iScience. 2023 Mar 2;26(4):106330. doi: 10.1016/j.isci.2023.106330. eCollection 2023 Apr 21.

ABSTRACT

Neoadjuvant therapy (NAT) is currently recommended to patients with human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) that typically exhibit a poor prognosis. The tumor immune microenvironment profoundly affects the efficacy of NAT. However, the correlation between tumor-infiltrating lymphocytes or their specific subpopulations and the response to NAT in HER2+ BC remains largely unknown. In our study, the immune infiltration status of 295 patients was classified as "immune-rich" or "immune-poor" phenotypes. The "immune-rich" phenotype was significantly positively related to pathological complete response (pCR). Ten genes were correlated with both pCR and the immune phenotype based on the results of spline and logistic regression. We constructed a generalized non-linear model combining linear and non-linear gene effects and successfully validated its predictive power using an internal and external validation set (AUC = 0.819, 0.797; respectively) and a clinical set (accuracy = 0.75).

PMID:36950120 | PMC:PMC10025957 | DOI:10.1016/j.isci.2023.106330

Open Forum Infect Dis. 2023 Feb 21;10(3):ofad095. doi: 10.1093/ofid/ofad095. eCollection 2023 Mar.

ABSTRACT

BACKGROUND: The ongoing circulation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a diagnostic challenge because symptoms of coronavirus disease 2019 (COVID-19) are difficult to distinguish from other respiratory diseases. Our goal was to use statistical analyses and machine learning to identify biomarkers that distinguish patients with COVID-19 from patients with influenza.

METHODS: Cytokine levels were analyzed in plasma and serum samples from patients with influenza and COVID-19, which were collected as part of the Centers for Disease Control and Prevention's Hospitalized Adult Influenza Vaccine Effectiveness Network (inpatient network) and the US Flu Vaccine Effectiveness (outpatient network).

RESULTS: We determined that interleukin (IL)-10 family cytokines are significantly different between COVID-19 and influenza patients. The results suggest that the IL-10 family cytokines are a potential diagnostic biomarker to distinguish COVID-19 and influenza infection, especially for inpatients. We also demonstrate that cytokine combinations, consisting of up to 3 cytokines, can distinguish SARS-CoV-2 and influenza infection with high accuracy in both inpatient (area under the receiver operating characteristics curve [AUC] = 0.84) and outpatient (AUC = 0.81) groups, revealing another potential screening tool for SARS-CoV-2 infection.

CONCLUSIONS: This study not only reveals prospective screening tools for COVID-19 infections that are independent of polymerase chain reaction testing or clinical condition, but it also emphasizes potential pathways involved in disease pathogenesis that act as potential targets for future mechanistic studies.

PMID:36949873 | PMC:PMC10026548 | DOI:10.1093/ofid/ofad095

Microbiome. 2023 Mar 23;11(1):58. doi: 10.1186/s40168-023-01481-6.

ABSTRACT

BACKGROUND: Sequencing has been widely used to study the composition of the oral microbiome present in various health conditions. The extent of the coverage of the 16S rRNA gene primers employed for this purpose has not, however, been evaluated in silico using oral-specific databases. This paper analyses these primers using two databases containing 16S rRNA sequences from bacteria and archaea found in the human mouth and describes some of the best primers for each domain.

RESULTS: A total of 369 distinct individual primers were identified from sequencing studies of the oral microbiome and other ecosystems. These were evaluated against a database reported in the literature of 16S rRNA sequences obtained from oral bacteria, which was modified by our group, and a self-created oral archaea database. Both databases contained the genomic variants detected for each included species. Primers were evaluated at the variant and species levels, and those with a species coverage (SC) ≥75.00% were selected for the pair analyses. All possible combinations of the forward and reverse primers were identified, with the resulting 4638 primer pairs also evaluated using the two databases. The best bacteria-specific pairs targeted the 3-4, 4-7, and 3-7 16S rRNA gene regions, with SC levels of 98.83-97.14%; meanwhile, the optimum archaea-specific primer pairs amplified regions 5-6, 3-6, and 3-6, with SC estimates of 95.88%. Finally, the best pairs for detecting both domains targeted regions 4-5, 3-5, and 5-9, and produced SC values of 95.71-94.54% and 99.48-96.91% for bacteria and archaea, respectively.

