Commun Biol. 2023 Nov 10;6(1):1142. doi: 10.1038/s42003-023-05513-7.

ABSTRACT

The branchpoint (BP) motif is an essential intronic element for spliceosomal pre-mRNA splicing. In mammals, its sequence composition, distance to the downstream exon, and number of BPs per 3´ splice site are highly variable, unlike the GT/AG dinucleotides at the intron ends. These variations appear to provide evolutionary advantages for fostering alternative splicing, satisfying more diverse cellular contexts, and promoting resilience to genetic changes, thus contributing to an extra layer of complexity for gene regulation. Importantly, variants in the BP motif itself or in genes encoding BP-interacting factors cause human genetic diseases or cancers, highlighting the critical function of BP motif and the need to precisely identify functional BPs for faithful interpretation of their roles in splicing. In this perspective, we will succinctly summarize the major findings related to BP motif variations, discuss the relevant issues/challenges, and provide our insights.

PMID:37949953 | DOI:10.1038/s42003-023-05513-7

Trends Immunol. 2023 Nov 9:S1471-4906(23)00216-8. doi: 10.1016/j.it.2023.10.009. Online ahead of print.

ABSTRACT

A binary classification of macrophage activation as inflammatory or resolving does not capture the diversity of macrophage states observed in tissues. However, framing macrophage activation as a continuous spectrum of states overlooks the intracellular and extracellular networks that regulate and coordinate macrophage responses. Here, we suggest that the systems biology concept of network motifs, which incorporate rules of local molecular interactions, is useful for reframing macrophage activation. Because network motifs can be used to regulate distinct biological functions, they offer a simplified unit that can be compared across organismal, tissue, and disease contexts. Moreover, defining macrophage states as combinations of functional modules regulated by network motifs offers a framework to ultimately predict and target macrophage responses arising in complex environments.

PMID:37949786 | DOI:10.1016/j.it.2023.10.009

J Am Chem Soc. 2023 Nov 10. doi: 10.1021/jacs.3c05753. Online ahead of print.

ABSTRACT

Adaptive and reversible self-assembly of supramolecular protein structures is a fundamental characteristic of dynamic living matter. However, the quantitative detection and assessment of the emergence of mesoscale protein complexes from small and dynamic oligomeric precursors remains highly challenging. Here, we present a novel approach utilizing a short membrane nanotube (sNT) pulled from a planar membrane reservoir as nanotemplates for molecular reconstruction, manipulation, and sensing of protein oligomerization and self-assembly at the mesoscale. The sNT reports changes in membrane shape and rigidity caused by membrane-bound proteins as variations of the ionic conductivity of the sNT lumen. To confine oligomerization to the sNT, we have designed and synthesized rigid oligoamide foldamer tapes (ROFTs). Charged ROFTs incorporate into the planar and sNT membranes, mediate protein binding to the membranes, and, driven by the luminal electric field, shuttle the bound proteins between the sNT and planar membranes. Using Annexin-V (AnV) as a prototype, we show that the sNT detects AnV oligomers shuttled into the nanotube by ROFTs. Accumulation of AnV on the sNT induces its self-assembly into a curved lattice, restricting the sNT geometry and inhibiting the material uptake from the reservoir during the sNT extension, leading to the sNT fission. By comparing the spontaneous and ROFT-mediated entry of AnV into the sNT, we reveal how intricate membrane curvature sensing by small AnV oligomers controls the lattice self-assembly. These results establish sNT-ROFT as a powerful tool for molecular reconstruction and functional analyses of protein oligomerization and self-assembly, with broad application to various membrane processes.

PMID:37948300 | DOI:10.1021/jacs.3c05753

Theory Biosci. 2023 Nov 10. doi: 10.1007/s12064-023-00408-x. Online ahead of print.

