Nat Genet. 2023 Mar 27. doi: 10.1038/s41588-023-01332-y. Online ahead of print.

ABSTRACT

Neuroblastoma, the most frequent solid tumor in infants, shows very diverse outcomes from spontaneous regression to fatal disease. When these different tumors originate and how they evolve are not known. Here we quantify the somatic evolution of neuroblastoma by deep whole-genome sequencing, molecular clock analysis and population-genetic modeling in a comprehensive cohort covering all subtypes. We find that tumors across the entire clinical spectrum begin to develop via aberrant mitoses as early as the first trimester of pregnancy. Neuroblastomas with favorable prognosis expand clonally after short evolution, whereas aggressive neuroblastomas show prolonged evolution during which they acquire telomere maintenance mechanisms. The initial aneuploidization events condition subsequent evolution, with aggressive neuroblastoma exhibiting early genomic instability. We find in the discovery cohort (n = 100), and validate in an independent cohort (n = 86), that the duration of evolution is an accurate predictor of outcome. Thus, insight into neuroblastoma evolution may prospectively guide treatment decisions.

PMID:36973454 | DOI:10.1038/s41588-023-01332-y

Nat Cancer. 2023 Mar 27. doi: 10.1038/s43018-023-00532-z. Online ahead of print.

ABSTRACT

Although the gain of function (GOF) of p53 mutants is well recognized, it remains unclear whether different p53 mutants share the same cofactors to induce GOFs. In a proteomic screen, we identified BACH1 as a cellular factor that recognizes the p53 DNA-binding domain depending on its mutation status. BACH1 strongly interacts with p53R175H but fails to effectively bind wild-type p53 or other hotspot mutants in vivo for functional regulation. Notably, p53R175H acts as a repressor for ferroptosis by abrogating BACH1-mediated downregulation of SLC7A11 to enhance tumor growth; conversely, p53R175H promotes BACH1-dependent tumor metastasis by upregulating expression of pro-metastatic targets. Mechanistically, p53R175H-mediated bidirectional regulation of BACH1 function is dependent on its ability to recruit the histone demethylase LSD2 to target promoters and differentially modulate transcription. These data demonstrate that BACH1 acts as a unique partner for p53R175H in executing its specific GOFs and suggest that different p53 mutants induce their GOFs through distinct mechanisms.

PMID:36973430 | DOI:10.1038/s43018-023-00532-z

Nat Med. 2023 Mar 27. doi: 10.1038/s41591-023-02303-w. Online ahead of print.

NO ABSTRACT

PMID:36973413 | DOI:10.1038/s41591-023-02303-w

Commun Biol. 2023 Mar 27;6(1):325. doi: 10.1038/s42003-023-04684-7.

ABSTRACT

The accumulation and transmission of mechanical stresses in the cell cortex and membrane determines the mechanics of cell shape and coordinates essential physical behaviors, from cell polarization to cell migration. However, the extent that the membrane and cytoskeleton each contribute to the transmission of mechanical stresses to coordinate diverse behaviors is unclear. Here, we reconstitute a minimal model of the actomyosin cortex within liposomes that adheres, spreads and ultimately ruptures on a surface. During spreading, accumulated adhesion-induced (passive) stresses within the membrane drive changes in the spatial assembly of actin. By contrast, during rupture, accumulated myosin-induced (active) stresses within the cortex determine the rate of pore opening. Thus, in the same system, devoid of biochemical regulation, the membrane and cortex can each play a passive or active role in the generation and transmission of mechanical stress, and their relative roles drive diverse biomimetic physical behaviors.

PMID:36973388 | DOI:10.1038/s42003-023-04684-7

Nat Commun. 2023 Mar 27;14(1):1699. doi: 10.1038/s41467-023-37429-5.

ABSTRACT

Metabolic phenotypes are pivotal for many areas, but disentangling how evolutionary history and environmental adaptation shape these phenotypes is an open problem. Especially for microbes, which are metabolically diverse and often interact in complex communities, few phenotypes can be determined directly. Instead, potential phenotypes are commonly inferred from genomic information, and rarely were model-predicted phenotypes employed beyond the species level. Here, we propose sensitivity correlations to quantify similarity of predicted metabolic network responses to perturbations, and thereby link genotype and environment to phenotype. We show that these correlations provide a consistent functional complement to genomic information by capturing how network context shapes gene function. This enables, for example, phylogenetic inference across all domains of life at the organism level. For 245 bacterial species, we identify conserved and variable metabolic functions, elucidate the quantitative impact of evolutionary history and ecological niche on these functions, and generate hypotheses on associated metabolic phenotypes. We expect our framework for the joint interpretation of metabolic phenotypes, evolution, and environment to help guide future empirical studies.