CONCLUSIONS: Given the three amplicon length categories (100-300, 301-600, and >600 base pairs), the primer pairs with the best coverage values for detecting oral bacteria were as follows: KP_F048-OP_R043 (region 3-4; primer pair position for Escherichia coli J01859.1: 342-529), KP_F051-OP_R030 (4-7; 514-1079), and KP_F048-OP_R030 (3-7; 342-1079). For detecting oral archaea, these were as follows: OP_F066-KP_R013 (5-6; 784-undefined), KP_F020-KP_R013 (3-6; 518-undefined), and OP_F114-KP_R013 (3-6; 340-undefined). Lastly, for detecting both domains jointly they were KP_F020-KP_R032 (4-5; 518-801), OP_F114-KP_R031 (3-5; 340-801), and OP_F066-OP_R121 (5-9; 784-1405). The primer pairs with the best coverage identified herein are not among those described most widely in the oral microbiome literature. Video Abstract.

PMID:36949474 | DOI:10.1186/s40168-023-01481-6

Nature. 2023 Mar 22. doi: 10.1038/s41586-023-05924-w. Online ahead of print.

NO ABSTRACT

PMID:36949206 | DOI:10.1038/s41586-023-05924-w

Nat Commun. 2023 Mar 22;14(1):1572. doi: 10.1038/s41467-023-37224-2.

ABSTRACT

The exchange of large and complex slide microscopy imaging data in biomedical research and pathology practice is impeded by a lack of data standardization and interoperability, which is detrimental to the reproducibility of scientific findings and clinical integration of technological innovations. We introduce Slim, an open-source, web-based slide microscopy viewer that implements the internationally accepted Digital Imaging and Communications in Medicine (DICOM) standard to achieve interoperability with a multitude of existing medical imaging systems. We showcase the capabilities of Slim as the slide microscopy viewer of the NCI Imaging Data Commons and demonstrate how the viewer enables interactive visualization of traditional brightfield microscopy and highly-multiplexed immunofluorescence microscopy images from The Cancer Genome Atlas and Human Tissue Atlas Network, respectively, using standard DICOMweb services. We further show how Slim enables the collection of standardized image annotations for the development or validation of machine learning models and the visual interpretation of model inference results in the form of segmentation masks, spatial heat maps, or image-derived measurements.

PMID:36949078 | DOI:10.1038/s41467-023-37224-2

Nat Commun. 2023 Mar 22;14(1):1582. doi: 10.1038/s41467-023-37079-7.

ABSTRACT

Comprehensive understanding of the human protein-protein interaction (PPI) network, aka the human interactome, can provide important insights into the molecular mechanisms of complex biological processes and diseases. Despite the remarkable experimental efforts undertaken to date to determine the structure of the human interactome, many PPIs remain unmapped. Computational approaches, especially network-based methods, can facilitate the identification of previously uncharacterized PPIs. Many such methods have been proposed. Yet, a systematic evaluation of existing network-based methods in predicting PPIs is still lacking. Here, we report community efforts initiated by the International Network Medicine Consortium to benchmark the ability of 26 representative network-based methods to predict PPIs across six different interactomes of four different organisms: A. thaliana, C. elegans, S. cerevisiae, and H. sapiens. Through extensive computational and experimental validations, we found that advanced similarity-based methods, which leverage the underlying network characteristics of PPIs, show superior performance over other general link prediction methods in the interactomes we considered.

