Systems Biology

Chromosome-scale genome sequence of <em>Suaeda glauca</em> sheds light on salt stress tolerance in halophytes

Wed, 2023-09-20 06:00

Hortic Res. 2023 Aug 10;10(9):uhad161. doi: 10.1093/hr/uhad161. eCollection 2023 Sep.

ABSTRACT

Soil salinity is a growing concern for global crop production and the sustainable development of humanity. Therefore, it is crucial to comprehend salt tolerance mechanisms and identify salt-tolerance genes to enhance crop tolerance to salt stress. Suaeda glauca, a halophyte species well adapted to the seawater environment, possesses a unique ability to absorb and retain high salt concentrations within its cells, particularly in its leaves, suggesting the presence of a distinct mechanism for salt tolerance. In this study, we performed de novo sequencing of the S. glauca genome. The genome has a size of 1.02 Gb (consisting of two sets of haplotypes) and contains 54 761 annotated genes, including alleles and repeats. Comparative genomic analysis revealed a strong synteny between the genomes of S. glauca and Beta vulgaris. Of the S. glauca genome, 70.56% comprises repeat sequences, with retroelements being the most abundant. Leveraging the allele-aware assembly of the S. glauca genome, we investigated genome-wide allele-specific expression in the analyzed samples. The results indicated that the diversity in promoter sequences might contribute to consistent allele-specific expression. Moreover, a systematic analysis of the ABCE gene families shed light on the formation of S. glauca's flower morphology, suggesting that dysfunction of A-class genes is responsible for the absence of petals in S. glauca. Gene family expansion analysis demonstrated significant enrichment of Gene Ontology (GO) terms associated with DNA repair, chromosome stability, DNA demethylation, cation binding, and red/far-red light signaling pathways in the co-expanded gene families of S. glauca and S. aralocaspica, in comparison with glycophytic species within the chenopodium family. Time-course transcriptome analysis under salt treatments revealed detailed responses of S. glauca to salt tolerance, and the enrichment of the transition-upregulated genes in the leaves associated with DNA repair and chromosome stability, lipid biosynthetic process, and isoprenoid metabolic process. Additionally, genome-wide analysis of transcription factors indicated a significant expansion of FAR1 gene family. However, further investigation is needed to determine the exact role of the FAR1 gene family in salt tolerance in S. glauca.

PMID:37727702 | PMC:PMC10506132 | DOI:10.1093/hr/uhad161

Categories: Literature Watch

Radiomics-based prediction of FIGO grade for placenta accreta spectrum

Tue, 2023-09-19 06:00

Eur Radiol Exp. 2023 Sep 20;7(1):54. doi: 10.1186/s41747-023-00369-2.

ABSTRACT

BACKGROUND: Placenta accreta spectrum (PAS) is a rare, life-threatening complication of pregnancy. Predicting PAS severity is critical to individualise care planning for the birth. We aim to explore whether radiomic analysis of T2-weighted magnetic resonance imaging (MRI) can predict severe cases by distinguishing between histopathological subtypes antenatally.

METHODS: This was a bi-centre retrospective analysis of a prospective cohort study conducted between 2018 and 2022. Women who underwent MRI during pregnancy and had histological confirmation of PAS were included. Radiomic features were extracted from T2-weighted images. Univariate regression and multivariate analyses were performed to build predictive models to differentiate between non-invasive (International Federation of Gynecology and Obstetrics [FIGO] grade 1 or 2) and invasive (FIGO grade 3) PAS using R software. Prediction performance was assessed based on several metrics including sensitivity, specificity, accuracy and area under the curve (AUC) at receiver operating characteristic analysis.

RESULTS: Forty-one women met the inclusion criteria. At univariate analysis, 0.64 sensitivity (95% confidence interval [CI] 0.0-1.00), specificity 0.93 (0.38-1.0), 0.58 accuracy (0.37-0.78) and 0.77 AUC (0.56-.097) was achieved for predicting severe FIGO grade 3 PAS. Using a multivariate approach, a support vector machine model yielded 0.30 sensitivity (95% CI 0.18-1.0]), 0.74 specificity (0.38-1.00), 0.58 accuracy (0.40-0.82), and 0.53 AUC (0.40-0.85).

