Specialized or secondary metabolites are small molecules of biological origin, often showing potent biological activities with applications in agriculture, engineering and medicine. Usually, the biosynthesis of these natural products is governed by sets of co-regulated and physically clustered genes known as biosynthetic gene clusters (BGCs). To share information about BGCs in a standardized and machine-readable way, the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard and repository was initiated in 2015. Since its conception, MIBiG has been regularly updated to expand data coverage and remain up to date with innovations in natural product research. Here, we describe MIBiG version 4.0, an extensive update to the data repository and the underlying data standard. In a massive community annotation effort, 267 contributors performed 8304 edits, creating 557 new entries and modifying 590 existing entries, resulting in a new total of 3059 curated entries in MIBiG. Particular attention was paid to ensuring high data quality, with automated data validation using a newly developed custom submission portal prototype, paired with a novel peer-reviewing model. MIBiG 4.0 also takes steps towards a rolling release model and a broader involvement of the scientific community. MIBiG 4.0 is accessible online at https://mibig.secondarymetabolites.org/.

Battery systems are essential components of the on-going energy transition and digitalization of society. With the need to power an increasing variety of portable and stationary systems, ranging from disposable point-of-care devices or smart packaging systems to applications in portable computers and electric cars, an increasing variety of batteries and battery systems are being developed, each aiming to specific sets of required performance parameters, including energy and power density, cycling stability, flexibility, degradability, environmental impact or improved integration into the specific application context. This work analyzed the state of the art of the different materials and geometries, performance parameters and applications of the different battery systems. We discuss the rationale behind each material selection, the processing technologies and the integration into the specific application, taking into account the whole life-cycle of the battery. Further, the main challenges posed for each battery type will provide a roadmap for their successful development and application.

Cryptococcus neoformans is notorious for causing severe pulmonary and central nervous system infections, particularly in immunocompromised patients. High mortality rates, associated with its tropism and adaptation to the brain microenvironment and its drug resistance profile, make this pathogen a public health threat and a World Health Organization (WHO) priority. This study presents the first reconstructed genome-scale metabolic model (GSMM), iRV890, for C. neoformans var. grubii, which comprises 890 genes, 2598 reactions, and 2047 metabolites across four compartments. The GSMM iRV890 model was reconstructed using the open-source software tool merlin 4.0.2 and is openly available in the well-established systems biology markup language (SBML) format and underwent validation using experimental data for specific growth and glucose consumption rates, and 222 nitrogen and carbon assimilation sources, with a 85% prediction rate. Based on the comparison with GSMMs available for other pathogenic yeasts, unique metabolic features were predicted for C. neoformans, including key pathways shaping dynamics between C. neoformans and human host, as well as its underlying adaptions to the brain environment. Finally, the 96 predicted essential genes from the validated model are investigated as potential novel antifungal drug targetsincluding Erg4, Chs1, Fol1, and Fas1which represent promising candidates for targeted drug development due to their absence in human cells.

The fungal pathogen Candida albicans colonizes the human gut, where short-chain fatty acids (SCFAs) serve as a source of carbon. This fungus harbors one of the largest microbial families of ATO (acetate transporter ortholog) genes, which encode putative SCFA transport proteins. Here, we generate C. albicans null mutants lacking individual or all known putative SCFA transporter genes and compare their phenotypes in vitro and in vivo. We show that blocking ATO function in C. albicans impairs SCFA uptake and growth, particularly on acetate. The uptake of acetate is largely dependent on a functional Ato1 (also known as Frp3/Ato3), and it is effectively abolished upon deletion of all ATO genes. We further demonstrate that deletion of the entire ATO gene family, but not inactivation of ATO1 alone, compromises the stable colonization of C. albicans in the murine gastrointestinal tract following bacterial disruption by broad-spectrum antibiotics. Our data suggest that the ATO gene family has expanded and diversified during the evolution of C. albicans to promote the fitness of this fungal commensal during gut colonization, in part through SCFA utilization.

Candida albicans is a fungal commensal of humans that often causes mucosal infections in otherwise healthy individuals and also serious infections in immunocompromised patients. The capacity of this fungus to colonize and cause disease relies on its ability to grow within the host, adapting to various nutrient restrictions and physicochemical conditions. The presence of alternative carbon sources, such as the lactate produced by the local microbiota, influences C. albicans antifungal drug resistance and immune evasion. In this study, we used genome-wide transcriptomic analysis to investigate the effect of lactate exposure upon metabolic rewiring. We provide evidence that C. albicans cells respond to growth in the presence of lactate at pH 5 by regulating genes encoding micronutrient transporters, notably iron transporters. More specifically, lactate triggers the downregulation of genes on the reductive iron uptake pathway, inferring a diminished requirement for high-affinity iron uptake. This is supported by the observation that lactate promotes the intracellular accumulation of iron by C. albicans cells. Lactate even enhances the growth of iron-transport defective C. albicans cells under iron-limited conditions. Lactate is known to activate protein kinase A (PKA) signaling. However, lactate-induced iron assimilation is PKA-independent. This study provides new insights into the role of lactate in iron homeostasis—two important factors that promote C. albicans virulence in the mammalian host, where nutritional immunity is a key antimicrobial strategy.

Candida albicans, a commensal opportunistic pathogen, exhibits remarkable metabolic flexibility and adaptability to environmental changes. In glucose-limited niches, it utilizes alternative carbon sources such as carboxylic acids, which may influence its pathogenicity. In Saccharomyces cerevisiae, the uptake of monocarboxylates occurs through regulated plasma membrane (PM) transport proteins, such as Ato1 (Ady2), which belongs to the Acetate Uptake Transporter (AceTr) family. In C. albicans, these proteins are notably expanded, consisting of ten Ato-like proteins (ATO1-ATO10), whose functions remain unknown. Here, we investigated the role of Ato proteins in carboxylic acid utilization by C. albicans using in-silico and functional analysis. Our data revealed that several C. albicans Atos retain conserved AceTr motifs but possess distinct structural features, including differences in pore radius and binding sites for acetate and lactate. Expression analysis revealed that Ato1, Ato2, Ato3, and Ato6 exhibit distinct cellular localization and expression levels on the plasma membrane, depending on the presence or absence of monocarboxylates. Remarkably, deletion of ATO1 impaired Ato2 and Ato3 expression and caused ER retention of a distinct form of Ato2, suggesting a central regulatory role for Ato1 in the Ato transport system. Finally, we identified a novel Ato-related protein family in vertebrates. This family has three consecutive 6-helix transport domains and a unique C-terminal fusion with Sua5/YciO/YrdC, an enzyme involved in tRNA modification. Overall, our data suggests that the Ato protein family might play a critical role in the utilization of acetic or lactic acids in C. albicans. It also proposes potential functional redundancy among its members, which may contribute to rapid environmental adaptation and pathogenicity.

In this paper, the performance of different railway structures – ballasted and two types of slab tracks (Rheda system and a ballastless track only constituted by the concrete slab) – is evaluated in terms of stresses and permanent deformations through the selection of some important parameters: wavelength of the unevenness profile, train’s speed, subgrade’s characteristics and spatial variability of the track unevenness profile. The elastodynamic response of 60 case studies is computed through a 2.5D model FEM-PML and the long-term behaviour is assessed by the implementation of a permanent deformation model. The obtained results are analysed through innovative stress and permanent deformation amplification factors in the subgrade layer. This study concludes that the train’s speed and the mechanical properties of the subgrade are the factors that most affect the long-term performance of the subgrade of railway structures, which must be considered for further optimization of the rail track structures.