ABSTRACT

Counting transcripts of mRNA are a key method of observation in modern biology. With advances in counting transcripts in single cells (single-cell RNA sequencing or scRNA-seq), these data are routinely used to identify cells by their transcriptional profile, and to identify genes with differential cellular expression. Because the total number of transcripts counted per cell can vary for technical reasons, the first step of many commonly used scRNA-seq workflows is to normalize by sequencing depth, transforming counts into proportional abundances. The primary objective of this step is to reshape the data such that cells with similar biological proportions of transcripts end up with similar transformed measurements. But there is growing concern that normalization and other transformations result in unintended distortions that hinder both analyses and the interpretation of results. This has led to an intense focus on optimizing methods for normalization and transformation of scRNA-seq data. Here, we take an alternative approach, by avoiding normalization and transformation altogether. We abandon the use of distances to compare cells, and instead use a restricted algebra, motivated by measurement theory and abstract algebra, that preserves the count nature of the data. We demonstrate that this restricted algebra is sufficient to draw meaningful and practical comparisons of gene expression through the use of the dot product and other elementary operations. This approach sidesteps many of the problems with common transformations, and has the added benefit of being simpler and more intuitive. We implement our approach in the package countland, available in python and R.

PMID:37947999 | DOI:10.1007/s12064-023-00408-x

Bioinformatics. 2023 Nov 8:btad674. doi: 10.1093/bioinformatics/btad674. Online ahead of print.

ABSTRACT

MOTIVATION: Biological tissues are dynamic and highly organized. Multi-scale models are helpful tools to analyze and understand the processes determining tissue dynamics. These models usually depend on parameters that need to be inferred from experimental data to achieve a quantitative understanding, to predict the response to perturbations, and to evaluate competing hypotheses. However, even advanced inference approaches such as Approximate Bayesian Computation (ABC) are difficult to apply due to the computational complexity of the simulation of multi-scale models. Thus, there is a need for a scalable pipeline for modeling, simulating, and parameterizing multi-scale models of multi-cellular processes.

RESULTS: Here, we present FitMultiCell, a computationally efficient and user-friendly open-source pipeline that can handle the full workflow of modeling, simulating, and parameterizing for multi-scale models of multi-cellular processes. The pipeline is modular and integrates the modeling and simulation tool Morpheus and the statistical inference tool pyABC. The easy integration of high-performance infrastructure allows to scale to computationally expensive problems. The introduction of a novel standard for the formulation of parameter inference problems for multi-scale models additionally ensures reproducibility and reusability. By applying the pipeline to multiple biological problems, we demonstrate its broad applicability, which will benefit in particular image-based systems biology.

AVAILABILITY: FitMultiCell is available open-source at https://gitlab.com/fitmulticell/fit.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:37947308 | DOI:10.1093/bioinformatics/btad674

J Neuroendocrinol. 2023 Nov 10:e13354. doi: 10.1111/jne.13354. Online ahead of print.

ABSTRACT

Pituitary adenylate cyclase-activating polypeptide (PACAP) and the homologous peptide, vasoactive intestinal peptide (VIP), participate in glucose homeostasis using insulinotropic and counterregulatory processes. The role of VIP receptor 2 (VPAC2R) in these opposing actions needs further characterization. In this study, we examined the participation of VPAC2R on basal glycemia, fasted levels of glucoregulatory hormones and on glycemia responses during metabolic and psychogenic stress using gene-deleted (Vipr2-/- ) female mice. The mean basal glycemia was significantly greater in Vipr2-/- in the fed state and after an 8-h overnight fast as compared to wild-type (WT) mice. Insulin tolerance testing following a 5-h fast (morning fast, 0.38 U/kg insulin) indicated no effect of genotype. However, during a more intense metabolic challenge (8 h, ON fast, 0.25 U/kg insulin), Vipr2-/- females displayed significantly impaired insulin hypoglycemia. During immobilization stress, the hyperglycemic response and plasma epinephrine levels were significantly elevated above basal in Vipr2-/- , but not WT mice, in spite of similar stress levels of plasma corticosterone. Together, these results implicate participation of VPAC2R in upregulated counterregulatory processes influenced by enhanced sympathoexcitation. Moreover, the suppression of plasma GLP-1 levels in Vipr2-/- mice may have removed the inhibition on hepatic glucose production and the promotion of glucose disposal by GLP-1. qPCR analysis indicated deregulation of central gene markers of PACAP/VIP signaling in Vipr2-/- , upregulated medulla tyrosine hydroxylase (Th) and downregulated hypothalamic Vip transcripts. These results demonstrate a physiological role for VPAC2R in glucose metabolism, especially during insulin challenge and psychogenic stress, likely involving the participation of sympathoadrenal activity and/or metabolic hormones.

