. fischeri does not influence its virulence. These results suggest that gliotoxin and secondary metabolite production are virulence factors in the genomic and phenotypic background of the major pathogen A. fumigatus but are much less important in the background of the non-pathogen A. fischeri. We submit that understanding the observed spectrum of pathogenicity across closely related pathogenic and non-pathogenic Aspergillus species will require detailed characterization of their biological, chemical, and genomic similarities and differences.IMPORTANCEAspergillus fumigatus is a major opportunistic fungal pathogen of humans but most of its close relatives are non-pathogenic. Why is that so? This important, yet largely unanswered, question can be addressed by examining how A. fumigatus and its non-pathogenic close relatives are similar or different with respect to virulence-associated traits. We investigated whether Aspergillus fischeri, a non-pathogenic close relative of A. fumigatus, can produce gliotoxin, a mycotoxin known to contribute to A. fumigatus virulence. We discovered that the non-pathogenic A. fischeri produces gliotoxin under the same conditions as the major pathogen A. fumigatus. However, we also discovered that, in contrast to what has been previously observed in A. fumigatus, loss of secondary metabolite, including gliotoxin, production in A. fischeri does not alter its virulence. Our results are consistent with the “cards of virulence” model of opportunistic fungal disease, where the ability to cause disease stems from the combination (“hand”) of individual virulence factors (“cards”), but not from individual factors per se.

scholarly journals Gliotoxin, a Known Virulence Factor in the Major Human Pathogen Aspergillus fumigatus, Is Also Biosynthesized by Its Nonpathogenic Relative Aspergillus fischeri

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Sonja L. Knowles ◽  
Matthew E. Mead ◽  
Lilian Pereira Silva ◽  
Huzefa A. Raja ◽  
Jacob L. Steenwyk ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Aspergillus Fumigatus ◽  
Secondary Metabolite ◽  
Virulence Factors ◽  
Secondary Metabolite Production ◽  
Human Pathogen ◽  
Content Type ◽  
Metabolite Production ◽  
Aspergillus Fischeri ◽  
Similarities And Differences

ABSTRACT Aspergillus fumigatus is a major opportunistic human pathogen. Multiple traits contribute to A. fumigatus pathogenicity, including its ability to produce specific secondary metabolites, such as gliotoxin. Gliotoxin is known to inhibit the host immune response, and genetic mutants that inactivate gliotoxin biosynthesis (or secondary metabolism in general) attenuate A. fumigatus virulence. The genome of Aspergillus fischeri, a very close nonpathogenic relative of A. fumigatus, contains a biosynthetic gene cluster that is homologous to the A. fumigatus gliotoxin cluster. However, A. fischeri is not known to produce gliotoxin. To gain further insight into the similarities and differences between the major pathogen A. fumigatus and the nonpathogen A. fischeri, we examined whether A. fischeri strain NRRL 181 biosynthesizes gliotoxin and whether the production of secondary metabolites influences the virulence profile of A. fischeri. We found that A. fischeri biosynthesizes gliotoxin under the same conditions as A. fumigatus. However, whereas loss of laeA, a master regulator of secondary metabolite production (including gliotoxin biosynthesis), has previously been shown to reduce A. fumigatus virulence, we found that laeA loss (and loss of secondary metabolite production) in A. fischeri does not influence its virulence. These results suggest that LaeA-regulated secondary metabolites are virulence factors in the genomic and phenotypic background of the major pathogen A. fumigatus but are much less important in the background of the nonpathogen A. fischeri. Understanding the observed spectrum of pathogenicity across closely related pathogenic and nonpathogenic Aspergillus species will require detailed characterization of their biological, chemical, and genomic similarities and differences. IMPORTANCE Aspergillus fumigatus is a major opportunistic fungal pathogen of humans, but most of its close relatives are nonpathogenic. Why is that so? This important, yet largely unanswered, question can be addressed by examining how A. fumigatus and its close nonpathogenic relatives are similar or different with respect to virulence-associated traits. We investigated whether Aspergillus fischeri, a nonpathogenic close relative of A. fumigatus, can produce gliotoxin, a mycotoxin known to contribute to A. fumigatus virulence. We discovered that the nonpathogenic A. fischeri produces gliotoxin under the same conditions as those of the major pathogen A. fumigatus. However, we also discovered that, in contrast to what has previously been observed in A. fumigatus, the loss of secondary metabolite production in A. fischeri does not alter its virulence. Our results are consistent with the “cards of virulence” model of opportunistic fungal disease, in which the ability to cause disease stems from the combination (“hand”) of virulence factors (“cards”) but not from individual factors per se.

scholarly journals VeA Regulates Conidiation, Gliotoxin Production, and Protease Activity in the Opportunistic Human Pathogen Aspergillus fumigatus

