Essays Biochem. 2024 May 7:EBC20230094. doi: 10.1042/EBC20230094. Online ahead of print.

ABSTRACT

The vast structural diversity of sulfated polysaccharides demands an equally diverse array of enzymes known as polysaccharide sulfotransferases (PSTs). PSTs are present across all kingdoms of life, including algae, fungi and archaea, and their sulfation pathways are relatively unexplored. Sulfated polysaccharides possess anti-inflammatory, anticoagulant and anti-cancer properties and have great therapeutic potential. Current identification of PSTs using Pfam has been predominantly focused on the identification of glycosaminoglycan (GAG) sulfotransferases because of their pivotal roles in cell communication, extracellular matrix formation and coagulation. As a result, our knowledge of non-GAG PSTs structure and function remains limited. The major sulfotransferase families, Sulfotransfer_1 and Sulfotransfer_2, display broad homology and should enable the capture of a wide assortment of sulfotransferases but are limited in non-GAG PST sequence annotation. In addition, sequence annotation is further restricted by the paucity of biochemical analyses of PSTs. There are now high-throughput and robust assays for sulfotransferases such as colorimetric PAPS (3'-phosphoadenosine 5'-phosphosulfate) coupled assays, Europium-based fluorescent probes for ratiometric PAP (3'-phosphoadenosine-5'-phosphate) detection, and NMR methods for activity and product analysis. These techniques provide real-time and direct measurements to enhance the functional annotation and subsequent analysis of sulfated polysaccharides across the tree of life to improve putative PST identification and characterisation of function. Improved annotation and biochemical analysis of PST sequences will enhance the utility of PSTs across biomedical and biotechnological sectors.

PMID:38712401 | DOI:10.1042/EBC20230094

NAR Genom Bioinform. 2024 May 6;6(2):lqae046. doi: 10.1093/nargab/lqae046. eCollection 2024 Jun.

ABSTRACT

Variations in serum amino acid levels are linked to a multitude of complex disorders. We report the largest genome-wide association study (GWAS) on nine serum amino acids in the UK Biobank participants (117 944, European descent). We identified 34 genomic loci for circulatory levels of alanine, 48 loci for glutamine, 44 loci for glycine, 16 loci for histidine, 11 loci for isoleucine, 19 loci for leucine, 9 loci for phenylalanine, 32 loci for tyrosine and 20 loci for valine. Our gene-based analysis mapped 46-293 genes associated with serum amino acids, including MIP, GLS2, SLC gene family, GCKR, LMO1, CPS1 and COBLL1.The gene-property analysis across 30 tissues highlighted enriched expression of the identified genes in liver tissues for all studied amino acids, except for isoleucine and valine, in muscle tissues for serum alanine and glycine, in adrenal gland tissues for serum isoleucine and leucine, and in pancreatic tissues for serum phenylalanine. Mendelian randomization (MR) phenome-wide association study analysis and subsequent two-sample MR analysis provided evidence that every standard deviation increase in valine is associated with 35% higher risk of type 2 diabetes and elevated levels of serum alanine and branched-chain amino acids with higher levels of total cholesterol, triglyceride and low-density lipoprotein, and lower levels of high-density lipoprotein. In contrast to reports by observational studies, MR analysis did not support a causal association between studied amino acids and coronary artery disease, Alzheimer's disease, breast cancer or prostate cancer. In conclusion, we explored the genetic architecture of serum amino acids and provided evidence supporting a causal role of amino acids in cardiometabolic health.

PMID:38711861 | PMC:PMC11071119 | DOI:10.1093/nargab/lqae046

Front Med (Lausanne). 2024 Apr 22;11:1243659. doi: 10.3389/fmed.2024.1243659. eCollection 2024.