PMID:37946684 | DOI:10.1111/jne.13354

Sci China Life Sci. 2023 Nov 7. doi: 10.1007/s11427-023-2398-y. Online ahead of print.

ABSTRACT

Invertebrate species are a natural reservoir of viral genetic diversity, and invertebrate pests are widely distributed in crop fields. However, information on viruses infecting invertebrate pests of crops is limited. In this report, we describe the deep metatranscriptomic sequencing of 88 invertebrate samples covering all major invertebrate pests in rice fields. We identified 296 new RNA viruses and 13 known RNA viruses. These viruses clustered within 31 families, with many highly divergent viruses constituting potentially new families and genera. Of the identified viruses, 13 RNA viruses clustered within the Fiersviridae family of bacteriophages, and 48 RNA viruses clustered within families and genera of mycoviruses. We detected known rice viruses in novel invertebrate hosts at high abundances. Furthermore, some novel RNA viruses have genome structures closely matching to known plant viruses and clustered within genera of several plant virus species. Forty-five potential insect pathogenic RNA viruses were detected in invertebrate species. Our analysis revealed that host taxonomy plays a major role and geographical location plays an important role in structuring viral diversity. Cross-species transmission of RNA viruses was detected between invertebrate hosts. Newly identified viral genomes showed extensive variation for invertebrate viral families or genera. Together, the large-scale metatranscriptomic analysis greatly expands our understanding of RNA viruses in rice invertebrate species, the results provide valuable information for developing efficient strategies to manage insect pests and virus-mediated crop diseases.

PMID:37946067 | DOI:10.1007/s11427-023-2398-y

Nat Med. 2023 Nov 9. doi: 10.1038/s41591-023-02684-y. Online ahead of print.

NO ABSTRACT

PMID:37946059 | DOI:10.1038/s41591-023-02684-y

Geroscience. 2023 Nov 10. doi: 10.1007/s11357-023-00969-1. Online ahead of print.

ABSTRACT

Among land vertebrates, the laying hen stands out due to its great reproductive efficiency: producing an egg daily all year long. This production rate makes the laying hen a special model animal to study the general process of reproduction and aging. One unique aspect of hens is their ability to undergo reproductive plasticity and to rejuvenate their reproductive tract during molting, a standard industrial feed restriction protocol for transiently pausing reproduction, followed by improved laying efficiency almost to peak production. Here we use longitudinal metabolomics, immunology, and physiological assays to show that molting promotes reproduction, compresses morbidity, and restores youthfulness when applied to old hens. We identified circulating metabolic biomarkers that quantitatively predict the reproduction and age of individuals. Lastly, we introduce metabolic noise, a robust, unitless, and quantifiable measure for heterogeneity of the complete metabolome as a general marker that can indicate the rate of aging of a population. Indeed, metabolic noise increased with age in control hens, whereas molted hens exhibited reduced noise following molting, indicating systemic rejuvenation. Our results suggest that metabolic noise can be used as a quick and universal proxy for assessing successful aging treatments, accelerating the timeline for drug development.

PMID:37946010 | DOI:10.1007/s11357-023-00969-1

Nat Genet. 2023 Nov 9. doi: 10.1038/s41588-023-01551-3. Online ahead of print.

ABSTRACT

Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA-positive medulloblastoma were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. A subset of tumors harbored multiple ecDNA lineages, each containing distinct amplified oncogenes. Multimodal sequencing, imaging and CRISPR inhibition experiments in medulloblastoma models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent putative 'enhancer rewiring' events on ecDNA. This study reveals the frequency and diversity of ecDNA in medulloblastoma, stratified into molecular subgroups, and suggests copy number heterogeneity and enhancer rewiring as oncogenic features of ecDNA.

