Architecture of the dynamic fungal cell wall

The fungal cell wall is essential for growth and survival, and is a key target for antifungal drugs and the immune system. The cell wall must be robust but flexible, protective and shielding yet porous to nutrients and membrane vesicles and receptive to exogenous signals. Most fungi have a common inner wall skeleton of chitin and β-glucans that functions as a flexible viscoelastic frame to which a more diverse set of outer cell wall polymers and glycosylated proteins are attached. Whereas the inner wall largely determines shape and strength, the outer wall confers properties of hydrophobicity, adhesiveness, and chemical and immunological heterogeneity. The spatial organization and dynamic regulation of the wall in response to prevailing growth conditions enable fungi to thrive within changing, diverse and often hostile environments. Understanding this architecture provides opportunities to develop diagnostics and drugs to combat life-threatening fungal infections

The role of the Candida biofilm matrix in drug and immune protection

This is the final version. Available on open access from Elsevier via the DOI in this recordWellcome TrustMedical Research Council (MRC)National Institute for Health and Care Research (NIHR

Empowering Women: Moving from Awareness to Action at the Immunology of Fungal Infections Gordon Research Conference

This is the final version. Available on open access from MDPI via the DOI in this recordDespite the high prevalence of women in graduate degree programs and equal or more women earning PhDs, MDs, and MD/PhDs, and despite efforts at individual and institutional levels to promote women in STEM fields, there remains a disparity in pay and academic advancement of women. Likewise, there is a paucity of women in top scientific and academic leadership positions. The causes of this gender disparity are complex and multi-factorial and to date no "magic bullet" approach has been successful in changing the landscape for women in academic and scientific fields. In this report we detail our experiences with a novel mechanism for promoting discussion and raising awareness of the challenges of gender disparity in the sciences. The Gordon Research Conferences (GRC) launched the Power Hour at its meetings in 2016: a dedicated, scheduled session held during the scientific meeting to facilitate discussion of challenges specific to women in science. Here we share our experience with hosting the second Power Hour at the 2019 GRC Immunology of Fungal Infections (IFI) meeting held in Galveston, TX. We will discuss the overall structure, key discussion points, and feedback from participants with the aim of supporting future efforts to empower women and underrepresented minority groups in science.National Institutes of Health (NIH)Wellcome TrustRoyal SocietyMedical Research Council (MRC)Department of Veterans Affair

Top five unanswered questions in fungal cell surface research

This is the final version. Available on open access from Elsevier via the DOI in this record. We sent requests to authors of manuscripts published in The Cell Surface and community researchers working on fungal cell walls to send notes about what they considered were the top five unanswered questions in the field of fungal cell wall and cell surface biology. This article summarizes the feedback that was received by them as well as the views of the authors. In this issue you can find equivalent syntheses for researchers working on bacterial, unicellular parasite and plant systems.Wellcome TrustMedical Research Council (MRC)National Institutes of Healt

Clonal evolution of Candida albicans, Candida glabrata and Candida dubliniensis at oral niche level in health and disease

This is the final version. Available on open access from Taylor & Francis via the DOI in this recordBackground:Candida species have long been recognised as aetiological agents of opportunistic infections of the oral mucosa, and more recently, as players of polymicrobial interactions driving caries, periodontitis and oral carcinogenesis. Methods: We studied the clonal structure of Candida spp. at oral niche resolution in patients (n = 20) with a range of oral health profiles over 22 months. Colonies from oral micro-environments were examined with multilocus sequencing typing. Results:Candida spp. identified were C. albicans, C. glabrata and C. dubliniensis. Increased propensity for micro-variations giving rise to multiple diploid strain types (DST), as a result of loss of heterozygosity, was observed among C. albicans clade 1 isolates compared to other clades. Micro-variations among isolates were also observed in C. dubliniensis contra to expectations of stable population structures for this species. Multiple sequence types were retrieved from patients without clinical evidence of oral candidosis, while single sequence types were isolated from oral candidosis patients. Conclusion: This is the first study to describe the clonal population structure, persistence and stability of Candida spp. at oral niche level. Future research investigating links between Candida spp. clonality and oral disease should recognise the propensity to micro-variations amongst oral niches in C. albicans and C. dubliniensis identified here.Medical Research Council (MRC)Wellcome Trus