CONCLUSION: Our results demonstrate a predictive potential of this machine learning pipeline for classifying severe PAS cases.

RELEVANCE STATEMENT: This study demonstrates the potential use of radiomics from MR images to identify severe cases of placenta accreta spectrum antenatally.

KEY POINTS: • Identifying severe cases of placenta accreta spectrum from imaging is challenging. • We present a methodological approach for radiomics-based prediction of placenta accreta. • We report certain radiomic features are able to predict severe PAS subtypes. • Identifying severe PAS subtypes ensures safe and individualised care planning for birth.

PMID:37726591 | DOI:10.1186/s41747-023-00369-2

Categories: Literature Watch

Data-driven transcriptomics analysis identifies PCSK9 as a novel key regulator in liver aging

Tue, 2023-09-19 06:00

Geroscience. 2023 Sep 20. doi: 10.1007/s11357-023-00928-w. Online ahead of print.

ABSTRACT

The liver, as a crucial metabolic organ, undergoes significant pathological changes during the aging process, which can have a profound impact on overall health. To gain a comprehensive understanding of these alterations, we employed data-driven approaches, along with biochemical methods, histology, and immunohistochemistry techniques, to systematically investigate the effects of aging on the liver. Our study utilized a well-established rat aging model provided by the National Institute of Aging. Systems biology approaches were used to analyze genome-wide transcriptomics data from liver samples obtained from young (4-5 months old) and aging (20-21 months old) Fischer 344 rats. Our findings revealed pathological changes occurring in various essential biological processes in aging livers. These included mitochondrial dysfunction, increased oxidative/nitrative stress, decreased NAD + content, impaired amino acid and protein synthesis, heightened inflammation, disrupted lipid metabolism, enhanced apoptosis, senescence, and fibrosis. These results were validated using independent datasets from both human and rat aging studies. Furthermore, by employing co-expression network analysis, we identified novel driver genes responsible for liver aging, confirmed our findings in human aging subjects, and pointed out the cellular localization of the driver genes using single-cell RNA-sequencing human data. Our study led to the discovery and validation of a liver-specific gene, proprotein convertase subtilisin/kexin type 9 (PCSK9), as a potential therapeutic target for mitigating the pathological processes associated with aging in the liver. This finding envisions new possibilities for developing interventions aimed to improve liver health during the aging process.

PMID:37726433 | DOI:10.1007/s11357-023-00928-w

Categories: Literature Watch

Structure preserving adversarial generation of labeled training samples for single-cell segmentation

Tue, 2023-09-19 06:00

Cell Rep Methods. 2023 Sep 13:100592. doi: 10.1016/j.crmeth.2023.100592. Online ahead of print.

ABSTRACT

We introduce a generative data augmentation strategy to improve the accuracy of instance segmentation of microscopy data for complex tissue structures. Our pipeline uses regular and conditional generative adversarial networks (GANs) for image-to-image translation to construct synthetic microscopy images along with their corresponding masks to simulate the distribution and shape of the objects and their appearance. The synthetic samples are then used for training an instance segmentation network (for example, StarDist or Cellpose). We show on two single-cell-resolution tissue datasets that our method improves the accuracy of downstream instance segmentation tasks compared with traditional training strategies using either the raw data or basic augmentations. We also compare the quality of the object masks with those generated by a traditional cell population simulation method, finding that our synthesized masks are closer to the ground truth considering Fréchet inception distances.

PMID:37725984 | DOI:10.1016/j.crmeth.2023.100592

Categories: Literature Watch

Drug discovery-based approach identifies new nitrification inhibitors

Tue, 2023-09-19 06:00

J Environ Manage. 2023 Sep 17;346:118996. doi: 10.1016/j.jenvman.2023.118996. Online ahead of print.