PMID:37945900 | DOI:10.1038/s41588-023-01551-3

J Ethnopharmacol. 2023 Nov 7:117387. doi: 10.1016/j.jep.2023.117387. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Pluchea indica (L.) Less (family Asteraceae) is popularly consumed as a medicinal vegetable and used in ethnomedicine to treat various diseases including gastrointestinal problems such as dysentery and leucorrhoea, which are due to bacterial, fungal or parasitic infections. There have been numerous studies on the antimicrobial effects of the plant due to these ethnomedicine use.

AIM OF THIS REVIEW: This review is comprehensively discussed the information on the anti-infective properties of P. indica and its secondary metabolites, and highlight the potential of the plant as a new source of anti-infective agents.

MATERIALS AND METHODS: Scientific databases such as Web of Science, Google Scholar, Science Direct, PubMed, Wiley Online Library, and ACS Publications were used to gather the relevant information on the ability of P. indica to fight infections, with the leaves and roots receiving most of the attention.

RESULTS: Anti-bacterial, anti-mycobacterial, anti-malarial, and anti-viral activities have been the most exploited. Most studies were carried out on the crude extracts of the plant and in most studies the bioactive extracts were not standardized or chemically characterized. Several studies have reported the anti-infective activity of several bioactive components of P. indica including caffeoylquinic acids, terpenoid glycosides, thiophenes, and kaempferol.

CONCLUSIONS: The strong anti-infective effect and underlying mechanisms of the compounds provide insights into the potential of P. indica as a source of new leads for the development of anti-infective agents for use in food and pharmaceutical industries.

PMID:37944874 | DOI:10.1016/j.jep.2023.117387

Antiviral Res. 2023 Nov 7:105738. doi: 10.1016/j.antiviral.2023.105738. Online ahead of print.

ABSTRACT

Coronavirus Disease 2019 (COVID-19) pandemic is severely impacting the world, and tremendous efforts have been made to deal with it. Despite many advances in vaccines and therapeutics, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants remains an intractable challenge. We present a bivalent Receptor Binding Domain (RBD)-specific synthetic antibody, specific for the RBD of wild-type (lineage A), developed from a non-antibody protein scaffold composed of LRR (Leucine-rich repeat) modules through phage display. We further reinforced the unique feature of the synthetic antibody by constructing a tandem dimeric form. The resulting bivalent form showed a broader neutralizing activity against the variants. The in vivo neutralizing efficacy of the bivalent synthetic antibody was confirmed using a human ACE2-expressing mouse model that significantly alleviated viral titer and lung infection. The present approach can be used to develop a synthetic antibody showing a broader neutralizing activity against a multitude of SARS-CoV-2 variants.

PMID:37944822 | DOI:10.1016/j.antiviral.2023.105738

J Theor Biol. 2023 Nov 7:111655. doi: 10.1016/j.jtbi.2023.111655. Online ahead of print.

ABSTRACT

Michael Savageau's Biochemical Systems Analysis I, II, IIIpapers, published in volumes 25 and 26 of the journal,kickstarted a research programme that originated many of the core concepts and tools of Systems Biology. This article briefly summarizes these papers anddiscusses the most relevant developments in Biochemical Systems Theory since their publication.

PMID:37944592 | DOI:10.1016/j.jtbi.2023.111655

Cell Syst. 2023 Nov 3:S2405-4712(23)00299-5. doi: 10.1016/j.cels.2023.10.007. Online ahead of print.

