Cell Syst. 2023 Jun 21;14(6):512-524.e12. doi: 10.1016/j.cels.2023.05.004.

ABSTRACT

To build therapeutic strains, Escherichia coli Nissle (EcN) have been engineered to express antibiotics, toxin-degrading enzymes, immunoregulators, and anti-cancer chemotherapies. For efficacy, the recombinant genes need to be highly expressed, but this imposes a burden on the cell, and plasmids are difficult to maintain in the body. To address these problems, we have developed landing pads in the EcN genome and genetic circuits to control therapeutic gene expression. These tools were applied to EcN SYNB1618, undergoing clinical trials as a phenylketonuria treatment. The pathway for converting phenylalanine to trans-cinnamic acid was moved to a landing pad under the control of a circuit that keeps the pathway off during storage. The resulting strain (EcN SYN8784) achieved higher activity than EcN SYNB1618, reaching levels near when the pathway is carried on a plasmid. This work demonstrates a simple system for engineering EcN that aids quantitative strain design for therapeutics.

PMID:37348465 | DOI:10.1016/j.cels.2023.05.004

Cell Syst. 2023 Jun 21;14(6):501-511.e4. doi: 10.1016/j.cels.2023.05.002.

ABSTRACT

The transcriptional effector domains of transcription factors play a key role in controlling gene expression; however, their functional nature is poorly understood, hampering our ability to explore this fundamental dimension of gene regulatory networks. To map the trans-regulatory landscape in a complex eukaryote, we systematically characterized the putative transcriptional effector domains of over 400 Arabidopsis thaliana transcription factors for their capacity to modulate transcription. We demonstrate that transcriptional effector activity can be integrated into gene regulatory networks capable of elucidating the functional dynamics underlying gene expression patterns. We further show how our characterized domains can enhance genome engineering efforts and reveal how plant transcriptional activators share regulatory features conserved across distantly related eukaryotes. Our results provide a framework to systematically characterize the regulatory role of transcription factors at a genome-scale in order to understand the transcriptional wiring of biological systems.

PMID:37348464 | DOI:10.1016/j.cels.2023.05.002

J Proteome Res. 2023 Jun 22. doi: 10.1021/acs.jproteome.3c00215. Online ahead of print.

ABSTRACT

Osteogenesis is modulated by multiple regulatory networks. Recent studies showed that RNA modifications and their reader, writer, and eraser (RWE) proteins are involved in regulating various biological processes. Few studies, however, were conducted to investigate the functions of RNA modifications and their RWE proteins in osteogenesis. By using LC-MS/MS in parallel-reaction monitoring (PRM) mode, we performed a comprehensive quantitative assessment of 154 epitranscriptomic RWE proteins throughout the entire time course of osteogenic differentiation in H9 human embryonic stem cells (ESCs). We found that approximately half of the 127 detected RWE proteins were down-regulated during osteogenic differentiation, and they included mainly proteins involved in RNA methylation and pseudouridylation. Protein-protein interaction (PPI) network analysis unveiled significant associations between the down-regulated epitranscriptomic RWE proteins and osteogenesis-related proteins. Gene set enrichment analysis (GSEA) of publicly available RNA-seq data obtained from osteogenesis imperfecta patients suggested a potential role of METTL1 in osteogenesis through the cytokine network. Together, this is the first targeted profiling of epitranscriptomic RWE proteins during osteogenic differentiation of human ESCs, and our work unveiled potential regulatory roles of these proteins in osteogenesis. LC-MS/MS data were deposited on ProteomeXchange (PXD039249).

PMID:37348120 | DOI:10.1021/acs.jproteome.3c00215

Genetics. 2023 Jun 22:iyad115. doi: 10.1093/genetics/iyad115. Online ahead of print.

ABSTRACT

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-seq data in GTEx v8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased WGS data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.

PMID:37348055 | DOI:10.1093/genetics/iyad115

Science. 2023 Jun 23;380(6651):1275-1281. doi: 10.1126/science.adf0752. Epub 2023 Jun 22.