ABSTRACT

Nitrogen (N) fertilization is crucial to sustain global food security, but fertilizer N production is energy-demanding and subsequent environmental N losses contribute to biodiversity loss and climate change. N losses can be mitigated be interfering with microbial nitrification, and therefore the use of nitrification inhibitors in enhanced efficiency fertilizers (EEFs) is an important N management strategy to increase N use efficiency and reduce N pollution. However, currently applied nitrification inhibitors have limitations and do not target all nitrifying microorganisms. Here, to identify broad-spectrum nitrification inhibitors, we adopted a drug discovery-based approach and screened 45,400 small molecules on different groups of nitrifying microorganisms. Although a high number of potential nitrification inhibitors were identified, none of them targeted all nitrifier groups. Moreover, a high number of new nitrification inhibitors were shown to be highly effective in culture but did not reduce ammonia consumption in soil. One archaea-targeting inhibitor was not only effective in soil, but even reduced - when co-applied with a bacteria-targeting inhibitor - ammonium consumption and greenhouse gas emissions beyond what is achieved with currently applied nitrification inhibitors. This advocates for combining different types of nitrification inhibitors in EEFs to optimize N management practices and make agriculture more sustainable.

PMID:37725864 | DOI:10.1016/j.jenvman.2023.118996

Categories: Literature Watch

Unannotated microprotein EMBOW regulates the interactome and chromatin and mitotic functions of WDR5

Tue, 2023-09-19 06:00

Cell Rep. 2023 Sep 18;42(9):113145. doi: 10.1016/j.celrep.2023.113145. Online ahead of print.

ABSTRACT

The conserved WD40-repeat protein WDR5 interacts with multiple proteins both inside and outside the nucleus. However, it is currently unclear whether and how the distribution of WDR5 between complexes is regulated. Here, we show that an unannotated microprotein EMBOW (endogenous microprotein binder of WDR5) dually encoded in the human SCRIB gene interacts with WDR5 and regulates its binding to multiple interaction partners, including KMT2A and KIF2A. EMBOW is cell cycle regulated, with two expression maxima at late G1 phase and G2/M phase. Loss of EMBOW decreases WDR5 interaction with KIF2A, aberrantly shortens mitotic spindle length, prolongs G2/M phase, and delays cell proliferation. In contrast, loss of EMBOW increases WDR5 interaction with KMT2A, leading to WDR5 binding to off-target genes, erroneously increasing H3K4me3 levels, and activating transcription of these genes. Together, these results implicate EMBOW as a regulator of WDR5 that regulates its interactions and prevents its off-target binding in multiple contexts.

PMID:37725512 | DOI:10.1016/j.celrep.2023.113145

Categories: Literature Watch

MIST-CF: Chemical Formula Inference from Tandem Mass Spectra

Tue, 2023-09-19 06:00

J Chem Inf Model. 2023 Sep 19. doi: 10.1021/acs.jcim.3c01082. Online ahead of print.

ABSTRACT

Chemical formula annotation for tandem mass spectrometry (MS/MS) data is the first step toward structurally elucidating unknown metabolites. While great strides have been made toward solving this problem, the current state-of-the-art method depends on time-intensive, proprietary, and expert-parametrized fragmentation tree construction and scoring. In this work, we extend our previous spectrum Transformer methodology into an energy-based modeling framework, MIST-CF: Metabolite Inference with Spectrum Transformers for Chemical Formula prediction, for learning to rank chemical formula and adduct assignments given an unannotated MS/MS spectrum. Importantly, MIST-CF learns in a data-dependent fashion using a Formula Transformer neural network architecture and circumvents the need for fragmentation tree construction. We train and evaluate our model on a large open-access database, showing an absolute improvement of 10% top 1 accuracy over other neural network architectures. We further validate our approach on the CASMI2022 challenge data set, achieving nearly equivalent performance to the winning entry within the positive mode category without any manual curation or postprocessing of our results. These results demonstrate an exciting strategy to more powerfully leverage MS2 fragment peaks for predicting MS1 precursor chemical formulas with data-driven learning.

PMID:37725368 | DOI:10.1021/acs.jcim.3c01082

Categories: Literature Watch

BondGraphs.jl: Composable energy-based modelling in systems biology

Tue, 2023-09-19 06:00

Bioinformatics. 2023 Sep 19:btad578. doi: 10.1093/bioinformatics/btad578. Online ahead of print.

ABSTRACT

SUMMARY: BondGraphs.jl is a Julia implementation of bond graphs. Bond graphs provide a modelling framework that describes energy flow through a physical system and by construction enforce thermodynamic constraints. The framework is widely used in engineering and has recently been shown to be a powerful approach for modelling biology. Models are mutable, hierarchical, multi-scale, multi-physics, and BondGraphs.jl is compatible with the Julia modelling ecosystem.