PMID:36973280 | DOI:10.1038/s41467-023-37429-5

Gene. 2023 Mar 25:147402. doi: 10.1016/j.gene.2023.147402. Online ahead of print.

ABSTRACT

OBJECTIVE: Clostridium botulinum type A is a neurotoxin-producing, spore-forming anaerobic bacterium that causes botulism in humans. The evolutionary genomic context of this organism is not yet known to understand its molecular virulence mechanisms in the human intestinal tract. Hence, this study aimed to investigate the mechanisms underlying virulence and pathogenesis by comparing the genomic contexts across species, serotypes, and subtypes.

METHODS: A comparative genomic approach was used to analyze evolutionary genomic relationships, intergenomic distances, syntenic blocks, replication origins, and gene abundance with phylogenomic neighbors.

RESULTS: Type A strains have shown genomic proximity to group I strains with distinct accessory genes and vary even within subtypes. Phylogenomic data showed that type C and D strains were distantly related to a group I and group II strains. Synthetic plots indicated that orthologous genes might have evolved from Clostridial ancestry to subtype A3 strains, whereas syntonic out-paralogs might have emerged between subtypes A3 and A1 through α-events. Gene abundance analysis revealed the key roles of genes involved in biofilm formation, cell-cell communication, human diseases, and drug resistance compared to the pathogenic Clostridia. Moreover, we identified 43 unique genes in the type A3 genome, of which 29 were involved in the pathophysiological processes and other genes contributed to amino acid metabolism. The C. botulinum type A3 genome contains 14 new virulence proteins that can provide the ability to confer antibiotic resistance, virulence exertion and adherence to host cells, the host immune system, and mobility of extrachromosomal genetic elements.

CONCLUSION: The results of our study provide insight into the understanding of new virulence mechanisms to discover new therapeutics for the treatment of human diseases caused by type A3 strains.

PMID:36972858 | DOI:10.1016/j.gene.2023.147402

J Genet Genomics. 2023 Mar 25:S1673-8527(23)00073-5. doi: 10.1016/j.jgg.2023.03.009. Online ahead of print.

NO ABSTRACT

PMID:36972797 | DOI:10.1016/j.jgg.2023.03.009

Circulation. 2023 Mar 28;147(13):1047-1049. doi: 10.1161/CIRCULATIONAHA.122.060317. Epub 2023 Mar 27.

NO ABSTRACT

PMID:36972346 | DOI:10.1161/CIRCULATIONAHA.122.060317

PLoS Pathog. 2023 Mar 27;19(3):e1011231. doi: 10.1371/journal.ppat.1011231. Online ahead of print.

ABSTRACT

Mutations continue to accumulate within the SARS-CoV-2 genome, and the ongoing epidemic has shown no signs of ending. It is critical to predict problematic mutations that may arise in clinical environments and assess their properties in advance to quickly implement countermeasures against future variant infections. In this study, we identified mutations resistant to remdesivir, which is widely administered to SARS-CoV-2-infected patients, and discuss the cause of resistance. First, we simultaneously constructed eight recombinant viruses carrying the mutations detected in in vitro serial passages of SARS-CoV-2 in the presence of remdesivir. We confirmed that all the mutant viruses didn't gain the virus production efficiency without remdesivir treatment. Time course analyses of cellular virus infections showed significantly higher infectious titers and infection rates in mutant viruses than wild type virus under treatment with remdesivir. Next, we developed a mathematical model in consideration of the changing dynamic of cells infected with mutant viruses with distinct propagation properties and defined that mutations detected in in vitro passages canceled the antiviral activities of remdesivir without raising virus production capacity. Finally, molecular dynamics simulations of the NSP12 protein of SARS-CoV-2 revealed that the molecular vibration around the RNA-binding site was increased by the introduction of mutations on NSP12. Taken together, we identified multiple mutations that affected the flexibility of the RNA binding site and decreased the antiviral activity of remdesivir. Our new insights will contribute to developing further antiviral measures against SARS-CoV-2 infection.