ABSTRACT

Skin cancer mortality rates continue to rise, and survival analysis is increasingly needed to understand who is at risk and what interventions improve outcomes. However, current statistical methods are limited by inability to synthesize multiple data types, such as patient genetics, clinical history, demographics, and pathology and reveal significant multimodal relationships through predictive algorithms. Advances in computing power and data science enabled the rise of artificial intelligence (AI), which synthesizes vast amounts of data and applies algorithms that enable personalized diagnostic approaches. Here, we analyze AI methods used in skin cancer survival analysis, focusing on supervised learning, unsupervised learning, deep learning, and natural language processing. We illustrate strengths and weaknesses of these approaches with examples. Our PubMed search yielded 14 publications meeting inclusion criteria for this scoping review. Most publications focused on melanoma, particularly histopathologic interpretation with deep learning. Such concentration on a single type of skin cancer amid increasing focus on deep learning highlight growing areas for innovation; however, it also demonstrates opportunity for additional analysis that addresses other types of cutaneous malignancies and expands the scope of prognostication to combine both genetic, histopathologic, and clinical data. Moreover, researchers may leverage multiple AI methods for enhanced benefit in analyses. Expanding AI to this arena may enable improved survival analysis, targeted treatments, and outcomes.

PMID:38711781 | PMC:PMC11070520 | DOI:10.3389/fmed.2024.1243659

Data Brief. 2024 Apr 20;54:110449. doi: 10.1016/j.dib.2024.110449. eCollection 2024 Jun.

ABSTRACT

In the last few decades, perennial mountain streams are becoming increasingly intermittent, due to global climate change and anthropogenic pressures. This phenomenon leads to negative effects on benthic communities' biodiversity and river ecosystems functionality. However, the impact of flow intermittency in previously perennial Alpine streams is still poorly investigated. This dataset consists of all the data collected during a spring sampling campaign performed in April-May 2017 along 13 mountain streams located in the SW Italian Alps. These watercourses have been selected because it was possible to identify two different sampling sites: one perennial, where water has always been flowing throughout the years, and one intermittent, which showed flowing water during the sampling campaign but, in the last decade, has experienced summer dry phases. All the sites have been characterized defining the microhabitats in which samples were retrieved, and physico-chemical data were collected at each site. Biological sampling included benthic macroinvertebrates and diatoms. Therefore, the present dataset offers various biological, ecological and physico-chemical information regarding Alpine streams which have recently become intermittent. Potentially, it could be used for comparisons with different benthic communities present in mountain rivers worldwide which are facing drying events too. The broad range of information present in this dataset offers the possibility to examine only the perennial sites themselves, as an example of good river functionality due to continuous flowing water, or only the intermittent ones, to better understand the effects of drying events on these peculiar ecosystems.

PMID:38711741 | PMC:PMC11070659 | DOI:10.1016/j.dib.2024.110449

Front Immunol. 2024 Apr 22;15:1395642. doi: 10.3389/fimmu.2024.1395642. eCollection 2024.

ABSTRACT

[This corrects the article DOI: 10.3389/fimmu.2022.935692.].

PMID:38711502 | PMC:PMC11070787 | DOI:10.3389/fimmu.2024.1395642

iScience. 2024 Apr 16;27(5):109736. doi: 10.1016/j.isci.2024.109736. eCollection 2024 May 17.

ABSTRACT

Discovering causal effects is at the core of scientific investigation but remains challenging when only observational data are available. In practice, causal networks are difficult to learn and interpret, and limited to relatively small datasets. We report a more reliable and scalable causal discovery method (iMIIC), based on a general mutual information supremum principle, which greatly improves the precision of inferred causal relations while distinguishing genuine causes from putative and latent causal effects. We showcase iMIIC on synthetic and real-world healthcare data from 396,179 breast cancer patients from the US Surveillance, Epidemiology, and End Results program. More than 90% of predicted causal effects appear correct, while the remaining unexpected direct and indirect causal effects can be interpreted in terms of diagnostic procedures, therapeutic timing, patient preference or socio-economic disparity. iMIIC's unique capabilities open up new avenues to discover reliable and interpretable causal networks across a range of research fields.