AVAILABILITY AND IMPLEMENTATION: BondGraphs.jl is freely available under the MIT license. Source code and documentation can be found at https://github.com/jedforrest/BondGraphs.jl.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:37725363 | DOI:10.1093/bioinformatics/btad578

Categories: Literature Watch

The value of connections

Tue, 2023-09-19 06:00

Elife. 2023 Sep 19;12:e92319. doi: 10.7554/eLife.92319.

ABSTRACT

High proportions of gut bacteria that produce their own food can be an indicator for poor gut health.

PMID:37725094 | DOI:10.7554/eLife.92319

Categories: Literature Watch

Anti-Cancer Effect of <em>Dorema Ammoniacum Gum</em> by Targeting Metabolic Reprogramming by Regulating <em>APC, P53, KRAS</em> Gene Expression in HT-29 Human Colon Cancer Cells

Tue, 2023-09-19 06:00

Rep Biochem Mol Biol. 2023 Apr;12(1):127-135. doi: 10.52547/rbmb.12.1.127.

ABSTRACT

BACKGROUND: Colorectal cancer is a heterogeneous disease that leads to metabolic disorders due to multiple upstream genetic and molecular changes and interactions. The development of new therapies, especially herbal medicines, has received much global attention. Dorema ammoniacum is a medicinal plant. Its gum is used in healing known ailments. Studying metabolome profiles based on nuclear magnetic resonance 1HNMR as a non-invasive and reproducible tool can identify metabolic changes as a reflection of intracellular fluxes, especially in drug responses. This study aimed to investigate the anti-cancer effects of different gum extracts on metabolic changes and their impact on gene expression in HT-29 cell.

METHODS: Extraction of Dorema ammoniacum gum with hexane, chloroform, and dichloromethane organic solvents was performed. Cell inhibition growth percentage and IC50 were assessed. Following treating the cells with dichloromethane extract, p53, APC, and KRAS gene expression were determined. 1HNMR spectroscopy was conducted. Eventually, systems biology software tools interpreted combined metabolites and genes simultaneously.

RESULTS: The lowest determined IC50 concentration was related to dichloromethane solvent, and the highest was hexane and chloroform. The expression of the KRAS oncogene gene decreased significantly after treatment with dichloromethane extract compared to the control group, and the expression of tumor suppressor gene p53 and APC increased significantly. Most gene-altered convergent metabolic phenotypes.

CONCLUSION: This study's results indicate that the dichloromethane solvent of Dorema ammoniacum gum exhibits its antitumor properties by altering the expression of genes involved in HT-29 cells and the consequent change in downstream metabolic reprogramming.

PMID:37724146 | PMC:PMC10505474 | DOI:10.52547/rbmb.12.1.127

Categories: Literature Watch

Lift force in odd compressible fluids

Tue, 2023-09-19 06:00

Phys Rev E. 2023 Aug;108(2):L023101. doi: 10.1103/PhysRevE.108.L023101.

ABSTRACT

When a body moves through a fluid, it can experience a force orthogonal to its movement called lift force. Odd viscous fluids break parity and time-reversal symmetry, suggesting the existence of an odd lift force on tracer particles, even at vanishing Reynolds numbers and for symmetric geometries. It was previously found that an incompressible odd fluid cannot induce lift force on a tracer particle with no-slip boundary conditions, making signatures of odd viscosity in the two-dimensional bulk elusive. By computing the response matrix for a tracer particle, we show that an odd compressible fluid can produce an odd lift force. Using shell localization, we provide analytic expressions for the drag and odd lift forces acting on the tracer particle in a steady state and also at finite frequency. Importantly, we find that the existence of an odd lift force in a steady state requires taking into account the nonconservation of the fluid mass density due to the coupling between the two-dimensional surface and the three-dimensional bulk fluid.

PMID:37723786 | DOI:10.1103/PhysRevE.108.L023101

Categories: Literature Watch

Navigating phase space transport with the origin-fate map

Tue, 2023-09-19 06:00

Phys Rev E. 2023 Aug;108(2-1):024211. doi: 10.1103/PhysRevE.108.024211.

