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  1. Article ; Online: Host populations, challenges, and commercialization of cryptococcal vaccines.

    Maurizio Del Poeta / Floyd L Wormley / Xiaorong Lin

    PLoS Pathogens, Vol 19, Iss 2, p e

    2023  Volume 1011115

    Abstract: Vaccines are one of the most effective public health tools to prevent and manage infectious diseases. Since the first clinical use of vaccines in the late 18th century, many vaccines have been successfully developed to combat bacterial and viral ... ...

    Abstract Vaccines are one of the most effective public health tools to prevent and manage infectious diseases. Since the first clinical use of vaccines in the late 18th century, many vaccines have been successfully developed to combat bacterial and viral infections, including the most recent Coronavirus Disease 2019 (COVID-19) pandemic. However, there remains no vaccine that is clinically available to treat or prevent invasive fungal diseases, including cryptococcal meningoencephalitis. This fungal disease is uniformly fatal without treatment and has a global mortality rate of over 70%. Despite a dire need for an effective cryptococcal vaccine, there are many scientific and economic challenges to overcome prior to making it a reality. Here, we discuss some of these challenges as well as steps that the community is taking for commercialization of effective cryptococcal vaccines.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2023-02-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Host populations, challenges, and commercialization of cryptococcal vaccines

    Maurizio Del Poeta / Floyd L. Wormley / Xiaorong Lin

    PLoS Pathogens, Vol 19, Iss

    2023  Volume 2

    Abstract: Vaccines are one of the most effective public health tools to prevent and manage infectious diseases. Since the first clinical use of vaccines in the late 18th century, many vaccines have been successfully developed to combat bacterial and viral ... ...

    Abstract Vaccines are one of the most effective public health tools to prevent and manage infectious diseases. Since the first clinical use of vaccines in the late 18th century, many vaccines have been successfully developed to combat bacterial and viral infections, including the most recent Coronavirus Disease 2019 (COVID-19) pandemic. However, there remains no vaccine that is clinically available to treat or prevent invasive fungal diseases, including cryptococcal meningoencephalitis. This fungal disease is uniformly fatal without treatment and has a global mortality rate of over 70%. Despite a dire need for an effective cryptococcal vaccine, there are many scientific and economic challenges to overcome prior to making it a reality. Here, we discuss some of these challenges as well as steps that the community is taking for commercialization of effective cryptococcal vaccines.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2023-02-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Identification and Characterization of an Intergenic “Safe Haven” Region in Human Fungal Pathogen Cryptococcus gattii

    Yeqi Li / Tuyetnhu Pham / Xiaofeng Xie / Xiaorong Lin

    Journal of Fungi, Vol 8, Iss 178, p

    2022  Volume 178

    Abstract: Cryptococcus gattii is a primary fungal pathogen, which causes pulmonary and brain infections in healthy as well as immunocompromised individuals. Genetic manipulations in this pathogen are widely employed to study its biology and pathogenesis, and ... ...

    Abstract Cryptococcus gattii is a primary fungal pathogen, which causes pulmonary and brain infections in healthy as well as immunocompromised individuals. Genetic manipulations in this pathogen are widely employed to study its biology and pathogenesis, and require integration of foreign DNA into the genome. Thus, identification of gene free regions where integrated foreign DNA can be expressed without influencing, or being influenced by, nearby genes would be extremely valuable. To achieve this goal, we examined publicly available genomes and transcriptomes of C. gattii , and identified two intergenic regions in the reference strain R265 as potential “safe haven” regions, named as CgSH1 and CgSH2. We found that insertion of a fluorescent reporter gene and a selection marker at these two intergenic regions did not affect the expression of their neighboring genes and were also expressed efficiently, as expected. Furthermore, DNA integration at CgSH1 or CgSH2 had no apparent effect on the growth of C. gattii , its response to various stresses, or phagocytosis by macrophages. Thus, the identified safe haven regions in C. gattii provide an effective tool for researchers to reduce variation and increase reproducibility in genetic experiments.
    Keywords Cryptococcus gattii ; safe haven ; ectopic integration ; genome editing ; complementation ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Long non-coding RNA and non-coding nucleic acids

    Xiaorong Lin / Man-Li Luo / Erwei Song

    Cell Insight, Vol 1, Iss 1, Pp 100004- (2022)

    Signaling players in the networks of the tumor ecosystem

    2022  

    Abstract: Recent findings have revealed that human genome encodes tens of thousands long noncoding RNAs (lncRNAs), which play essential roles in broad spectrum of cellular processes. Emerging evidence has uncovered a new archetype of lncRNAs which functions as key ...