PMID:38711452 | PMC:PMC11070693 | DOI:10.1016/j.isci.2024.109736

Brief Bioinform. 2024 Mar 27;25(3):bbae217. doi: 10.1093/bib/bbae217.

ABSTRACT

Hi-C data are commonly normalized using single sample processing methods, with focus on comparisons between regions within a given contact map. Here, we aim to compare contact maps across different samples. We demonstrate that unwanted variation, of likely technical origin, is present in Hi-C data with replicates from different individuals, and that properties of this unwanted variation change across the contact map. We present band-wise normalization and batch correction, a method for normalization and batch correction of Hi-C data and show that it substantially improves comparisons across samples, including in a quantitative trait loci analysis as well as differential enrichment across cell types.

PMID:38711367 | DOI:10.1093/bib/bbae217

Elife. 2024 May 7;13:e85694. doi: 10.7554/eLife.85694.

ABSTRACT

Collaborative hunting, in which predators play different and complementary roles to capture prey, has been traditionally believed to be an advanced hunting strategy requiring large brains that involve high-level cognition. However, recent findings that collaborative hunting has also been documented in smaller-brained vertebrates have placed this previous belief under strain. Here, using computational multi-agent simulations based on deep reinforcement learning, we demonstrate that decisions underlying collaborative hunts do not necessarily rely on sophisticated cognitive processes. We found that apparently elaborate coordination can be achieved through a relatively simple decision process of mapping between states and actions related to distance-dependent internal representations formed by prior experience. Furthermore, we confirmed that this decision rule of predators is robust against unknown prey controlled by humans. Our computational ecological results emphasize that collaborative hunting can emerge in various intra- and inter-specific interactions in nature, and provide insights into the evolution of sociality.

PMID:38711355 | DOI:10.7554/eLife.85694

J Extracell Vesicles. 2024 May;13(5):e12445. doi: 10.1002/jev2.12445.

ABSTRACT

Small extracellular vesicles (sEV) derived from various cell sources have been demonstrated to enhance cardiac function in preclinical models of myocardial infarction (MI). The aim of this study was to compare different sources of sEV for cardiac repair and determine the most effective one, which nowadays remains limited. We comprehensively assessed the efficacy of sEV obtained from human primary bone marrow mesenchymal stromal cells (BM-MSC), human immortalized MSC (hTERT-MSC), human embryonic stem cells (ESC), ESC-derived cardiac progenitor cells (CPC), human ESC-derived cardiomyocytes (CM), and human primary ventricular cardiac fibroblasts (VCF), in in vitro models of cardiac repair. ESC-derived sEV (ESC-sEV) exhibited the best pro-angiogenic and anti-fibrotic effects in vitro. Then, we evaluated the functionality of the sEV with the most promising performances in vitro, in a murine model of MI-reperfusion injury (IRI) and analysed their RNA and protein compositions. In vivo, ESC-sEV provided the most favourable outcome after MI by reducing adverse cardiac remodelling through down-regulating fibrosis and increasing angiogenesis. Furthermore, transcriptomic, and proteomic characterizations of sEV derived from hTERT-MSC, ESC, and CPC revealed factors in ESC-sEV that potentially drove the observed functions. In conclusion, ESC-sEV holds great promise as a cell-free treatment for promoting cardiac repair following MI.

PMID:38711334 | DOI:10.1002/jev2.12445

BMC Plant Biol. 2024 May 7;24(1):369. doi: 10.1186/s12870-024-05036-1.

ABSTRACT

BACKGROUND: The increasing demand for saffron metabolites in various commercial industries, including medicine, food, cosmetics, and dyeing, is driven by the discovery of their diverse applications. Saffron, derived from Crocus sativus stigmas, is the most expensive spice, and there is a need to explore additional sources to meet global consumption demands. In this study, we focused on yellow-flowering crocuses and examined their tepals to identify saffron-like compounds.