ABSTRACT

We introduce and demonstrate the usage of the origin-fate map (OFM) as a tool for the detailed investigation of phase space transport in reactant-product-type systems. For these systems, which exhibit clearly defined start and end states, it is possible to build a comprehensive picture of the lobe dynamics by considering backward and forward integration of sets of initial conditions to index their origin and fate. We illustrate the method and its utility in the study of a two degrees of freedom caldera potential with four exits, demonstrating that the OFM not only recapitulates results from classical manifold theory but even provides more detailed information about complex lobe structures. The OFM allows the detection of dynamically significant transitions caused by the creation of new lobes and is also able to guide the prediction of the position of unstable periodic orbits (UPOs). Further, we compute the OFM on the periodic orbit dividing surface (PODS) associated with the transition state of a caldera entrance, which allows for a powerful analysis of reactive trajectories. The intersection of the manifolds corresponding to this UPO with other manifolds in the phase space results in the appearance of lobes on the PODS, which are directly classified by the OFM. This allows computations of branching ratios and the exploration of a fractal cascade of lobes as the caldera is stretched, which results in fluctuations in the branching ratio and chaotic selectivity. The OFM is found to be a simple and very useful tool with a vast range of descriptive and quantitative applications.

PMID:37723690 | DOI:10.1103/PhysRevE.108.024211

Categories: Literature Watch

A fluorescence-based assay for Trichomonas vaginalis drug screening

Mon, 2023-09-18 06:00

Parasit Vectors. 2023 Sep 18;16(1):329. doi: 10.1186/s13071-023-05919-6.

ABSTRACT

BACKGROUND: The emergence and spread of drug resistance in Trichomonas vaginalis parasites has become an important concern in trichomoniasis treatment. Fast and reliable growth assessment is critical for validating in vitro drug susceptibility and high-throughput screening of newly developed drugs.

METHODS: Modified media without yeast extract were evaluated for their ability to support the growth of T. vaginalis parasites. The potential of the nucleic acid-binding dye SYBR Green I for detecting T. vaginalis drug resistance was characterized, and seeding parasite concentration and incubation time were optimized. The fluorescence assay based on SYBR Green I was further validated in four T. vaginalis isolates with different susceptibilities to the antibiotics metronidazole, tinidazole, ornidazole and secnidazole, and compared with the traditional method that detects minimum lethal concentrations (MLCs).

RESULTS: A modified medium consisting of RPMI 1640 and Tryptone Plus as replacements for yeast extract and tryptone, respectively, in traditional trypticase-yeast extract-maltose (TYM) medium exhibited similar performance as TYM medium in maintaining T. vaginalis growth, while it showed much lower background fluorescent signals. The T. vaginalis SYBR Green I-based fluorescence (TSF) drug assay was found to have to satisfy one of two conditions to demonstrate the 50% inhibitory concentration of metronidazole for the sensitive isolate TV-334: (i) a seeding density of 3 × 104 parasites/ml and an incubation time of 48 h; or (ii) a seeding density of 1 × 104 parasites/ml and an incubation time of 72 h. Subsequent validation experiments revealed that the 48-h incubation/3 × 104 parasites/ml seeding density condition had a greater sensitivity to detect drug resistance than the 72-h condition. The TSF assay also exhibited high efficiency in identifying parasite drug resistance, as evidenced by its strong correlation with the standard MLC assay results (P = 0.003).

CONCLUSIONS: This study presents a robust TSF assay that has the potential to facilitate high-throughput, automated in vitro anti-trichomoniasis susceptibility testing for drug resistance monitoring and drug development. In comparison to the standard MLC method, this assay offers the advantages of reduced labor and elimination of subjective examination.

PMID:37723582 | DOI:10.1186/s13071-023-05919-6

Categories: Literature Watch

Author Correction: SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC)

Mon, 2023-09-18 06:00

Nat Immunol. 2023 Sep 18. doi: 10.1038/s41590-023-01646-3. Online ahead of print.

NO ABSTRACT

PMID:37723351 | DOI:10.1038/s41590-023-01646-3

Categories: Literature Watch

Single-cell multi-omics sequencing of human spermatogenesis reveals a DNA demethylation event associated with male meiotic recombination

Mon, 2023-09-18 06:00

Nat Cell Biol. 2023 Sep 18. doi: 10.1038/s41556-023-01232-7. Online ahead of print.