    Abstract Recent findings have revealed that human genome encodes tens of thousands long noncoding RNAs (lncRNAs), which play essential roles in broad spectrum of cellular processes. Emerging evidence has uncovered a new archetype of lncRNAs which functions as key components of cell signaling pathways. In this review, we describe how lncRNAs interact with proteins to regulate cancer intracellular signaling and intercellular signaling in the tumor microenvironment (TME), which enable cancer cells to acquire malignant hallmarks. Moreover, besides lncRNAs, non-coding nucleic acids, such as neutrophil extracellular trap-DNA (NET-DNA), endogenous DNA and RNA, can act as signal molecules to connect cells from distant organs and trigger systemic responses in the macroenvironment of tumor-bearing hosts. Overall, the widely observed dysregulation of non-coding nucleic acids in cancer alters signaling networks in the tumor ecosystem, providing a rich resource for the identification of cancer biomarkers and therapeutic targets.
    Keywords Long non-coding RNA ; Non-coding nucleic acid ; Signaling transduction ; Tumor ecosystem ; Biology (General) ; QH301-705.5 ; Medicine (General) ; R5-920
    Subject code 572
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Current Perspectives on Uniparental Mitochondrial Inheritance in Cryptococcus neoformans

    Amber R. Matha / Xiaorong Lin

    Pathogens, Vol 9, Iss 743, p

    2020  Volume 743

    Abstract: The mitochondrion is a vital organelle in most eukaryotic cells. It contains its own DNA which differs from nuclear DNA, since it is often inherited from only one parent during sexual reproduction. In anisogamous mammals, this is largely due to the fact ... ...

    Abstract The mitochondrion is a vital organelle in most eukaryotic cells. It contains its own DNA which differs from nuclear DNA, since it is often inherited from only one parent during sexual reproduction. In anisogamous mammals, this is largely due to the fact that the oocyte has over 1000 times more copies of mitochondrial DNA than the sperm. However, in the isogamous fungus Cryptococcus neoformans , uniparental mitochondrial inheritance (UMI) still occurs during sexual reproduction. It is proposed that UMI might have evolved in the last common ancestor of eukaryotes. Thus, understanding the fundamental process of UMI in lower eukaryotes may give insights into how the process might have evolved in eukaryotic ancestors. In this review, we discuss the current knowledge regarding the cellular features as well as the molecular underpinnings of UMI in Cryptococcus during the mating process, and open questions that need to be answered to solve the mystery of UMI in this eukaryotic microbe.
    Keywords Cryptococcus neoformans ; uniparental mitochondrial inheritance ; mating ; bisexual reproduction ; pheromone sensing pathway ; Medicine ; R
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: On the History and Applications of Congenic Strains in Cryptococcus Research

    Benjamin J. Chadwick / Xiaorong Lin

    Pathogens, Vol 9, Iss 750, p

    2020  Volume 750

    Abstract: Congenic strains have been utilized in numerous model organisms to determine the genetic underpinning of various phenotypic traits. Congenic strains are usually derived after 10 backcrosses to a recipient parent, at which point they are 99.95% ... ...

    Abstract Congenic strains have been utilized in numerous model organisms to determine the genetic underpinning of various phenotypic traits. Congenic strains are usually derived after 10 backcrosses to a recipient parent, at which point they are 99.95% genetically identical to the parental strain. In recent decades, congenic pairs have provided an invaluable tool for genetics and molecular biology research in the Cryptococcus neoformans species complex. Here, we summarize the history of Cryptococcus congenic pairs and their application in Cryptococcus research on topics including the impact of the mating type locus on unisexual reproduction, virulence, tissue tropism, uniparental mitochondrial inheritance, and the genetic underpinning of other various traits. We also discuss the limitations of these approaches and other biological questions, which could be explored by employing congenic pairs.
    Keywords Cryptococcus ; congenic pair ; mating type locus ; morphogenesis ; neurotropism ; QTL mapping ; Medicine ; R
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Aiming for a bull's-eye

    Richard B Meagher / Zachary A Lewis / Suresh Ambati / Xiaorong Lin

    PLoS Pathogens, Vol 17, Iss 7, p e

    Targeting antifungals to fungi with dectin-decorated liposomes.