PMID:36972312 | DOI:10.1371/journal.ppat.1011231

Development. 2023 Mar 27:dev.201112. doi: 10.1242/dev.201112. Online ahead of print.

ABSTRACT

Our understanding of the molecular events driving cell specification in early mammalian development relies mainly on mouse studies, and it remains unclear whether these mechanisms are conserved across mammals, including humans. We have shown that the establishment of cell polarity via aPKC is a conserved event in the initiation of the trophectoderm (TE) placental program in mouse, cow, and human embryos. However, the mechanisms transducing cell polarity into cell fate in cow and human embryos are unknown. Here, we have examined the evolutionary conservation of Hippo signalling, which is thought to function downstream of aPKC activity, in four different mammalian species: mouse, rat, cow, and human. In all four species, inhibition of the Hippo pathway by targeting LATS kinases is sufficient to drive ectopic TE initiation and downregulation of SOX2. However, the timing and localisation of molecular markers differs across species with rat embryos more closely recapitulating human and cow developmental dynamics, compared to the mouse. Our comparative embryology approach uncovered intriguing differences as well as similarities in a fundamental developmental process among mammals, reinforcing the importance of cross-species investigations.

PMID:36971487 | DOI:10.1242/dev.201112

EMBO J. 2023 Mar 27:e111980. doi: 10.15252/embj.2022111980. Online ahead of print.

ABSTRACT

Homologous recombination (HR) is a key DNA damage repair pathway that is tightly adjusted to the state of a cell. A central regulator of homologous recombination is the conserved helicase-containing Bloom syndrome complex, renowned for its crucial role in maintaining genome integrity. Here, we show that in Arabidopsis thaliana, Bloom complex activity is controlled by selective autophagy. We find that the recently identified DNA damage regulator KNO1 facilitates K63-linked ubiquitination of RMI1, a structural component of the complex, thereby triggering RMI1 autophagic degradation and resulting in increased homologous recombination. Conversely, reduced autophagic activity makes plants hypersensitive to DNA damage. KNO1 itself is also controlled at the level of proteolysis, in this case mediated by the ubiquitin-proteasome system, becoming stabilized upon DNA damage via two redundantly acting deubiquitinases, UBP12 and UBP13. These findings uncover a regulatory cascade of selective and interconnected protein degradation steps resulting in a fine-tuned HR response upon DNA damage.

PMID:36970874 | DOI:10.15252/embj.2022111980

J Exp Biol. 2023 Mar 27:jeb.245355. doi: 10.1242/jeb.245355. Online ahead of print.

ABSTRACT

Lipids make up more than half of the human brain's dry weight, yet the composition and function of the brain lipidome is not well characterized. They not only provide the structural basis of cell membranes, but also take part in a wide variety of biochemical processes. In neurodegenerative diseases, lipids can facilitate neuroprotection and serve as diagnostic biomarkers. The study of organisms adapted to extreme environments may prove particularly valuable in understanding mechanisms that protect against stressful conditions and prevent neurodegeneration. The brain of the hooded seal (Cystophora cristata) exhibits a remarkable tolerance to low tissue oxygen levels (hypoxia). While neurons of most terrestrial mammals suffer irreversible damage after only short periods of hypoxia, in vitro experiments revealed that neurons of the hooded seal show prolonged functional integrity even in severe hypoxia. How the brain lipidome may contribute to the hypoxia tolerance of marine mammals has been poorly studied. We performed an untargeted lipidomics analysis, which revealed that lipid species are significantly modulated in marine mammals compared with non-diving mammals. Increased levels of sphingomyelin species may have important implications in efficient signal transduction in the seal brain. Substrate assays revealed elevated normoxic tissue levels of glucose and lactate, which may suggest an enhanced glycolytic capacity. Additionally, the neurotransmitters glutamate and glutamine were decreased, which may indicate decreased excitatory synaptic signaling in marine mammals. Analysis of hypoxia-exposed brain tissue suggests that these represent constitutive mechanisms rather than an induced response towards hypoxic conditions.