RESULTS: Through metabolomic and transcriptomic approaches, our investigation provides valuable insights into the biosynthesis of compounds in yellow-tepal crocuses that are similar to those found in saffron. The results of our study support the potential use of yellow-tepal crocuses as a source of various crocins (crocetin glycosylated derivatives) and flavonoids.

CONCLUSIONS: Our findings suggest that yellow-tepal crocuses have the potential to serve as a viable excessive source of some saffron metabolites. The identification of crocins and flavonoids in these crocuses highlights their suitability for meeting the demands of various industries that utilize saffron compounds. Further exploration and utilization of yellow-tepal crocuses could contribute to addressing the growing global demand for saffron-related products.

PMID:38711012 | DOI:10.1186/s12870-024-05036-1

NPJ Syst Biol Appl. 2024 May 6;10(1):47. doi: 10.1038/s41540-024-00372-2.

ABSTRACT

Understanding and manipulating cell fate determination is pivotal in biology. Cell fate is determined by intricate and nonlinear interactions among molecules, making mathematical model-based quantitative analysis indispensable for its elucidation. Nevertheless, obtaining the essential dynamic experimental data for model development has been a significant obstacle. However, recent advancements in large-scale omics data technology are providing the necessary foundation for developing such models. Based on accumulated experimental evidence, we can postulate that cell fate is governed by a limited number of core regulatory circuits. Following this concept, we present a conceptual control framework that leverages single-cell RNA-seq data for dynamic molecular regulatory network modeling, aiming to identify and manipulate core regulatory circuits and their master regulators to drive desired cellular state transitions. We illustrate the proposed framework by applying it to the reversion of lung cancer cell states, although it is more broadly applicable to understanding and controlling a wide range of cell-fate determination processes.

PMID:38710700 | DOI:10.1038/s41540-024-00372-2

Nat Commun. 2024 May 6;15(1):3789. doi: 10.1038/s41467-024-48045-2.

ABSTRACT

The CUL3-RING E3 ubiquitin ligases (CRL3s) play an essential role in response to extracellular nutrition and stress stimuli. The ubiquitin ligase function of CRL3s is activated through dimerization. However, how and why such a dimeric assembly is required for its ligase activity remains elusive. Here, we report the cryo-EM structure of the dimeric CRL3KLHL22 complex and reveal a conserved N-terminal motif in CUL3 that contributes to the dimerization assembly and the E3 ligase activity of CRL3KLHL22. We show that deletion of the CUL3 N-terminal motif impairs dimeric assembly and the E3 ligase activity of both CRL3KLHL22 and several other CRL3s. In addition, we found that the dynamics of dimeric assembly of CRL3KLHL22 generates a variable ubiquitination zone, potentially facilitating substrate recognition and ubiquitination. These findings demonstrate that a CUL3 N-terminal motif participates in the assembly process and provide insights into the assembly and activation of CRL3s.

PMID:38710693 | DOI:10.1038/s41467-024-48045-2

Nat Commun. 2024 May 6;15(1):3781. doi: 10.1038/s41467-024-47742-2.

ABSTRACT

Taking inspiration from natural systems, in which molecular switches are ubiquitous in the biochemistry regulatory network, we aim to design and construct synthetic molecular switches driven by DNA-modifying enzymes, such as DNA polymerase and nicking endonuclease. The enzymatic treatments on our synthetic DNA constructs controllably switch ON or OFF the sticky end cohesion and in turn cascade to the structural association or disassociation. Here we showcase the concept in multiple DNA nanostructure systems with robust assembly/disassembly performance. The switch mechanisms are first illustrated in minimalist systems with a few DNA strands. Then the ON/OFF switches are realized in complex DNA lattice and origami systems with designated morphological changes responsive to the specific enzymatic treatments.