    2021  Volume 1009699

    Abstract: Globally, there are several million individuals with life-threatening invasive fungal diseases such as candidiasis, aspergillosis, cryptococcosis, Pneumocystis pneumonia (PCP), and mucormycosis. The mortality rate for these diseases generally exceeds 40%. ...

    Abstract Globally, there are several million individuals with life-threatening invasive fungal diseases such as candidiasis, aspergillosis, cryptococcosis, Pneumocystis pneumonia (PCP), and mucormycosis. The mortality rate for these diseases generally exceeds 40%. Annual medical costs to treat these invasive fungal diseases in the United States exceed several billion dollars. In addition to AIDS patients, the risks of invasive mycoses are increasingly found in immune-impaired individuals or in immunosuppressed patients following stem cell or organ transplant or implantation of medical devices. Current antifungal drug therapies are not meeting the challenge, because (1) at safe doses, they do not provide sufficient fungal clearance to prevent reemergence of infection; (2) most become toxic with extended use; (3) drug-resistant fungal isolates are emerging; and (4) only one new class of antifungal drugs has been approved for clinical use in the last 2 decades. DectiSomes represent a novel design of drug delivery to drastically increase drug efficacy. Antifungals packaged in liposomes are targeted specifically to where the pathogen is, through binding to the fungal cell walls or exopolysaccharide matrices using the carbohydrate recognition domains of pathogen receptors. Relative to untargeted liposomal drug, DectiSomes show order of magnitude increases in the binding to and killing of Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus in vitro and similarly improved efficacy in mouse models of pulmonary aspergillosis. DectiSomes have the potential to usher in a new antifungal drug treatment paradigm.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2021-07-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: The RAM signaling pathway links morphology, thermotolerance, and CO2 tolerance in the global fungal pathogen Cryptococcus neoformans

    Benjamin J Chadwick / Tuyetnhu Pham / Xiaofeng Xie / Laura C Ristow / Damian J Krysan / Xiaorong Lin

    eLife, Vol

    2022  Volume 11

    Abstract: The environmental pathogen Cryptococcus neoformans claims over 180,000 lives each year. Survival of this basidiomycete at host CO2 concentrations has only recently been considered an important virulence trait. Through screening gene knockout libraries ... ...

    Abstract The environmental pathogen Cryptococcus neoformans claims over 180,000 lives each year. Survival of this basidiomycete at host CO2 concentrations has only recently been considered an important virulence trait. Through screening gene knockout libraries constructed in a CO2-tolerant clinical strain, we found mutations leading to CO2 sensitivity are enriched in pathways activated by heat stress, including calcineurin, Ras1-Cdc24, cell wall integrity, and Regulator of Ace2 and Morphogenesis (RAM). Overexpression of Cbk1, the conserved terminal kinase of the RAM pathway, partially restored defects of these mutants at host CO2 or temperature levels. In ascomycetes such as Saccharomyces cerevisiae and Candida albicans, transcription factor Ace2 is an important target of Cbk1, activating genes responsible for cell separation. However, no Ace2 homolog or any downstream component of the RAM pathway has been identified in basidiomycetes. Through in vitro evolution and comparative genomics, we characterized mutations in suppressors of cbk1Δ in C. neoformans that partially rescued defects in CO2 tolerance, thermotolerance, and morphology. One suppressor is the RNA translation repressor Ssd1, which is highly conserved in ascomycetes and basidiomycetes. The other is a novel ribonuclease domain-containing protein, here named PSC1, which is present in basidiomycetes and humans but surprisingly absent in most ascomycetes. Loss of Ssd1 in cbk1Δ partially restored cryptococcal ability to survive and amplify in the inhalation and intravenous murine models of cryptococcosis. Our discoveries highlight the overlapping regulation of CO2 tolerance and thermotolerance, the essential role of the RAM pathway in cryptococcal adaptation to the host condition, and the potential importance of post-transcriptional control of virulence traits in this global pathogen.
    Keywords genetics ; suppressor screen ; medical mycology ; virulence traits ; pathogenesis ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2022-11-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: The Antidepressant Sertraline Induces the Formation of Supersized Lipid Droplets in the Human Pathogen Cryptococcus neoformans