PMID:36970764 | DOI:10.1242/jeb.245355

Front Microbiol. 2023 Mar 9;14:1100501. doi: 10.3389/fmicb.2023.1100501. eCollection 2023.

ABSTRACT

Malolactic fermentation (MLF) positively influences the quality of the wine, and it occurs as a result of a lactic acid bacteria's metabolism, mainly of the Oenococcus oeni species. However, delays and halting of MLF are frequent problems in the wine industry. This is mainly because O. oeni's development is inhibited by different kinds of stress. Even though the sequencing of the genome of the PSU-1 strain of O. oeni, as well as other strains, has made it possible to identify genes involved in the resistance to some types of stress, all of the factors that could be involved are still unknown. With the aim of contributing to this knowledge, the random mutagenesis technique was used in this study as a strategy for genetic improvement of strains of the O. oeni species. The technique proved to be capable of generating a different and improved strain when compared to the PSU-1 strain (the parent from which it descends). Then, we evaluated the metabolic behavior of both strains in three different wines. We used synthetic MaxOeno wine (pH 3.5; 15% v/v ethanol), red wine (Cabernet Sauvignon), and white wine (Chardonnay). Furthermore, we compared the transcriptome of both strains, grown in MaxOeno synthetic wine. The specific growth rate of the E1 strain was on average 39% higher in comparison to the PSU-1 strain. Interestingly, E1 strain showed an overexpression of the OEOE_1794 gene, which encodes a UspA-like protein, which has been described as promoting growth. We observed that the E1 strain was able to convert, on average, 34% more malic acid into lactate than the PSU-1 strain, regardless of the wine being used. On the other hand, the E1 strain showed a flux rate of fructose-6-phosphate production that was 86% higher than the mannitol production rate, and the internal flux rates increase in the direction of pyruvate production. This coincides with the higher number of OEOE_1708 gene transcripts observed in the E1 strain grown in MaxOeno. This gene encodes for an enzyme fructokinase (EC 2.7.1.4) involved in the transformation of fructose to fructose-6-phosphate.

PMID:36970676 | PMC:PMC10033693 | DOI:10.3389/fmicb.2023.1100501

Front Neurol. 2023 Mar 9;14:1090631. doi: 10.3389/fneur.2023.1090631. eCollection 2023.

ABSTRACT

INTRODUCTION: Multiple sclerosis (MS), a non-contagious and chronic disease of the central nervous system, is an unpredictable and indirectly inherited disease affecting different people in different ways. Using Omics platforms genomics, transcriptomics, proteomics, epigenomics, interactomics, and metabolomics database, it is now possible to construct sound systems biology models to extract full knowledge of the MS and recognize the pathway to uncover the personalized therapeutic tools.

METHODS: In this study, we used several Bayesian Networks in order to find the transcriptional gene regulation networks that drive MS disease. We used a set of BN algorithms using the R add-on package bnlearn. The BN results underwent further downstream analysis and were validated using a wide range of Cytoscape algorithms, web based computational tools and qPCR amplification of blood samples from 56 MS patients and 44 healthy controls. The results were semantically integrated to improve understanding of the complex molecular architecture underlying MS, distinguishing distinct metabolic pathways and providing a valuable foundation for the discovery of involved genes and possibly new treatments.

RESULTS: Results show that the LASP1, TUBA1C, and S100A6 genes were most likely playing a biological role in MS development. Results from qPCR showed a significant increase (P < 0.05) in LASP1 and S100A6 gene expression levels in MS patients compared to that in controls. However, a significant down regulation of TUBA1C gene was observed in the same comparison.

CONCLUSION: This study provides potential diagnostic and therapeutic biomarkers for enhanced understanding of gene regulation underlying MS.

PMID:36970516 | PMC:PMC10035600 | DOI:10.3389/fneur.2023.1090631

Front Cardiovasc Med. 2023 Mar 10;10:1037357. doi: 10.3389/fcvm.2023.1037357. eCollection 2023.

ABSTRACT

Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a severely progressive condition with uncertain physiological course. Hence, it has become increasingly relevant to clarify the specific mechanisms of molecular modification, which is crucial to identify more treatment strategies. With the rapid development of high-throughput sequencing, omics technology gives access to massive experimental data and advanced techniques for systems biology, permitting comprehensive assessment of disease occurrence and progression. In recent years, significant progress has been made in the study of PAH-CHD and omics. To provide a comprehensive description and promote further in-depth investigation of PAH-CHD, this review attempts to summarize the latest developments in genomics, transcriptomics, epigenomics, proteomics, metabolomics, and multi-omics integration.