ABSTRACT

Growth coordination between cell layers is essential for development of most multicellular organisms. Coordination may be mediated by molecular signaling and/or mechanical connectivity between cells, but how genes modify mechanical interactions between layers is unknown. Here we show that genes driving brassinosteroid synthesis promote growth of internal tissue, at least in part, by reducing mechanical epidermal constraint. We identified a brassinosteroid-deficient dwarf mutant in the aquatic plant Utricularia gibba with twisted internal tissue, likely caused by mechanical constraint from a slow-growing epidermis. We tested this hypothesis by showing that a brassinosteroid mutant in Arabidopsis enhances epidermal crack formation, indicative of increased tissue stress. We propose that by remodeling cell walls, brassinosteroids reduce epidermal constraint, showing how genes can control growth coordination between layers by means of mechanics.

PMID:37347863 | DOI:10.1126/science.adf0752

Elife. 2023 Jun 22;12:e86842. doi: 10.7554/eLife.86842.

ABSTRACT

Somatostatin interneurons are the earliest born population of cortical inhibitory cells. They are crucial to support normal brain development and function; however, the mechanisms underlying their integration into nascent cortical circuitry are not well understood. In this study, we begin by demonstrating that the maturation of somatostatin interneurons in mouse somatosensory cortex is activity dependent. We then investigated the relationship between activity, alternative splicing, and synapse formation within this population. Specifically, we discovered that the Nova family of RNA-binding proteins are activity-dependent and are essential for the maturation of somatostatin interneurons, as well as their afferent and efferent connectivity. Within this population, Nova2 preferentially mediates the alternative splicing of genes required for axonal formation and synaptic function independently from its effect on gene expression. Hence, our work demonstrates that the Nova family of proteins through alternative splicing are centrally involved in coupling developmental neuronal activity to cortical circuit formation.

PMID:37347149 | DOI:10.7554/eLife.86842

Front Microbiol. 2023 Jun 6;14:1209940. doi: 10.3389/fmicb.2023.1209940. eCollection 2023.

ABSTRACT

The use of non-Saccharomyces yeasts as starters in winemaking has increased exponentially in the last years. For instance, non-conventional yeasts have proven useful for the improvement of the organoleptic profile and biocontrol. Active dry yeast starter production has been optimized for Saccharomyces cerevisiae, which may entail problems for the propagation of non-Saccharomyces yeasts. This work shows that the poor growth of Hanseniaspora vineae and Metschnikowia pulcherrima in molasses is related to a deficient sucrose consumption, linked to their low invertase activity. In order to address this issue, simple modifications to the cultivation media based hydrolysis and the reduction of sucrose concentration were performed. We performed biomass propagation simulations at a bench-top and bioreactor scale. The results show that cultivation in a hexose-based media improved biomass production in both species, as it solves their low invertase activity. The reduction in sugar concentration promoted a metabolic shift to a respiratory metabolism, which allowed a higher biomass yield, but did not improve total biomass production, due to the lower sugar availability. To evaluate the technological performance of these adaptations, we performed mixed grape juice fermentations with biomass produced in such conditions of M. pulcherrima and S. cerevisiae. The analysis of wines produced revealed that the different treatments we have tested did not have any negative impact on wine quality, further proving their applicability at an industrial level for the improvement of biomass production.

PMID:37346752 | PMC:PMC10280074 | DOI:10.3389/fmicb.2023.1209940

Front Cell Dev Biol. 2023 Jun 6;11:1201673. doi: 10.3389/fcell.2023.1201673. eCollection 2023.

ABSTRACT

The issue of reproducibility of computational models and the related FAIR principles (findable, accessible, interoperable, and reusable) are examined in a specific test case. I analyze a computational model of the segment polarity network in Drosophila embryos published in 2000. Despite the high number of citations to this publication, 23 years later the model is barely accessible, and consequently not interoperable. Following the text of the original publication allowed successfully encoding the model for the open source software COPASI. Subsequently saving the model in the SBML format allowed it to be reused in other open source software packages. Submission of this SBML encoding of the model to the BioModels database enables its findability and accessibility. This demonstrates how the FAIR principles can be successfully enabled by using open source software, widely adopted standards, and public repositories, facilitating reproducibility and reuse of computational cell biology models that will outlive the specific software used.

PMID:37346177 | PMC:PMC10279958 | DOI:10.3389/fcell.2023.1201673

Front Plant Sci. 2023 Jun 6;14:1178239. doi: 10.3389/fpls.2023.1178239. eCollection 2023.