PMID:36949045 | DOI:10.1038/s41467-023-37079-7

Nat Commun. 2023 Mar 22;14(1):1566. doi: 10.1038/s41467-023-36878-2.

ABSTRACT

Whereas the contribution of tumor microenvironment to the profound immune suppression of glioblastoma (GBM) is clear, tumor-cell intrinsic mechanisms that regulate resistance to CD8 T cell mediated killing are less understood. Kinases are potentially druggable targets that drive tumor progression and might influence immune response. Here, we perform an in vivo CRISPR screen to identify glioma intrinsic kinases that contribute to evasion of tumor cells from CD8 T cell recognition. The screen reveals checkpoint kinase 2 (Chek2) to be the most important kinase contributing to escape from CD8 T-cell recognition. Genetic depletion or pharmacological inhibition of Chek2 with blood-brain-barrier permeable drugs that are currently being evaluated in clinical trials, in combination with PD-1 or PD-L1 blockade, lead to survival benefit in multiple preclinical glioma models. Mechanistically, loss of Chek2 enhances antigen presentation, STING pathway activation and PD-L1 expression in mouse gliomas. Analysis of human GBMs demonstrates that Chek2 expression is inversely associated with antigen presentation and T-cell activation. Collectively, these results support Chek2 as a promising target for enhancement of response to immune checkpoint blockade therapy in GBM.

PMID:36949040 | DOI:10.1038/s41467-023-36878-2

J Immunol. 2023 Apr 1;210(7):843-844. doi: 10.4049/jimmunol.2300097.

NO ABSTRACT

PMID:36947825 | DOI:10.4049/jimmunol.2300097

Mol Cell Proteomics. 2023 Mar 20:100533. doi: 10.1016/j.mcpro.2023.100533. Online ahead of print.

ABSTRACT

Mycobacterium avium is one of the prominent disease-causing bacteria in humans. It causes lymphadenitis, chronic and extrapulmonary, and disseminated infections in adults, children, and immunocompromised patients. M. avium has ∼4,500 predicted protein-coding regions on average, which can help discover several variants at the proteome level. Many of them are potentially associated with virulence; thus, identifying such proteins can be a helpful feature in developing panel-based theranostics. In line with such a long-term goal, we carried out an in-depth proteomic analysis of M. avium with both data-dependent and data-independent acquisition methods. Further, a set of proteogenomic investigations were carried out using i) a protein database for Mycobacterium tuberculosis, ii) a M. avium genome six-frame translated database, and iii) a variant protein database of M. avium. A search of mass spectrometry data against M. avium protein database resulted in identifying 2,954 proteins. Further, proteogenomic analyses aided in identifying 1,301 novel peptide sequences and correcting translation start sites for 15 proteins. Ultimately, we created a spectral library of M. avium proteins, including novel genome search-specific peptides and variant peptides detected in this study. We validated the spectral library by a data-independent acquisition of the M. avium proteome. Thus, we present an M. avium spectral library of 29,033 peptide precursors supported by 0.4 million fragment ions for further use by the biomedical community.

PMID:36948415 | DOI:10.1016/j.mcpro.2023.100533

Sci Total Environ. 2023 Mar 20:162993. doi: 10.1016/j.scitotenv.2023.162993. Online ahead of print.