ABSTRACT

Methylation of CG dinucleotides (mCGs), which regulates eukaryotic genome functions, is epigenetically propagated by Dnmt1/MET1 methyltransferases. How mCG is established and transmitted across generations despite imperfect enzyme fidelity is unclear. Whether mCG variation in natural populations is governed by genetic or epigenetic inheritance also remains mysterious. Here, we show that MET1 de novo activity, which is enhanced by existing proximate methylation, seeds and stabilizes mCG in Arabidopsis thaliana genes. MET1 activity is restricted by active demethylation and suppressed by histone variant H2A.Z, producing localized mCG patterns. Based on these observations, we develop a stochastic mathematical model that precisely recapitulates mCG inheritance dynamics and predicts intragenic mCG patterns and their population-scale variation given only CG site spacing. Our results demonstrate that intragenic mCG establishment, inheritance, and variance constitute a unified epigenetic process, revealing that intragenic mCG undergoes large, millennia-long epigenetic fluctuations and can therefore mediate evolution on this timescale.

PMID:37944515 | DOI:10.1016/j.cels.2023.10.007

Cell. 2023 Nov 1:S0092-8674(23)01128-5. doi: 10.1016/j.cell.2023.10.012. Online ahead of print.

ABSTRACT

A fundamental feature of cellular growth is that total protein and RNA amounts increase with cell size to keep concentrations approximately constant. A key component of this is that global transcription rates increase in larger cells. Here, we identify RNA polymerase II (RNAPII) as the limiting factor scaling mRNA transcription with cell size in budding yeast, as transcription is highly sensitive to the dosage of RNAPII but not to other components of the transcriptional machinery. Our experiments support a dynamic equilibrium model where global RNAPII transcription at a given size is set by the mass action recruitment kinetics of unengaged nucleoplasmic RNAPII to the genome. However, this only drives a sub-linear increase in transcription with size, which is then partially compensated for by a decrease in mRNA decay rates as cells enlarge. Thus, limiting RNAPII and feedback on mRNA stability work in concert to scale mRNA amounts with cell size.

PMID:37944513 | DOI:10.1016/j.cell.2023.10.012

Cell Host Microbe. 2023 Nov 8;31(11):1866-1881.e10. doi: 10.1016/j.chom.2023.10.007.

ABSTRACT

The commensal microflora provides a repertoire of antigens that illicit mucosal antibodies. In some cases, these antibodies can cross-react with host proteins, inducing autoimmunity, or with other microbial antigens. We demonstrate that the oral microbiota can induce salivary anti-SARS-CoV-2 Spike IgG antibodies via molecular mimicry. Anti-Spike IgG antibodies in the saliva correlated with enhanced abundance of Streptococcus salivarius 1 month after anti-SARS-CoV-2 vaccination. Several human commensal bacteria, including S. salivarius, were recognized by SARS-CoV-2-neutralizing monoclonal antibodies and induced cross-reactive anti-Spike antibodies in mice, facilitating SARS-CoV-2 clearance. A specific S. salivarius protein, RSSL-01370, contains regions with homology to the Spike receptor-binding domain, and immunization of mice with RSSL-01370 elicited anti-Spike IgG antibodies in the serum. Additionally, oral S. salivarius supplementation enhanced salivary anti-Spike antibodies in vaccinated individuals. Altogether, these data show that distinct species of the human microbiota can express molecular mimics of SARS-CoV-2 Spike protein, potentially enhancing protective immunity.

PMID:37944493 | DOI:10.1016/j.chom.2023.10.007

Eur Heart J. 2023 Nov 7:ehad662. doi: 10.1093/eurheartj/ehad662. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Developing novel therapies to battle the global public health burden of heart failure remains challenging. This study investigates the underlying mechanisms and potential treatment for 4-hydroxynonenal (4-HNE) deleterious effects in heart failure.

METHODS: Biochemical, functional, and histochemical measurements were applied to identify 4-HNE adducts in rat and human failing hearts. In vitro studies were performed to validate 4-HNE targets.