PMID:36970344 | PMC:PMC10036813 | DOI:10.3389/fcvm.2023.1037357

Front Physiol. 2023 Mar 9;14:1102393. doi: 10.3389/fphys.2023.1102393. eCollection 2023.

ABSTRACT

Liver resection is an important surgical technique in the treatment of cancers and transplantation. We used ultrasound imaging to study the dynamics of liver regeneration following two-thirds partial hepatectomy (PHx) in male and female rats fed via Lieber-deCarli liquid diet protocol of ethanol or isocaloric control or chow for 5-7 weeks. Ethanol-fed male rats did not recover liver volume to the pre-surgery levels over the course of 2 weeks after surgery. By contrast, ethanol-fed female rats as well as controls of both sexes showed normal volume recovery. Contrary to expectations, transient increases in both portal and hepatic artery blood flow rates were seen in most animals, with ethanol-fed males showing higher peak portal flow than any other experimental group. A computational model of liver regeneration was used to evaluate the contribution of physiological stimuli and estimate the animal-specific parameter intervals. The results implicate lower metabolic load, over a wide range of cell death sensitivity, in matching the model simulations to experimental data of ethanol-fed male rats. However, in the ethanol-fed female rats and controls of both sexes, metabolic load was higher and in combination with cell death sensitivity matched the observed volume recovery dynamics. We conclude that adaptation to chronic ethanol intake has a sex-dependent impact on liver volume recovery following liver resection, likely mediated by differences in the physiological stimuli or cell death responses that govern the regeneration process. Immunohistochemical analysis of pre- and post-resection liver tissue validated the results of computational modeling by associating lack of sensitivity to cell death with lower rates of cell death in ethanol-fed male rats. Our results illustrate the potential for non-invasive ultrasound imaging to assess liver volume recovery towards supporting development of clinically relevant computational models of liver regeneration.

PMID:36969577 | PMC:PMC10033530 | DOI:10.3389/fphys.2023.1102393

Curr Pediatr Rep. 2022 Sep;10(3):93-108. doi: 10.1007/s40124-022-00267-y. Epub 2022 Aug 1.

ABSTRACT

PURPOSE OF REVIEW: Review work to create and evaluate educational materials that could serve as a primary prevention strategy to help both providers and patients in Panama, Colombia, and the USA reduce disease burden of Toxoplasma infections.

RECENT FINDINGS: Educational programs had not been evaluated for efficacy in Panama, USA, or Colombia.

SUMMARY: Educational programs for high school students, pregnant women, medical students and professionals, scientists, and lay personnel were created. In most settings, short-term effects were evaluated. In Panama, Colombia, and USA, all materials showed short-term utility in transmitting information to learners. These educational materials can serve as a component of larger public health programs to lower disease burden from congenital toxoplasmosis. Future priorities include conducting robust longitudinal studies of whether education correlates with reduced adverse disease outcomes, modifying educational materials as new information regarding region-specific risk factors is discovered, and ensuring materials are widely accessible.

PMID:36969368 | PMC:PMC10035399 | DOI:10.1007/s40124-022-00267-y

Front Med (Lausanne). 2023 Mar 9;10:1126697. doi: 10.3389/fmed.2023.1126697. eCollection 2023.

ABSTRACT

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the leading cause of poor long-term survival after lung transplantation (LT). Systems prediction of Chronic Lung Allograft Dysfunction (SysCLAD) aimed to predict CLAD.

METHODS: To predict CLAD, we investigated the clinicome of patients with LT; the exposome through assessment of airway microbiota in bronchoalveolar lavage cells and air pollution studies; the immunome with works on activation of dendritic cells, the role of T cells to promote the secretion of matrix metalloproteinase-9, and subpopulations of T and B cells; genome polymorphisms; blood transcriptome; plasma proteome studies and assessment of MSK1 expression.