ABSTRACT

Quantification of reaction fluxes of metabolic networks can help us understand how the integration of different metabolic pathways determine cellular functions. Yet, intracellular fluxes cannot be measured directly but are estimated with metabolic flux analysis (MFA) that relies on the patterns of isotope labeling of metabolites in the network. For metabolic systems, typical for plants, where all potentially labeled atoms effectively have only one source atom pool, only isotopically nonstationary MFA can provide information about intracellular fluxes. There are several global approaches that implement MFA for an entire metabolic network and estimate, at once, a steady-state flux distribution for all reactions with identifiable fluxes in the network. In contrast, local approaches deal with estimation of fluxes for a subset of reactions, with smaller data demand for flux estimation. Here we present a systematic comparative review and benchmarking of the existing local approaches for isotopically nonstationary MFA. The comparison is conducted with respect to the required data and underlying computational problems solved on a synthetic network example. Furthermore, we benchmark the performance of these approaches in estimating fluxes for a subset of reactions using data obtained from the simulation of nitrogen fluxes in the Arabidopsis thaliana core metabolism. The findings pinpoint practical aspects that need to be considered when applying local approaches for flux estimation in large-scale plant metabolic networks.

PMID:37346134 | PMC:PMC10280729 | DOI:10.3389/fpls.2023.1178239

mBio. 2023 Jun 22:e0100723. doi: 10.1128/mbio.01007-23. Online ahead of print.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, drastically modifies infected cells to optimize virus replication. One such modification is the activation of the host p38 mitogen-activated protein kinase (MAPK) pathway, which plays a major role in inflammatory cytokine production, a hallmark of severe COVID-19. We previously demonstrated that inhibition of p38/MAPK activity in SARS-CoV-2-infected cells reduced both cytokine production and viral replication. Here, we combined quantitative genetic screening, genomics, proteomics, and phosphoproteomics to better understand mechanisms underlying the dependence of SARS-CoV-2 on the p38 pathway. We found that p38β is a critical host factor for SARS-CoV-2 replication in multiple relevant cell lines and that it functions at a step after viral mRNA expression. We identified putative host and viral p38β substrates in the context of SARS-CoV-2 infection and found that most host substrates have intrinsic antiviral activities. Taken together, this study reveals a unique proviral function for p38β and supports exploring p38β inhibitor development as a strategy toward creating a new class of COVID-19 therapies. IMPORTANCE SARS-CoV-2 is the causative agent of the COVID-19 pandemic that has claimed millions of lives since its emergence in 2019. SARS-CoV-2 infection of human cells requires the activity of several cellular pathways for successful replication. One such pathway, the p38 MAPK pathway, is required for virus replication and disease pathogenesis. Here, we applied systems biology approaches to understand how MAPK pathways benefit SARS-CoV-2 replication to inform the development of novel COVID-19 drug therapies.

PMID:37345956 | DOI:10.1128/mbio.01007-23

Plant Physiol. 2023 Jun 22:kiad360. doi: 10.1093/plphys/kiad360. Online ahead of print.

ABSTRACT

Thousands of long intergenic noncoding RNAs (lincRNAs) have been identified in plant genomes. While some lincRNAs have been characterized as important regulators in different biological processes, little is known about the transcriptional regulation for most plant lincRNAs. Through the integration of eight annotation resources, we defined 6,599 high-confidence lincRNA loci in Arabidopsis (Arabidopsis thaliana). For lincRNAs belonging to different evolutionary age categories, we identified major differences in sequence and chromatin features, as well as in the level of conservation and purifying selection acting during evolution. Spatiotemporal gene expression profiles combined with transcription factor (TF) chromatin immunoprecipitation data were used to construct a TF-lincRNA regulatory network containing 2,659 lincRNAs and 15,686 interactions. We found that properties characterizing lincRNA expression, conservation and regulation differ between plants and animals. Experimental validation confirmed the role of three TFs, KANADI 1 (KAN1), MYB DOMAIN PROTEIN 44 (MYB44), and PHYTOCHROME INTERACTING FACTOR 4 (PIF4), as key regulators controlling root-specific lincRNA expression, demonstrating the predictive power of our network. Furthermore, we identified 58 lincRNAs, regulated by these TFs, showing strong root cell-type specific expression or chromatin accessibility, which are linked with GWAS genetic associations related to root system development and growth. The multi-level genome-wide characterization covering chromatin state information, promoter conservation, and ChIP-based TF binding, for all detectable lincRNAs across 769 expression samples, permits rapidly defining the biological context and relevance of Arabidopsis lincRNAs through regulatory networks.