2012 ◽  
Vol 11 (12) ◽  
pp. 1531-1543 ◽  
Author(s):  
Sourabh Dhingra ◽  
David Andes ◽  
Ana M. Calvo
Keyword(s):  
Aspergillus Fumigatus ◽  
Protease Activity ◽  
Regulatory Gene ◽  
Hydrolytic Activity ◽  
Infection Model ◽  
Wild Type ◽  
Content Type ◽  
Cellular Processes ◽  
Mouse Infection Model ◽  
Opportunistic Human Pathogen

ABSTRACTInvasive aspergillosis byAspergillus fumigatusis a leading cause of infection-related mortality in immunocompromised patients. In this study, we show thatveA, a major conserved regulatory gene that is unique to fungi, is necessary for normal morphogenesis in this medically relevant fungus. Although deletion ofveAresults in a strain with reduced conidiation, overexpression of this gene further reduced conidial production, indicating thatveAhas a major role as a regulator of development inA. fumigatusand that normal conidiation is only sustained in the presence of wild-type VeA levels. Furthermore, our studies revealed thatveAis a positive regulator in the production of gliotoxin, a secondary metabolite known to be a virulent factor inA. fumigatus. Deletion ofveAresulted in a reduction of gliotoxin production with respect to that of the wild-type control. This reduction in toxin coincided with a decrease ingliZandgliPexpression, which is necessary for gliotoxin biosynthesis. Interestingly,veAalso influences protease activity in this organism. Specifically, deletion ofveAresulted in a reduction of protease activity; this is the first report of aveAhomolog with a role in controlling fungal hydrolytic activity. AlthoughveAaffects several cellular processes inA. fumigatus, pathogenicity studies in a neutropenic mouse infection model indicated thatveAis dispensable for virulence.

scholarly journals Contributions of Spore Secondary Metabolites to UV-C Protection and Virulence Vary in Different Aspergillus fumigatus Strains

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Adriana Blachowicz ◽  
Nicholas Raffa ◽  
Jin Woo Bok ◽  
Tsokyi Choera ◽  
Benjamin Knox ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Uv Radiation ◽  
Human Pathogen ◽  
Zebrafish Model ◽  
Protective Properties ◽  
Content Type ◽  
Uv C

ABSTRACT Fungi are versatile organisms which thrive in hostile environments, including the International Space Station (ISS). Several isolates of the human pathogen Aspergillus fumigatus have been found contaminating the ISS, an environment with increased exposure to UV radiation. Secondary metabolites (SMs) in spores, such as melanins, have been shown to protect spores from UV radiation in other fungi. To test the hypothesis that melanin and other known spore SMs provide UV protection to A. fumigatus isolates, we subjected SM spore mutants to UV-C radiation. We found that 1,8-dihydroxynaphthalene (DHN)-melanin mutants of two clinical A. fumigatus strains (Af293 and CEA17) but not an ISS-isolated strain (IF1SW-F4) were more sensitive to UV-C than their respective wild-type (WT) strains. Because DHN-melanin has been shown to shield A. fumigatus from the host immune system, we examined all DHN mutants for virulence in the zebrafish model of invasive aspergillosis. Following recent studies highlighting the pathogenic variability of different A. fumigatus isolates, we found DHN-melanin to be a virulence factor in CEA17 and IF1SW-F4 but not Af293. Three additional spore metabolites were examined in Af293, where fumiquinazoline also showed UV-C-protective properties, but two other spore metabolites, monomethylsulochrin and fumigaclavine, provided no UV-C-protective properties. Virulence tests of these three SM spore mutants indicated a slight increase in virulence of the monomethylsulochrin deletion strain. Taken together, this work suggests differential roles of specific spore metabolites across Aspergillus isolates and by types of environmental stress. IMPORTANCE Fungal spores contain secondary metabolites that can protect them from a multitude of abiotic and biotic stresses. Conidia (asexual spores) of the human pathogen Aspergillus fumigatus synthesize several metabolites, including melanin, which has been reported to be important for virulence in this species and to be protective against UV radiation in other fungi. Here, we investigate the role of melanin in diverse isolates of A. fumigatus and find variability in its ability to protect spores from UV-C radiation or impact virulence in a zebrafish model of invasive aspergillosis in two clinical strains and one ISS strain. Further, we assess the role of other spore metabolites in a clinical strain of A. fumigatus and identify fumiquinazoline as an additional UV-C-protective molecule but not a virulence determinant. The results show differential roles of secondary metabolites in spore protection dependent on the environmental stress and strain of A. fumigatus. As protection from elevated levels of radiation is of paramount importance for future human outer space explorations, the discovery of small molecules with radiation-protective potential may result in developing novel safety measures for astronauts.

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