Dependence on Dectin-1 Varies With Multiple Candida Species

This is the final version. Available from Frontiers Media via the DOI in this recordFour Candida spp. (albicans, glabrata, tropicalis, parapsilosis) cause >95% of invasive Candida infections. C. albicans elicits immune responses via pathogen recognition receptors including C-type lectin-like receptors (CLRs). The CLR, Dectin-1 is important for host immunity to C. albicans and C. glabrata, however, whether Dectin-1 is important for host defense against C. tropicalis or C. parapsilosis is unknown. Therefore, we compared the involvement of Dectin-1 in response to these four diverse Candida spp. We found that Dectin-1 mediates innate cytokine responses to these Candida spp. in a species- and cell-dependent manner. Dectin-1 KO mice succumbed to infection with highly virulent C. albicans while they mostly survived infection with less virulent Candida spp. However, Dectin-1 KO mice displayed increased fungal burden following infection with each Candida spp. Additionally, T cells from Dectin-1 KO mice displayed enhanced effector functions likely due to the inability of Dectin-1 KO mice to clear the infections. Together, these data indicate that Dectin-1 is important for host defense to multiple Candida spp., although the specific roles for Dectin-1 varies with different Candida spp.Wellcome TrustRoyal SocietyUK Dementia Research InstituteMRC Centre for Medical Mycolog

Non-canonical signalling mediates changes in fungal cell wall PAMPs that drive immune evasion

This is the final version. Available from the publisher via the DOI in this record.To colonise their host, pathogens must counter local environmental and immunological challenges. Here, we reveal that the fungal pathogen Candida albicans exploits diverse host-associated signals to promote immune evasion by masking of a major pathogen-associated molecular pattern (PAMP), β-glucan. Certain nutrients, stresses and antifungal drugs trigger β-glucan masking, whereas other inputs, such as nitrogen sources and quorum sensing molecules, exert limited effects on this PAMP. In particular, iron limitation triggers substantial changes in the cell wall that reduce β-glucan exposure. This correlates with reduced phagocytosis by macrophages and attenuated cytokine responses by peripheral blood mononuclear cells. Iron limitation-induced β-glucan masking depends on parallel signalling via the iron transceptor Ftr1 and the iron-responsive transcription factor Sef1, and the protein kinase A pathway. Our data reveal that C. albicans exploits a diverse range of specific host signals to trigger protective anticipatory responses against impending phagocytic attack and promote host colonisation.Medical Research Council (MRC)European CommissionWellcome Trus

Особенности конструкции термической печи с барабанным механизмом перемещения заготовок

One of the most energy-intensive industries is ferrous metallurgy. The metallurgical sector in industrially developed countries is reducing its specific energy consumption per one ton of products by approximately 1.0 - 1.5 % per annum. In Russia, obsolete technology is the main reason for the high-energy intensity of industrial product. Energy saving in industrial production is associated with production technology and the scope of fuel and energy resources consumption. Therefore, ways to improve energy efficiency focus on reducing energy consumption of any kind during a specific process in a specific process or thermal unit. Ensuring the economical operation of furnace units requires detailed preliminary and verification analyses, upgrading and introduction of state-of-the-art equipment. The study presents a flow diagram and features of thermal operation of a new drum-type chamber furnace for heating metal products for quenching. The technical parameters of the furnace, the results of the thermo-technical analysis, the heat balance and the specific fuel consumption as applicable to the created design are also presented. The flow diagram of the furnace has significant advantages in terms of the energy efficiency of fuel as compared to the roller and conveyor methods of metal transportation. Placing blanks on the drum significantly reduces the complexity of their transportation. Thanks to its small length the proposed design is compact and easy to place in a workshop. The use of a recuperative fuel burning device allows the efficient use of the heat of waste gases in the heating process. The proposed design and method of products transportation in the furnace working space can be used for the heat treatment of bars, pipes, strips, as well as rolled steel of various shapes. © 2021 National University of Science and Technology MISIS. All rights reserved