ABSTRACT

Human spermatogenesis is a highly ordered process; however, the roles of DNA methylation and chromatin accessibility in this process remain largely unknown. Here by simultaneously investigating the chromatin accessibility, DNA methylome and transcriptome landscapes using the modified single-cell chromatin overall omic-scale landscape sequencing approach, we revealed that the transcriptional changes throughout human spermatogenesis were correlated with chromatin accessibility changes. In particular, we identified a set of transcription factors and cis elements with potential functions. A round of DNA demethylation was uncovered upon meiosis initiation in human spermatogenesis, which was associated with male meiotic recombination and conserved between human and mouse. Aberrant DNA hypermethylation could be detected in leptotene spermatocytes of certain nonobstructive azoospermia patients. Functionally, the intervention of DNA demethylation affected male meiotic recombination and fertility. Our work provides multi-omics landscapes of human spermatogenesis at single-cell resolution and offers insights into the association between DNA demethylation and male meiotic recombination.

PMID:37723297 | DOI:10.1038/s41556-023-01232-7

Categories: Literature Watch

Function and phylogeny support the independent evolution of an ASIC-like Deg/ENaC channel in the Placozoa

Mon, 2023-09-18 06:00

Commun Biol. 2023 Sep 18;6(1):951. doi: 10.1038/s42003-023-05312-0.

ABSTRACT

ASIC channels are bilaterian proton-gated sodium channels belonging to the large and functionally-diverse Deg/ENaC family that also includes peptide- and mechanically-gated channels. Here, we report that the non-bilaterian invertebrate Trichoplax adhaerens possesses a proton-activated Deg/ENaC channel, TadNaC2, with a unique combination of biophysical features including tachyphylaxis like ASIC1a, reduced proton sensitivity like ASIC2a, biphasic macroscopic currents like ASIC3, as well as low sensitivity to the Deg/ENaC channel blocker amiloride and Ca2+ ions. Structural modeling and mutation analyses reveal that TadNaC2 proton gating is different from ASIC channels, lacking key molecular determinants, and involving unique residues within the palm and finger regions. Phylogenetic analysis reveals that a monophyletic clade of T. adhaerens Deg/ENaC channels, which includes TadNaC2, is phylogenetically distinct from ASIC channels, instead forming a clade with BASIC channels. Altogether, this work suggests that ASIC-like channels evolved independently in T. adhaerens and its phylum Placozoa. Our phylogenetic analysis also identifies several clades of uncharacterized metazoan Deg/ENaC channels, and provides phylogenetic evidence for the existence of Deg/ENaC channels outside of Metazoa, present in the gene data of select unicellular heterokont and filasterea-related species.

PMID:37723223 | DOI:10.1038/s42003-023-05312-0

Categories: Literature Watch

Author Correction: Highly specific and non-invasive imaging of Piezo1-dependent activity across scales using GenEPi

Mon, 2023-09-18 06:00

Nat Commun. 2023 Sep 18;14(1):5787. doi: 10.1038/s41467-023-41606-x.

NO ABSTRACT

PMID:37723163 | DOI:10.1038/s41467-023-41606-x

Categories: Literature Watch

Application of Multiple Omics to Understand Postoperative Delirium Pathophysiology in Humans

Mon, 2023-09-18 06:00

Gerontology. 2023 Sep 18. doi: 10.1159/000533789. Online ahead of print.

ABSTRACT

Delirium, an acute change in cognition, is common, morbid, and costly, particularly among hospitalized older adults. Despite growing knowledge of its epidemiology, far less is known about delirium pathophysiology. Initial work understanding delirium pathogenesis has focused on assaying single or a limited subset of molecules or genetic loci. Recent technological advances at the forefront of biomarker and drug target discovery have facilitated application of multiple "omics" approaches aimed to provide a more complete understanding of complex disease processes such as delirium. At its basic level, "omics" involves comparison of genes (genomics, epigenomics), transcripts (transcriptomics), proteins (proteomics), metabolites (metabolomics), or lipids (lipidomics) in biological fluids or tissues obtained from patients who have a certain condition (i.e., delirium), and those who do not. Multi-omics analyses of these various types of molecules combined with machine learning and systems biology enables the discovery of biomarkers, biological pathways, and predictors of delirium, thus elucidating its pathophysiology. This review provides an overview of the most recent omics techniques, their current impact on identifying delirium biomarkers, and future potential in enhancing our understanding of delirium pathogenesis. We summarize challenges in identification of specific biomarkers of delirium, and more importantly, in discovering the mechanisms underlying delirium pathophysiology. Based on mounting evidence, we highlight a heightened inflammatory response as one common pathway in delirium risk and progression, and we suggest other promising biological mechanisms that have recently emerged. Advanced multiple omics approaches coupled with bioinformatics methodologies have great promise to yield important discoveries that will advance delirium research.