PMID:38710688 | DOI:10.1038/s41467-024-47742-2

J Ethnopharmacol. 2024 May 4:118295. doi: 10.1016/j.jep.2024.118295. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Phlomis crinita Cav. (Lamiaceae), locally known as "El Khayata" or "Kayat El Adjarah", is traditionally used in Algeria for its wound-healing properties.

AIM OF THE STUDY: Investigate, for the first time, the phytochemical profile, safety, antioxidant and wound-healing activities of the flowering tops methanolic extract of P. crinita (PCME) collected from Bouira Province in the North of Algeria.

MATERIALS AND METHODS: Preliminary phytochemical assays were carried out on PCME to quantify the main classes of bioactive compounds, such as total phenols, flavonoids, and tannins. An in-depth LC-DAD-ESI-MS analysis was carried out to elucidate the phytochemical profile of this plant species. Antioxidant activity was investigated by several colorimetric and fluorimetric assays (DPPH, TEAC, FRAP, ORAC, β-carotene bleaching and ferrozine assay). The acute oral toxicity of PCME (2000 mg/kg b.w.) was tested in vivo on Swiss albino mice, whereas the acute dermal toxicity and wound-healing properties of the PCME ointment (1-5% PCMO) were tested in vivo on Wistar albino rats. Biochemical and histological analyses were carried out on biological samples.

RESULTS: The phytochemical screening highlighted a high content of phenolic compounds (175.49 ± 0.8 mg of gallic acid equivalents/g of dry extract), mainly flavonoids (82.28 ± 0.44 mg of quercetin equivalents/g of dry extract). Fifty-seven compounds were identified by LC-DAD-ESI-MS analysis, belonging mainly to the class of flavones (32.27%), with luteolin 7-(6''-acetylglucoside) as the most abundant compound and phenolic acids (32.54%), with salvianolic acid C as the most abundant compound. A conspicuous presence of phenylethanoids (15.26%) was also found, of which the major constituent is forsythoside B. PCME showed a strong antioxidant activity with half-inhibitory activity (IC50) ranging from 1.88 to 37.88 μg/mL and a moderate iron chelating activity (IC50 327.44 μg/mL). PCME appears to be safe with Lethal Dose 50 (LD50) ≥ 2000 mg/kg b.w. No mortality or toxicity signs, including any statistically significant changes in body weight gain and relative organs' weight with respect to the control group, were recorded. A significant (p < 0.001) wound contraction was observed in the 5% PCMO-treated group with respect to the untreated and petroleum jelly groups between 8 and 20 days, whereas no statistically significant results were observed at the two lower doses (1 and 2% PCMO). In addition, the 5% PCMO-treated group showed a statistically significant (p < 0.05) wound healing activity with respect to the reference drug-treated group, showing, at the end of the study, the highest wound contraction percentage (88.00 ± 0.16%).

CONCLUSION: PCME was safe and showed strong antioxidant and wound-healing properties, suggesting new interesting pharmaceutical applications for P. crinita based on its traditional use.

PMID:38710460 | DOI:10.1016/j.jep.2024.118295

Eur J Pharmacol. 2024 May 4:176634. doi: 10.1016/j.ejphar.2024.176634. Online ahead of print.