PMID:37345955 | DOI:10.1093/plphys/kiad360

Plant Cell. 2023 Jun 22:koad174. doi: 10.1093/plcell/koad174. Online ahead of print.

NO ABSTRACT

PMID:37345946 | DOI:10.1093/plcell/koad174

JCI Insight. 2023 Jun 22;8(12):e169937. doi: 10.1172/jci.insight.169937.

ABSTRACT

Defects in endoplasmic reticulum (ER) proteostasis have been linked to diseases in multiple organ systems. Here we examined the impact of perturbation of ER proteostasis in mice bearing thyrocyte-specific knockout of either HRD1 (to disable ER-associated protein degradation [ERAD]) or ATG7 (to disable autophagy) in the absence or presence of heterozygous expression of misfolded mutant thyroglobulin (the most highly expressed thyroid gene product, synthesized in the ER). Misfolding-inducing thyroglobulin mutations are common in humans but are said to yield only autosomal-recessive disease - perhaps because misfolded thyroglobulin protein might undergo disposal by ERAD or ER macroautophagy. We find that as single defects, neither ERAD, nor autophagy, nor heterozygous thyroglobulin misfolding altered circulating thyroxine levels, and neither defective ERAD nor defective autophagy caused any gross morphological change in an otherwise WT thyroid gland. However, heterozygous expression of misfolded thyroglobulin itself triggered significant ER stress and individual thyrocyte death while maintaining integrity of the surrounding thyroid epithelium. In this context, deficiency of ERAD (but not autophagy) resulted in patchy whole-follicle death with follicular collapse and degeneration, accompanied by infiltration of bone marrow-derived macrophages. Perturbation of thyrocyte ER proteostasis is thus a risk factor for both cell death and follicular demise.

PMID:37345654 | DOI:10.1172/jci.insight.169937

J Biomed Mater Res A. 2023 Jun 22. doi: 10.1002/jbm.a.37577. Online ahead of print.

ABSTRACT

Cryogels represent a class of porous sponge-like materials possessing unique properties including high-fidelity reproduction of tissue structure and maximized permeability. Their architecture is mainly based on an interconnected network of macropores that provides sufficient stability while allowing the movement of substances through the material. In most cryogel applications, the pore size is very important, especially when the material is used as a 3D scaffold for tissue culture, applied as a filter, or utilized as a membrane. In this study, poly(dimethylacrylamide-co-2-hydroxyethyl methacrylate) cryogels have been prepared by two preparation methods to investigate the reproducibility of homogeneous pore structures and pore sizes. Automated image analysis algorithms were developed to rapidly evaluate cryogel pore sizes based on scanning electron microscopy (SEM) images. The quantification approach contained a unique combination of classical and deep learning-based algorithms. To validate the accuracy of the two models, we compared the results obtained from automated SEM image analysis with those from manual pore size determinations and mercury intrusion porosimetry (MIP) measurements. Effect sizes were calculated to compare the results from manual and automated pore size measurements for the cryogel reproducibility series. 81% of the values obtained revealed only trivial differences, which strongly suggests that automated image analysis can reliably substitute the manual evaluation of cryogel pore sizes. The use of an adapted reactor setup yielded cryogels with heterogeneous morphologies in the absence of recognizable pore structures. With the conventional cryogel preparation using plastic syringes, the obtained cryogels represented highly reproducible morphologies and pore sizes in the range between 17 and 22 μm. Calculated effect sizes within the cryogel replicate series revealed only trivial differences between the obtained pore sizes in 83.5% or 99.4% of the data (classical approach and deep learning-based approach, respectively).

PMID:37345381 | DOI:10.1002/jbm.a.37577

Cancers (Basel). 2023 May 18;15(10):2809. doi: 10.3390/cancers15102809.