Mechanisms underlying the exquisite sensitivity of Candida albicans to combinatorial cationic and oxidative stress that enhances the potent fungicidal activity of phagocytes

This is the final version. Available on open access from the American Society for Microbiology via the DOI in this recordImmune cells exploit reactive oxygen species (ROS) and cationic fluxes to kill microbial pathogens, such as the fungus Candida albicans. Yet, C. albicans is resistant to these stresses in vitro. Therefore, what accounts for the potent antifungal activity of neutrophils? We show that simultaneous exposure to oxidative and cationic stresses is much more potent than the individual stresses themselves and that this combinatorial stress kills C. albicans synergistically in vitro. We also show that the high fungicidal activity of human neutrophils is dependent on the combinatorial effects of the oxidative burst and cationic fluxes, as their pharmacological attenuation with apocynin or glibenclamide reduced phagocytic potency to a similar extent. The mechanistic basis for the extreme potency of combinatorial cationic plus oxidative stress—a phenomenon we term stress pathway interference— lies with the inhibition of hydrogen peroxide detoxification by the cations. In C. albicans this causes the intracellular accumulation of ROS, the inhibition of Cap1 (a transcriptional activator that normally drives the transcriptional response to oxidative stress), and altered readouts of the stress-activated protein kinase Hog1. This leads to a loss of oxidative and cationic stress transcriptional outputs, a precipitous collapse in stress adaptation, and cell death. This stress pathway interference can be suppressed by ectopic catalase (Cat1) expression, which inhibits the intracellular accumulation of ROS and the synergistic killing of C. albicans cells by combinatorial cationic plus oxidative stress. Stress pathway interference represents a powerful fungicidal mechanism employed by the host that suggests novel approaches to potentiate antifungal therapy.IMPORTANCE The immune system combats infection via phagocytic cells that recognize and kill pathogenic microbes. Human neutrophils combat Candida infections by killing this fungus with a potent mix of chemicals that includes reactive oxygen species (ROS) and cations. Yet, Candida albicans is relatively resistant to these stresses in vitro. We show that it is the combination of oxidative plus cationic stresses that kills yeasts so effectively, and we define the molecular mechanisms that underlie this potency. Cations inhibit catalase. This leads to the accumulation of intracellular ROS and inhibits the transcription factor Cap1, which is critical for the oxidative stress response in C. albicans. This triggers a dramatic collapse in fungal stress adaptation and cell death. Blocking either the oxidative burst or cationic fluxes in human neutrophils significantly reduces their ability to kill this fungal pathogen, indicating that combinatorial stress is pivotal to immune surveillance.Biotechnology and Biological Sciences Research Council (BBSRC)Wellcome TrustEuropean CommissionNIAI

The importance of antimicrobial resistance in medical mycology.

Prior to the SARS-CoV-2 pandemic, antibiotic resistance was listed as the major global health care priority. Some analyses, including the O'Neill report, have predicted that deaths due to drug-resistant bacterial infections may eclipse the total number of cancer deaths by 2050. Although fungal infections remain in the shadow of public awareness, total attributable annual deaths are similar to, or exceeds, global mortalities due to malaria, tuberculosis or HIV. The impact of fungal infections has been exacerbated by the steady rise of antifungal drug resistant strains and species which reflects the widespread use of antifungals for prophylaxis and therapy, and in the case of azole resistance in Aspergillus, has been linked to the widespread agricultural use of antifungals. This review, based on a workshop hosted by the Medical Research Council and the University of Exeter, illuminates the problem of antifungal resistance and suggests how this growing threat might be mitigated