RESULTS: 4-HNE, a reactive aldehyde by-product of mitochondrial dysfunction in heart failure, covalently inhibits Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis. 4-HNE inhibition of Dicer impairs miRNA processing. Mechanistically, 4-HNE binds to recombinant human Dicer through an intermolecular interaction that disrupts both activity and stability of Dicer in a concentration- and time-dependent manner. Dithiothreitol neutralization of 4-HNE or replacing 4-HNE-targeted residues in Dicer prevents 4-HNE inhibition of Dicer in vitro. Interestingly, end-stage human failing hearts from three different heart failure aetiologies display defective 4-HNE clearance, decreased Dicer activity, and miRNA biogenesis impairment. Notably, boosting 4-HNE clearance through pharmacological re-activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) using Alda-1 or its improved orally bioavailable derivative AD-9308 restores Dicer activity. ALDH2 is a major enzyme responsible for 4-HNE removal. Importantly, this response is accompanied by improved miRNA maturation and cardiac function/remodelling in a pre-clinical model of heart failure.

CONCLUSIONS: 4-HNE inhibition of Dicer directly impairs miRNA biogenesis in heart failure. Strikingly, decreasing cardiac 4-HNE levels through pharmacological ALDH2 activation is sufficient to re-establish Dicer activity and miRNA biogenesis; thereby representing potential treatment for patients with heart failure.

PMID:37944136 | DOI:10.1093/eurheartj/ehad662

Science. 2023 Nov 10;382(6671):eabo7201. doi: 10.1126/science.abo7201. Epub 2023 Nov 10.

ABSTRACT

We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property-free knowledge base for future anticoronavirus drug discovery.

PMID:37943932 | DOI:10.1126/science.abo7201

Mol Plant Microbe Interact. 2023 Nov 9. doi: 10.1094/MPMI-05-23-0052-TA. Online ahead of print.

ABSTRACT

In plants, plasmodesmata establish cytoplasmic continuity between cells to allow for communication and resource exchange across the cell wall. While plant pathogens use plasmodesmata as a pathway for both molecular and physical invasion, the benefits of molecular invasion (cell-to-cell movement of pathogen effectors) are poorly understood. To establish a methodology for identification and characterization of the cell-to-cell mobility of effectors, we performed a quantitative live imaging-based screen of candidate effectors of the fungal pathogen Colletotrichum higginsianum. We predicted C. higginsianum effectors by their expression profiles, the presence of a secretion signal, and their predicted and in planta localization when fused to GFP. We assayed for cell-to-cell mobility of nucleo-cytosolic effectors and identified 14 that are cell-to-cell mobile. We identified that 3 of these effectors are "hypermobile", showing cell-to-cell mobility greater than expected for a protein of its size. To explore the mechanism of hypermobility we chose two hypermobile effectors and measured their impact on plasmodesmata function and found that even though they show no direct association with plasmodesmata, each increases the transport capacity of plasmodesmata. Thus, our methods for quantitative analysis of cell-to-cell mobility of candidate microbe-derived effectors, or any suite of host proteins, can identify cell-to-cell hypermobility and offer greater understanding of how proteins affect plasmodesmal function and intercellular connectivity.

PMID:37942798 | DOI:10.1094/MPMI-05-23-0052-TA

Front Med (Lausanne). 2023 Oct 24;10:1250499. doi: 10.3389/fmed.2023.1250499. eCollection 2023.

ABSTRACT

Medical language is in a constant state of evolution. Its grammar and vocabulary are not fixed by rigid rules. The interdisciplinary field of sepsis has become a meeting point for new insights arising from advances in systems biology, epidemiology, mechanistic understandings of disease process and antimicrobial interventions. This convergence has gained from our recent experience of SARS-CoV-2 infection and COVID-19 and possibilities inferred from emerging information technology. Biomedical descriptors have diverged along disciplinary lines creating an unfortunate disconnect between clinical and laboratory-based terminology. The resulting confusion between clinically determined sepsis and laboratory verified bloodstream infection raises practical questions that affect daily operational processes in the ward, clinic and laboratory. There is an urgent need to understand how the clinical sepsis pathway and corresponding clinical laboratory workflow can be better aligned as a single coherent entity. There is also an implicit need to understand how this process should produce actionable information in a timely and orderly manner, and identify residual obselete terminology that has crept into common usage. A widely accepted sepsis epistemology, ontology and heuristic will help us improve our clinical management of sepsis.

PMID:37942414 | PMC:PMC10627927 | DOI:10.3389/fmed.2023.1250499