ABSTRACT

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with immune dysregulation affecting colon inflammatory response. Recent studies have highlighted that neutrophil extracellular traps (NETs) play an important role in the pathogenesis of UC. Berbamine (BBM), one of the bioactive ingredients extracted from Chinese herbal medicine Berberis vulgaris L, has attracted intensive attentions due to its significant anti-inflammatory activity and a marketing drug for treating leukemia in China. However, the exact role and potential molecular mechanism of BBM against UC remains elusive. In the present study, our results showed that BBM could markedly improve the pathological phenotype and the colon inflammation in mice with dextran sulfate sodium (DSS)-induced colitis. Then, comprehensive approaches combining network pharmacology and molecular docking analyses were employed to predict the therapeutic potential of BBM in treating UC by peptidyl-arginine deiminase 4 (PAD4), a crucial molecule involved in NETs formation. The molecular docking results showed BBM had a high affinity for PAD4 with a binding energy of -9.3 kcal/mol Moreover, PAD4 expression and NETs productions, including citrullination of histone H3 (Cit-H3), neutrophil elastase (NE), myeloperoxidase (MPO) in both neutrophils and colonic tissue were reduced after BBM administration. However, in the mice with DSS-induced colitis pretreated with GSK484, a PAD4-specific inhibitor, BBM could not further reduce disease related indexes, expression of PAD4 and NETs productions. Above all, the identification of PAD4 as a potential target for BBM to inhibit NETs formation in colitis provides novel insights into the development of BBM-derived drugs for the clinical management of UC.

PMID:38710356 | DOI:10.1016/j.ejphar.2024.176634

Proc Natl Acad Sci U S A. 2024 May 14;121(20):e2316271121. doi: 10.1073/pnas.2316271121. Epub 2024 May 6.

ABSTRACT

Random mutagenesis, including when it leads to loss of gene function, is a key mechanism enabling microorganisms' long-term adaptation to new environments. However, loss-of-function mutations are often deleterious, triggering, in turn, cellular stress and complex homeostatic stress responses, called "allostasis," to promote cell survival. Here, we characterize the differential impacts of 65 nonlethal, deleterious single-gene deletions on Escherichia coli growth in three different growth environments. Further assessments of select mutants, namely, those bearing single adenosine triphosphate (ATP) synthase subunit deletions, reveal that mutants display reorganized transcriptome profiles that reflect both the environment and the specific gene deletion. We also find that ATP synthase α-subunit deleted (ΔatpA) cells exhibit elevated metabolic rates while having slower growth compared to wild-type (wt) E. coli cells. At the single-cell level, compared to wt cells, individual ΔatpA cells display near normal proliferation profiles but enter a postreplicative state earlier and exhibit a distinct senescence phenotype. These results highlight the complex interplay between genomic diversity, adaptation, and stress response and uncover an "aging cost" to individual bacterial cells for maintaining population-level resilience to environmental and genetic stress; they also suggest potential bacteriostatic antibiotic targets and -as select human genetic diseases display highly similar phenotypes, - a bacterial origin of some human diseases.

PMID:38709929 | DOI:10.1073/pnas.2316271121

Nucleic Acids Res. 2024 May 6:gkae330. doi: 10.1093/nar/gkae330. Online ahead of print.

ABSTRACT

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a human pathogen that is now endemic to several East Asian countries. The viral large (L) protein catalyzes viral transcription by stealing host mRNA caps via a process known as cap-snatching. Here, we establish an in vitro cap-snatching assay and present three high-quality electron cryo-microscopy (cryo-EM) structures of the SFTSV L protein in biologically relevant, transcription-specific states. In a priming-state structure, we show capped RNA bound to the L protein cap-binding domain (CBD). The L protein conformation in this priming structure is significantly different from published replication-state structures, in particular the N- and C-terminal domains. The capped-RNA is positioned in a way that it can feed directly into the RNA-dependent RNA polymerase (RdRp) ready for elongation. We also captured the L protein in an early-elongation state following primer-incorporation demonstrating that this priming conformation is retained at least in the very early stages of primer extension. This structural data is complemented by in vitro biochemical and cell-based assays. Together, these insights further our mechanistic understanding of how SFTSV and other bunyaviruses incorporate stolen host mRNA fragments into their viral transcripts thereby allowing the virus to hijack host cell translation machinery.

PMID:38709882 | DOI:10.1093/nar/gkae330

Nucleic Acids Res. 2024 May 6:gkae346. doi: 10.1093/nar/gkae346. Online ahead of print.