ABSTRACT

Invasive alien species are among the main global drivers of biodiversity loss posing major challenges to nature conservation and to managers of protected areas. The present study applied a methodological framework that combined invasive Species Distribution Models, based on propagule pressure, abiotic and biotic factors for 14 invasive alien plants of Union concern in Italy, with the local interpretable model-agnostic explanation analysis aiming to map, evaluate and analyse the risk of plant invasions across the country, inside and outside the network of protected areas. Using a hierarchical invasive Species Distribution Model, we explored the combined effect of propagule pressure, abiotic and biotic factors on shaping invasive alien plant occurrence across three biogeographic regions (Alpine, Continental, and Mediterranean) and realms (terrestrial and aquatic) in Italy. We disentangled the role of propagule pressure, abiotic and biotic factors on invasive alien plant distribution and projected invasion risk maps. We compared the risk posed by invasive alien plants inside and outside protected areas. Invasive alien plant distribution varied across biogeographic regions and realms and unevenly threatens protected areas. As an alien's occurrence and risk on a national scale are linked with abiotic factors followed by propagule pressure, their local distribution in protected areas is shaped by propagule pressure and biotic filters. The proposed modelling framework for the assessment of the risk posed by invasive alien plants across spatial scales and under different protection regimes represents an attempt to fill the gap between theory and practice in conservation planning helping to identify scale, site, and species-specific priorities of management, monitoring and control actions. Based on solid theory and on free geographic information, it has great potential for application to wider networks of protected areas in the world and to any invasive alien plant, aiding improved management strategies claimed by the environmental legislation and national and global strategies.

PMID:36948323 | DOI:10.1016/j.scitotenv.2023.162993

Structure. 2023 Mar 10:S0969-2126(23)00074-6. doi: 10.1016/j.str.2023.02.012. Online ahead of print.

ABSTRACT

PR65, a horseshoe-shaped scaffold composed of 15 HEAT (observed in Huntingtin, elongation factor 3, protein phosphatase 2A, and the yeast kinase TOR1) repeats, forms, together with catalytic and regulatory subunits, the heterotrimeric protein phosphatase PP2A. We examined the role of PR65 in enabling PP2A enzymatic activity with computations at various levels of complexity, including hybrid approaches that combine full-atomic and elastic network models. Our study points to the high flexibility of this scaffold allowing for end-to-end distance fluctuations of 40-50 Å between compact and extended conformations. Notably, the intrinsic dynamics of PR65 facilitates complexation with the catalytic subunit and is retained in the PP2A complex enabling PR65 to engage the two domains of the catalytic subunit and provide the mechanical framework for enzymatic activity, with support from the regulatory subunit. In particular, the intra-repeat coils at the C-terminal arm play an important role in allosterically mediating the collective dynamics of PP2A, pointing to target sites for modulating PR65 function.

PMID:36948205 | DOI:10.1016/j.str.2023.02.012

J Immunol. 2023 Apr 1;210(7):888-894. doi: 10.4049/jimmunol.2200610.

ABSTRACT

The thymus is an intricate organ consisting of a diverse population of thymic epithelial cells (TECs). Cortical and medullary TECs and their subpopulations have distinct roles in coordinating the development and selection of functionally competent and self-tolerant T cells. Recent advances made in technologies such as single-cell RNA sequencing have made it possible to investigate and resolve the heterogeneity in TECs. These findings have provided further understanding of the molecular mechanisms regulating TEC function and expression of tissue-restricted Ags. In this brief review, we focus on the newly characterized subsets of TECs and their diversity in relation to their functions in supporting T cell development. We also discuss recent discoveries in expression of self-antigens in the context of TEC development as well as the cellular and molecular changes occurring during embryonic development to thymic involution.

PMID:36947816 | DOI:10.4049/jimmunol.2200610

Mol Biol Evol. 2023 Mar 22:msad068. doi: 10.1093/molbev/msad068. Online ahead of print.