ABSTRACT

BACKGROUND: Previous studies on oocyte extract supplementation showed benefits in patients with liver tumours. In this trial, we hypothesized that the oocyte extract supplement impacted the QoL after hepatectomy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

METHODS: This was a multicentre, double-blind, randomized clinical trial designed to assess the QoL of patients receiving a supplement of oocyte extract or placebo postoperatively. QoL was assessed using the Short Form-36 questionnaire in participants randomly assigned to treatment (Synchrolevels) or placebo. All study personnel and participants were masked to treatment assignment. The endpoint was the change in the QoL score.

RESULTS: Between June 2018 and September 2022, 66 of 128 expected patients were considered as per interim analysis, of which 33 were assigned to the treatment and 33 to the placebo group. Baseline and clinicopathological characteristics were similar between the two groups. In the treatment group, the health, mental and psychological status improved for many of the items considered, reaching statistical significance, while in the placebo group, those items either did not change or were impaired in comparison with the corresponding baseline.

CONCLUSIONS: Supplementation with oocyte extract modifies QoL after liver surgery by enhancing functional recovery. Further in-depth studies are required to confirm this evidence.

PMID:37345146 | DOI:10.3390/cancers15102809

J Therm Biol. 2023 May;114:103572. doi: 10.1016/j.jtherbio.2023.103572. Epub 2023 Apr 26.

ABSTRACT

Maintaining a high and stable body temperature as observed in most endothermic mammals and birds is energetically costly and many heterothermic species reduce their metabolic demands during energetic bottlenecks through the use of torpor. With the increasing number of heterotherms revealed in a diversity of habitats, it becomes apparent that triggers and patterns of torpor use are more variable than previously thought. Here, we report the previously overlooked use of, shallow rest-time torpor (body temperature >30 °C) in African lesser bushbabies, Galago moholi. Body core temperature of three adult male bushbabies recorded over five months showed a clear bimodal distribution with an average active modal temperature of 39.2 °C and a resting modal body temperature of 36.7 °C. Shallow torpor was observed in two out of three males (n = 29 torpor bouts) between June and August (austral winter), with body temperatures dropping to an overall minimum of 30.7 °C and calculated energy savings of up to 10%. We suggest that shallow torpor may be an ecologically important, yet mostly overlooked energy-saving strategy employed by heterothermic mammals. Our data emphasise that torpor threshold temperatures need to be used with care if we aim to fully understand the level of physiological plasticity displayed by heterothermic species.

PMID:37344030 | DOI:10.1016/j.jtherbio.2023.103572

Environ Pollut. 2023 Jun 19:122066. doi: 10.1016/j.envpol.2023.122066. Online ahead of print.

ABSTRACT

The combination of a low-density geochemical survey, multispectral data obtained with Unmanned Aerial Vehicle-Remote Sensing (UAV-RS), and a machine learning technique was tested in the search for a statistically robust prediction of contaminant distribution in soil and vegetation for zones with a highly variable pollutant load. To this end, a novel methodology was devised by means of a limited geochemical study of topsoil and vegetation combined with multispectral data obtained by UAV-RS. The methodology was verified in an area affected by Hg and As contamination that typifies abandoned mining-metallurgy sites in recent decades. A broad selection of spectral indices were calculated to evaluate soil-plant system response, and four machine learning techniques (Multiple Linear Regression, Random Forest, Generalized Boosted Models, and Multivariate Adaptive Regression Spline) were tested to obtain robust statistical models. Random Forest (RF) provided the best non-biased models for As and Hg concentration in soil and vegetation, with R2 and rRMSE (%) ranging from 0.501 to 0.630 and from 180.72 to 46.31, respectively, and with acceptable values for RPD and RPIQ statistics. The prediction and mapping of contaminant content and distribution in the study area were well enough adjusted to the geochemical data and revealed superior accuracy for As than Hg, and for vegetation than topsoil. The results were more precise than those obtained in comparable studies that applied satellite or spectrometry data. In conclusion, the methodology presented emerges as a powerful tool for studies addressing soil and vegetation pollution and an alternative approach to classical geochemical studies, which are time-consuming and expensive.