ABSTRACT

Small ubiquitin-like modifiers (SUMOs) are tiny but important protein regulators involved in orchestrating a broad spectrum of biological processes, either by covalently modifying protein substrates or by noncovalently interacting with other proteins. Here, we report an updated server, GPS-SUMO 2.0, for the prediction of SUMOylation sites and SUMO-interacting motifs (SIMs). For predictor training, we adopted three machine learning algorithms, penalized logistic regression (PLR), a deep neural network (DNN), and a transformer, and used 52 404 nonredundant SUMOylation sites in 8262 proteins and 163 SIMs in 102 proteins. To further increase the accuracy of predicting SUMOylation sites, a pretraining model was first constructed using 145 545 protein lysine modification sites, followed by transfer learning to fine-tune the model. GPS-SUMO 2.0 exhibited greater accuracy in predicting SUMOylation sites than did other existing tools. For users, one or multiple protein sequences or identifiers can be input, and the prediction results are shown in a tabular list. In addition to the basic statistics, we integrated knowledge from 35 public resources to annotate SUMOylation sites or SIMs. The GPS-SUMO 2.0 server is freely available at https://sumo.biocuckoo.cn/. We believe that GPS-SUMO 2.0 can serve as a useful tool for further analysis of SUMOylation and SUMO interactions.

PMID:38709873 | DOI:10.1093/nar/gkae346

PLoS Comput Biol. 2024 May 6;20(5):e1012067. doi: 10.1371/journal.pcbi.1012067. Online ahead of print.

ABSTRACT

Chromosome conformation capture (3C) technologies reveal the incredible complexity of genome organization. Maps of increasing size, depth, and resolution are now used to probe genome architecture across cell states, types, and organisms. Larger datasets add challenges at each step of computational analysis, from storage and memory constraints to researchers' time; however, analysis tools that meet these increased resource demands have not kept pace. Furthermore, existing tools offer limited support for customizing analysis for specific use cases or new biology. Here we introduce cooltools (https://github.com/open2c/cooltools), a suite of computational tools that enables flexible, scalable, and reproducible analysis of high-resolution contact frequency data. Cooltools leverages the widely-adopted cooler format which handles storage and access for high-resolution datasets. Cooltools provides a paired command line interface (CLI) and Python application programming interface (API), which respectively facilitate workflows on high-performance computing clusters and in interactive analysis environments. In short, cooltools enables the effective use of the latest and largest genome folding datasets.

PMID:38709825 | DOI:10.1371/journal.pcbi.1012067

PLoS Genet. 2024 May 6;20(5):e1011064. doi: 10.1371/journal.pgen.1011064. Online ahead of print.

ABSTRACT

The capacity for bacterial extracellular electron transfer via secreted metabolites is widespread in natural, clinical, and industrial environments. Recently, we discovered biological oxidation of phenazine-1-carboxylic acid (PCA), the first example of biological regeneration of a naturally produced extracellular electron shuttle. However, it remained unclear how PCA oxidation was catalyzed. Here, we report the mechanism, which we uncovered by genetically perturbing the branched electron transport chain (ETC) of the soil isolate Citrobacter portucalensis MBL. Biological PCA oxidation is coupled to anaerobic respiration with nitrate, fumarate, dimethyl sulfoxide, or trimethylamine-N-oxide as terminal electron acceptors. Genetically inactivating the catalytic subunits for all redundant complexes for a given terminal electron acceptor abolishes PCA oxidation. In the absence of quinones, PCA can still donate electrons to certain terminal reductases, albeit much less efficiently. In C. portucalensis MBL, PCA oxidation is largely driven by flux through the ETC, which suggests a generalizable mechanism that may be employed by any anaerobically respiring bacterium with an accessible cytoplasmic membrane. This model is supported by analogous genetic experiments during nitrate respiration by Pseudomonas aeruginosa.

PMID:38709821 | DOI:10.1371/journal.pgen.1011064