ABSTRACT

Epigenetic mechanisms such as DNA methylation (DNAme) are thought to comprise an invaluable adaptive toolkit in the early stages of local adaptation, especially when genetic diversity is constrained. However, the link between genetic diversity and DNAme has been scarcely examined in natural populations, despite its potential to shed light on the evolutionary forces acting on methylation state. Here, we analysed reduced-representation bisulfite sequencing and whole genome pool-seq data from marine and freshwater stickleback populations to examine the relationship between DNAme variation (between- and within-population), and nucleotide diversity in the context of freshwater adaptation. We find that sites that are differentially methylated between populations have higher underlying standing genetic variation, with diversity higher among sites that gained methylation in freshwater than those that lost it. Strikingly, while nucleotide diversity is generally lower in the freshwater population as expected from a population bottleneck, this is not the case for sites which lost methylation which instead have elevated nucleotide diversity in freshwater compared to marine. Subsequently, we show that nucleotide diversity is higher among sites with ancestrally variable methylation and also positively correlates with the sensitivity to environmentally induced methylation change. The results suggest that as selection on the control of methylation state becomes relaxed, so too does selection against mutations at the sites themselves. Increased epigenetic variance in a population is therefore likely to precede genetic diversification.

PMID:36947101 | DOI:10.1093/molbev/msad068

OMICS. 2023 Mar 22. doi: 10.1089/omi.2022.0182. Online ahead of print.

ABSTRACT

COVID-19 is a systemic disease whose effects are not limited to the respiratory system. The oral microbiome (OM)-brain axis is of growing interest in understanding the broader, neuropsychiatric, impacts of the COVID-19 pandemic through a systems biology lens. In this context, mental health and sleep disturbance are often reported by Asian Americans. In a cross-sectional observational study design, we examined the associations of the oral microbiome with mental health among Asian Americans during the COVID-19 pandemic (between November 2020 and April 2021). Participants (n = 20) were adult Chinese and Korean American immigrants in Atlanta, Georgia, and primarily born outside the United States (60%) with a mean age of 34.8 years ±14 (standard deviation). Participants reported depressive symptoms, anxiety, and sleep disturbance, as measured by standard questionnaires. The OM was characterized by 16S rRNA V3-V4 gene using saliva. Depressive symptoms and anxiety were reported by 60% (n = 12) of participants, whereas 35% (n = 7) reported sleep disturbance. The α-diversity was significantly associated with depressive symptoms, and marginally with anxiety. Participants with depressive symptoms and anxiety had enriched Rothia and Scardovia, respectively, whereas those without symptoms had enriched Fusobacterium. Individuals with sleep disturbance had enriched Kingella. In conclusion, this study suggests significant associations of the OM diversity with certain mental health dimensions such as depressive symptoms and anxiety. Specific taxa were associated with these symptoms. The present observations in a modest sample size suggest the possible relevance of the OM-brain axis in studies of mental health during COVID-19.

PMID:36946910 | DOI:10.1089/omi.2022.0182

Cancer Res. 2023 Mar 22:OF1-OF19. doi: 10.1158/0008-5472.CAN-22-1826. Online ahead of print.

ABSTRACT

Clinical management of melanomas with NRAS mutations is challenging. Targeting MAPK signaling is only beneficial to a small subset of patients due to resistance that arises through genetic, transcriptional, and metabolic adaptation. Identification of targetable vulnerabilities in NRAS-mutated melanoma could help improve patient treatment. Here, we used multiomics analyses to reveal that NRAS-mutated melanoma cells adopt a mesenchymal phenotype with a quiescent metabolic program to resist cellular stress induced by MEK inhibition. The metabolic alterations elevated baseline reactive oxygen species (ROS) levels, leading these cells to become highly sensitive to ROS induction. In vivo xenograft experiments and single-cell RNA sequencing demonstrated that intratumor heterogeneity necessitates the combination of a ROS inducer and a MEK inhibitor to inhibit both tumor growth and metastasis. Ex vivo pharmacoscopy of 62 human metastatic melanomas confirmed that MEK inhibitor-resistant tumors significantly benefited from the combination therapy. Finally, oxidative stress response and translational suppression corresponded with ROS-inducer sensitivity in 486 cancer cell lines, independent of cancer type. These findings link transcriptional plasticity to a metabolic phenotype that can be inhibited by ROS inducers in melanoma and other cancers.