PMID:37343919 | DOI:10.1016/j.envpol.2023.122066

Sci Total Environ. 2023 Jun 19:165000. doi: 10.1016/j.scitotenv.2023.165000. Online ahead of print.

ABSTRACT

Due to complex interactions between climate and land use changes, large forest fires have increased in frequency and severity over the last decades, impacting dramatically on biodiversity and society. In southern European countries affected by demographic challenges, fire risk and danger play special relevance at the wildland-urban interfaces (WUIs), where decision-making and land management have strong socio-ecological implications. WUIs have been historically typified according to both fire occurrence probability and settlement vulnerability, but those classifications lack generality regarding fire regime components. We aim to develop an integrated and comprehensive scheme for identifying the WUI typologies most at risk to fire severity across large territories. We selected fourteen large wildfires (over than 500 ha) occurred in Spain (2016-2021) containing different WUI scenarios. First, based on a building cartography and a multi-temporal series of Sentinel-2 imagery, each WUI was delimited and spatially characterized according to building density and pre-fire fuel characteristics (type, amount, and structure). Afterwards, a decision tree regression model was applied to identify the most relevant pre-fire vegetation parameters driving burn severity. The combined effect of the selected pre-fire vegetation drivers and the building density patterns on fire severity was evaluated using linear mixed models. Finally, the WUI typologies most prone to high burn severity were recognized using Tukey post-hoc tests. Results indicated that building density, land cover class and vegetation cover fraction determined fire severity in areas close to human settlements. Specifically, isolated, scattered and sparsely clustered buildings enclosed in a high-cover shrub matrix were the WUI typologies most susceptible to high-severity fires. These findings contribute to the development of appropriate strategies to minimize the risk of severe fires in WUIs and avoid potential losses of multiple ecosystem services valuable for society.

PMID:37343882 | DOI:10.1016/j.scitotenv.2023.165000

Mol Cell Proteomics. 2023 Jun 19:100602. doi: 10.1016/j.mcpro.2023.100602. Online ahead of print.

ABSTRACT

Treatment and relevant targets for breast cancer (BC) remain limited, especially for triple-negative BC (TNBC). We identified 6091 proteins of 76 human BC cell lines using data-independent acquisition (DIA). Integrating prior multi-omics datasets with our proteomic results, we found that including proteomics data improved drug sensitivity predictions and provided insights into mechanism of action. We then profiled the proteome changes in nine cell lines (five TNBC, four non-TNBC) treated with EGFR/AKT/mTOR inhibitors. In TNBC, metabolism pathways were dysregulated after EGFR/mTOR inhibitor treatment, while RNA modification and cell cycle pathways were affected by AKT inhibitor. This systematic multi-omics and in-depth analysis of the proteome of BC cells can help prioritize potential therapeutic targets and provides insights into adaptive resistance in TNBC.

PMID:37343696 | DOI:10.1016/j.mcpro.2023.100602

Ageing Res Rev. 2023 Jun 19:101987. doi: 10.1016/j.arr.2023.101987. Online ahead of print.

ABSTRACT

Alzheimer's disease (AD) is determined by various pathophysiological mechanisms starting 10 to 25 years before the onset of clinical symptoms. As multiple functionally interconnected molecular/cellular pathways appear disrupted in AD, the exploitation of high-throughput unbiased omics sciences is critical to elucidating the precise pathogenesis of AD. Among different omics, metabolomics is a fast-growing discipline allowing for the simultaneous detection and quantification of hundreds/thousands of perturbed metabolites in tissues or biofluids, reproducing the fluctuations of multiple networks affected by a disease. Here, we seek to critically depict the main metabolomics methodologies with the aim of identifying new potential AD biomarkers and further elucidating AD pathophysiological mechanisms. From a systems biology perspective, as metabolic alterations can occur before the development of clinical signs, metabolomics - coupled with existing accessible biomarkers used for AD screening and diagnosis - can support early disease diagnosis and help develop individualized treatment plans. Presently, the majority of metabolomic analyses emphasized that lipid metabolism is the most consistently altered pathway in AD pathogenesis. The possibility that metabolomics may reveal crucial steps in AD pathogenesis is undermined by the difficulty in discriminating between the causal or epiphenomenal or compensatory nature of metabolic findings.

PMID:37343679 | DOI:10.1016/j.arr.2023.101987