    Matthew R. Breuer / Ananya Dasgupta / Joseph G. Vasselli / Xiaorong Lin / Brian D. Shaw / Matthew S. Sachs

    Journal of Fungi, Vol 8, Iss 642, p

    2022  Volume 642

    Abstract: The prevalence and increasing incidence of fungal infections globally is a significant worldwide health problem. Cryptococcosis, primarily caused by the pathogenic yeast Cryptococcus neoformans , is responsible for approximately 181,000 estimated deaths ... ...

    Abstract The prevalence and increasing incidence of fungal infections globally is a significant worldwide health problem. Cryptococcosis, primarily caused by the pathogenic yeast Cryptococcus neoformans , is responsible for approximately 181,000 estimated deaths annually. The scarcity of treatments and the increasing resistance to current therapeutics highlight the need for the development of antifungal agents which have novel mechanisms of action and are suitable for clinical use. Repurposing existing FDA-approved compounds as antimycotic therapeutics is a promising strategy for the rapid development of such new treatments. Sertraline (SRT), a commonly prescribed antidepressant, is a broad-spectrum antifungal agent with particular efficacy against C. neoformans . However, the effect of SRT on fungal physiology is not understood. Here, we report that SRT induces the formation of supersized lipid droplets (SLDs) in C. neoformans , and in Candida albicans , Saccharomyces cerevisiae , and Aspergillus fumigatus . SLDs were not induced in C. neoformans by treatment with the antifungal fluconazole (FLC), consistent with SRT and FLC acting differently to perturb C. neoformans physiology. The formation of SLDs in response to SRT indicates that this compound alters the lipid metabolism of C. neoformans . Moreover, the SRT-induced enlargement of LDs in other fungal species may indicate a common fungal response to SRT.
    Keywords antifungal therapy ; Cryptococcus neoformans ; Aspergillus fumigatus ; Candida albicans ; Saccharomyces cerevisiae ; lipid droplets ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Interactions between Melanin Enzymes and Their Atypical Recruitment to the Secretory Pathway by Palmitoylation

    Srijana Upadhyay / Xinping Xu / Xiaorong Lin

    mBio, Vol 7, Iss 6, p e01925-

    2016  Volume 16

    Abstract: Melanins are biopolymers that confer coloration and protection to the host organism against biotic or abiotic insults. The level of protection offered by melanin depends on its biosynthesis and its subcellular localization. Previously, we discovered that ...

    Abstract Melanins are biopolymers that confer coloration and protection to the host organism against biotic or abiotic insults. The level of protection offered by melanin depends on its biosynthesis and its subcellular localization. Previously, we discovered that Aspergillus fumigatus compartmentalizes melanization in endosomes by recruiting all melanin enzymes to the secretory pathway. Surprisingly, although two laccases involved in the late steps of melanization are conventional secretory proteins, the four enzymes involved in the early steps of melanization lack a signal peptide or a transmembrane domain and are thus considered “atypical” secretory proteins. In this work, we found interactions among melanin enzymes and all melanin enzymes formed protein complexes. Surprisingly, the formation of protein complexes by melanin enzymes was not critical for their trafficking to the endosomal system. By palmitoylation profiling and biochemical analyses, we discovered that all four early melanin enzymes were strongly palmitoylated during conidiation. However, only the polyketide synthase (PKS) Alb1 was strongly palmitoylated during both vegetative hyphal growth and conidiation when constitutively expressed alone. This posttranslational lipid modification correlates the endosomal localization of all early melanin enzymes. Intriguingly, bioinformatic analyses predict that palmitoylation is a common mechanism for potential membrane association of polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs) in A. fumigatus. Our findings indicate that protein-protein interactions facilitate melanization by metabolic channeling, while posttranslational lipid modifications help recruit the atypical enzymes to the secretory pathway, which is critical for compartmentalization of secondary metabolism.
    Keywords Science ; Q ; Microbiology ; QR1-502
    Subject code 570
    Language English
    Publishing date 2016-11-01T00:00:00Z
    Publisher American Society for Microbiology
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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