SIGNIFICANCE: Metabolic reprogramming in drug-resistant NRAS-mutated melanoma cells confers sensitivity to ROS induction, which suppresses tumor growth and metastasis in combination with MAPK pathway inhibitors.

PMID:36946761 | DOI:10.1158/0008-5472.CAN-22-1826

J Med Virol. 2023 Mar 22. doi: 10.1002/jmv.28692. Online ahead of print.

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic and related public health intervention measures have been reported to have resulted in the reduction of infections caused by influenza viruses and other common respiratory viruses. However, the influence may be varied in areas that have different ecological, economic, and social conditions. This study investigated the changing epidemiology of 8 common respiratory pathogens, including Influenza A (IFVA), Influenza B (IFVB), Respiratory syncytial virus (HRSV), rhinovirus (RV), Human metapneumovirus (HMPV) Adenovirus (AdV), Human bocavirus (HBOV), and Mycoplasma pneumoniae, among hospitalized children during spring and early summer in 2019-2021 in two hospitals in Hainan Island, China, in the COVID-19 pandemic era. The results revealed a significant reduction in the prevalence of IFVA and IFVB in 2020 and 2021 than in 2019, whereas the prevalence of HRSV increased, and it became the dominant viral pathogen in 2021. RV was one of the leading pathogens in the three year period, where no significant difference was observed. Phylogenetic analysis revealed close relationships among the circulating respiratory viruses. Large scale studies are needed to study the changing epidemiology of seasonal respiratory viruses to inform responses to future respiratory virus pandemics. This article is protected by copyright. All rights reserved.

PMID:36946502 | DOI:10.1002/jmv.28692

Development. 2023 Mar 22:dev.200975. doi: 10.1242/dev.200975. Online ahead of print.

ABSTRACT

Collective cell rotations are widely used during animal organogenesis. Theoretical and in vitro studies have conceptualized rotating cells as identical rigid-point objects that stochastically break symmetry to move monotonously and perpetually within an inert environment. However, it is unclear if this notion can be extrapolated to a natural context, where rotations are ephemeral and heterogeneous cellular cohorts interact with an active epithelium. In zebrafish neuromasts nascent sibling hair cells invert positions by rotating≤180° around their geometric center after acquiring different identities via Notch1a-mediated asymmetric repression of Emx2. Here we show that this multicellular rotation is a three-phasic movement that progresses via coherent homotypic coupling and heterotypic junction remodeling. We found no correlation between rotations and epithelium-wide cellular flow or anisotropic resistive forces. Moreover, the Notch/Emx2 status of the cell dyad does not determine asymmetric interactions with the surrounding epithelium. Aided by computer modeling, we suggest that initial stochastic inhomogeneities generate a metastable state that poises cells to move, spontaneous intercellular coordination of the resulting instabilities enables persistently directional rotations, whereas Notch1a-determined symmetry breaking buffers rotational noise.

PMID:36946430 | DOI:10.1242/dev.200975

J Med Chem. 2023 Mar 22. doi: 10.1021/acs.jmedchem.2c01548. Online ahead of print.

ABSTRACT

Transcriptional enhanced associate domain (TEAD) proteins together with their transcriptional coactivator yes-associated protein (YAP) and transcriptional coactivator with the PDZ-binding motif (TAZ) are important transcription factors and cofactors that regulate gene expression in the Hippo pathway. In mammals, the TEAD families have four homologues: TEAD1 (TEF-1), TEAD2 (TEF-4), TEAD3 (TEF-5), and TEAD4 (TEF-3). Aberrant expression and hyperactivation of TEAD/YAP signaling have been implicated in a variety of malignancies. Recently, TEADs were recognized as being palmitoylated in cells, and the lipophilic palmitate pocket has been successfully targeted by both covalent and noncovalent ligands. In this report, we present the medicinal chemistry effort to develop MYF-03-176 (compound 22) as a selective, cysteine-covalent TEAD inhibitor. MYF-03-176 (compound 22) significantly inhibits TEAD-regulated gene expression and proliferation of the cell lines with TEAD dependence including those derived from mesothelioma and liposarcoma.