PMID:37722373 | DOI:10.1159/000533789

Categories: Literature Watch

Maximizing multi-reaction dependencies provides more accurate and precise predictions of intracellular fluxes than the principle of parsimony

Mon, 2023-09-18 06:00

PLoS Comput Biol. 2023 Sep 18;19(9):e1011489. doi: 10.1371/journal.pcbi.1011489. Online ahead of print.

ABSTRACT

Intracellular fluxes represent a joint outcome of cellular transcription and translation and reflect the availability and usage of nutrients from the environment. While approaches from the constraint-based metabolic framework can accurately predict cellular phenotypes, such as growth and exchange rates with the environment, accurate prediction of intracellular fluxes remains a pressing problem. Parsimonious flux balance analysis (pFBA) has become an approach of choice to predict intracellular fluxes by employing the principle of efficient usage of protein resources. Nevertheless, comparative analyses of intracellular flux predictions from pFBA against fluxes estimated from labeling experiments remain scarce. Here, we posited that steady-state flux distributions derived from the principle of maximizing multi-reaction dependencies are of improved accuracy and precision than those resulting from pFBA. To this end, we designed a constraint-based approach, termed complex-balanced FBA (cbFBA), to predict steady-state flux distributions that support the given specific growth rate and exchange fluxes. We showed that the steady-state flux distributions resulting from cbFBA in comparison to pFBA show better agreement with experimentally measured fluxes from 17 Escherichia coli strains and are more precise, due to the smaller space of alternative solutions. We also showed that the same principle holds in eukaryotes by comparing the predictions of pFBA and cbFBA against experimentally derived steady-state flux distributions from 26 knock-out mutants of Saccharomyces cerevisiae. Furthermore, our results showed that intracellular fluxes predicted by cbFBA provide better support for the principle of minimizing metabolic adjustment between mutants and wild types. Together, our findings point that other principles that consider the dynamics and coordination of steady states may govern the distribution of intracellular fluxes.

PMID:37721963 | DOI:10.1371/journal.pcbi.1011489

Categories: Literature Watch

SEC14-like condensate phase transitions at plasma membranes regulate root growth in Arabidopsis

Mon, 2023-09-18 06:00

PLoS Biol. 2023 Sep 18;21(9):e3002305. doi: 10.1371/journal.pbio.3002305. Online ahead of print.

ABSTRACT

Protein function can be modulated by phase transitions in their material properties, which can range from liquid- to solid-like; yet, the mechanisms that drive these transitions and whether they are important for physiology are still unknown. In the model plant Arabidopsis, we show that developmental robustness is reinforced by phase transitions of the plasma membrane-bound lipid-binding protein SEC14-like. Using imaging, genetics, and in vitro reconstitution experiments, we show that SEC14-like undergoes liquid-like phase separation in the root stem cells. Outside the stem cell niche, SEC14-like associates with the caspase-like protease separase and conserved microtubule motors at unique polar plasma membrane interfaces. In these interfaces, SEC14-like undergoes processing by separase, which promotes its liquid-to-solid transition. This transition is important for root development, as lines expressing an uncleavable SEC14-like variant or mutants of separase and associated microtubule motors show similar developmental phenotypes. Furthermore, the processed and solidified but not the liquid form of SEC14-like interacts with and regulates the polarity of the auxin efflux carrier PINFORMED2. This work demonstrates that robust development can involve liquid-to-solid transitions mediated by proteolysis at unique plasma membrane interfaces.

PMID:37721949 | DOI:10.1371/journal.pbio.3002305

Categories: Literature Watch

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