RESULTS: Clinicome: the best multivariate logistic regression analysis model for early-onset CLAD in 422 LT eligible patients generated a ROC curve with an area under the curve of 0.77. Exposome: chronic exposure to air pollutants appears deleterious on lung function levels in LT recipients (LTRs), might be modified by macrolides, and increases mortality. Our findings established a link between the lung microbial ecosystem, human lung function, and clinical stability post-transplant. Immunome: a decreased expression of CLEC1A in human lung transplants is predictive of the development of chronic rejection and associated with a higher level of interleukin 17A; Immune cells support airway remodeling through the production of plasma MMP-9 levels, a potential predictive biomarker of CLAD. Blood CD9-expressing B cells appear to favor the maintenance of long-term stable graft function and are a potential new predictive biomarker of BOS-free survival. An early increase of blood CD4 + CD57 + ILT2+ T cells after LT may be associated with CLAD onset. Genome: Donor Club cell secretory protein G38A polymorphism is associated with a decreased risk of severe primary graft dysfunction after LT. Transcriptome: blood POU class 2 associating factor 1, T-cell leukemia/lymphoma domain, and B cell lymphocytes, were validated as predictive biomarkers of CLAD phenotypes more than 6 months before diagnosis. Proteome: blood A2MG is an independent predictor of CLAD, and MSK1 kinase overexpression is either a marker or a potential therapeutic target in CLAD.

CONCLUSION: Systems prediction of Chronic Lung Allograft Dysfunction generated multiple fingerprints that enabled the development of predictors of CLAD. These results open the way to the integration of these fingerprints into a predictive handprint.

PMID:36968829 | PMC:PMC10033762 | DOI:10.3389/fmed.2023.1126697

Front Genet. 2023 Mar 8;14:1110899. doi: 10.3389/fgene.2023.1110899. eCollection 2023.

ABSTRACT

Robust Principal Component Analysis (RPCA) offers a powerful tool for recovering a low-rank matrix from highly corrupted data, with growing applications in computational biology. Biological processes commonly form intrinsic hierarchical structures, such as tree structures of cell development trajectories and tumor evolutionary history. The rapid development of single-cell sequencing (SCS) technology calls for the recovery of embedded tree structures from noisy and heterogeneous SCS data. In this study, we propose RobustTree, a unified framework to reconstruct the inherent topological structure underlying high-dimensional data with noise. By extending RPCA to handle tree structure optimization, RobustTree leverages data denoising, clustering, and tree structure reconstruction. It solves the tree optimization problem with an adaptive parameter selection scheme that we proposed. In addition to recovering real datasets, RobustTree can reconstruct continuous topological structure and discrete-state topological structure of underlying SCS data. We apply RobustTree on multiple synthetic and real datasets and demonstrate its high accuracy and robustness when analyzing high-noise SCS data with embedded complex structures. The code is available at https://github.com/ucasdp/RobustTree.

PMID:36968591 | PMC:PMC10030613 | DOI:10.3389/fgene.2023.1110899

ACS Cent Sci. 2023 Feb 14;9(3):381-392. doi: 10.1021/acscentsci.2c01176. eCollection 2023 Mar 22.

ABSTRACT

Heparin is a polydisperse, heterogeneous polysaccharide of the glycosaminoglycan (GAG) class that has found widespread clinical use as a potent anticoagulant and is classified as an essential medicine by the World Health Organization. The importance of rigorous monitoring and quality control of pharmaceutical heparin was highlighted in 2008, when the existing regulatory procedures failed to identify a life-threatening adulteration of pharmaceutical heparin with oversulfated chondroitin sulfate (OSCS). The subsequent contamination crisis resulted in the exploration of alternative approaches for which the use of multidimensional nuclear magnetic resonance (NMR) spectroscopy techniques and multivariate analysis emerged as the gold standard. This procedure is, however, technically demanding and requires access to expensive equipment. An alternative approach, utilizing attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) combined with multivariate analysis, has been developed. The method described enables the differentiation of diverse GAG samples, the classification of samples of distinct species provenance, and the detection of both established heparin contaminants and alien polysaccharides. This methodology has sensitivity comparable to that of NMR and can facilitate the rapid, cost-effective monitoring and analysis of pharmaceutical heparin. It is therefore suitable for future deployment throughout the supply chain.

PMID:36968539 | PMC:PMC10037494 | DOI:10.1021/acscentsci.2c01176