PMID:36946421 | DOI:10.1021/acs.jmedchem.2c01548

Proc Biol Sci. 2023 Mar 29;290(1995):20222456. doi: 10.1098/rspb.2022.2456. Epub 2023 Mar 22.

ABSTRACT

Polyploidy, i.e. the occurrence of multiple sets of chromosomes, is regarded as an important phenomenon in plant ecology and evolution, with all flowering plants likely having a polyploid ancestry. Owing to genome shock, minority cytotype exclusion and reduced fertility, polyploids emerging in diploid populations are expected to face significant challenges to successful establishment. Their establishment and persistence are often explained by possible fitness or niche differences that would relieve the competitive pressure with diploid progenitors. Experimental evidence for such advantages is, however, not unambiguous, and considerable niche overlap exists among most polyploid species and their diploid counterparts. Here, we develop a neutral spatially explicit eco-evolutionary model to understand whether neutral processes can explain the eco-evolutionary patterns of polyploids. We present a general mechanism for polyploid establishment by showing that sexually reproducing organisms assemble in space in an iterative manner, reducing frequency-dependent mating disadvantages and overcoming potential reduced fertility issues. Moreover, we construct a mechanistic theoretical framework that allows us to understand the long-term evolution of mixed-ploidy populations and show that our model is remarkably consistent with recent phylogenomic estimates of species extinctions in the Brassicaceae family.

PMID:36946113 | DOI:10.1098/rspb.2022.2456

bioRxiv. 2023 Mar 12:2023.03.10.532028. doi: 10.1101/2023.03.10.532028. Preprint.

ABSTRACT

The pancreas plays a critical role in maintaining glucose homeostasis through the secretion of hormones from the islets of Langerhans. Glucose-stimulated insulin secretion (GSIS) by the pancreatic β -cell is the main mechanism for reducing elevated plasma glucose. Here we present a systematic modeling workflow for the development of kinetic pathway models using the Systems Biology Markup Language (SBML). Steps include retrieval of information from databases, curation of experimental and clinical data for model calibration and validation, integration of heterogeneous data including absolute and relative measurements, unit normalization, data normalization, and model annotation. An important factor was the reproducibility and exchangeability of the model, which allowed the use of various existing tools. The workflow was applied to construct the first consensus model of GSIS in the pancreatic β -cell based on experimental and clinical data from 39 studies spanning 50 years of pancreatic, islet, and β -cell research in humans, rats, mice, and cell lines. The model consists of detailed glycolysis and equations for insulin secretion coupled to cellular energy state (ATP/ADP ratio). Key findings of our work are that in GSIS there is a glucose-dependent increase in almost all intermediates of glycolysis. This increase in glycolytic metabolites is accompanied by an increase in energy metabolites, especially ATP and NADH. One of the few decreasing metabolites is ADP, which, in combination with the increase in ATP, results in a large increase in ATP/ADP ratios in the β -cell with increasing glucose. Insulin secretion is dependent on ATP/ADP, resulting in glucose-stimulated insulin secretion. The observed glucose-dependent increase in glycolytic intermediates and the resulting change in ATP/ADP ratios and insulin secretion is a robust phenomenon observed across data sets, experimental systems and species. Model predictions of the glucose-dependent response of glycolytic intermediates and insulin secretion are in good agreement with experimental measurements. Our model predicts that factors affecting ATP consumption, ATP formation, hexokinase, phosphofructokinase, and ATP/ADP-dependent insulin secretion have a major effect on GSIS. In conclusion, we have developed and applied a systematic modeling workflow for pathway models that allowed us to gain insight into key mechanisms in GSIS in the pancreatic β -cell.

PMID:36945414 | PMC:PMC10028967 | DOI:10.1101/2023.03.10.532028