Front Plant Sci. 2023 Oct 24;14:1307327. doi: 10.3389/fpls.2023.1307327. eCollection 2023.

NO ABSTRACT

PMID:37941664 | PMC:PMC10628715 | DOI:10.3389/fpls.2023.1307327

Nucleic Acids Res. 2023 Nov 6:gkad956. doi: 10.1093/nar/gkad956. Online ahead of print.

ABSTRACT

The silkworm Bombyx mori is a domesticated insect that serves as an animal model for research and agriculture. The silkworm super-pan-genome dataset, which we published last year, is a unique resource for the study of global genomic diversity and phenotype-genotype association. Here we present SilkMeta (http://silkmeta.org.cn), a comprehensive database covering the available silkworm pan-genome and multi-omics data. The database contains 1082 short-read genomes, 546 long-read assembled genomes, 1168 transcriptomes, 294 phenotype characterizations (phenome), tens of millions of variations (variome), 7253 long non-coding RNAs (lncRNAs), 18 717 full length transcripts and a set of population statistics. We have compiled publications on functional genomics research and genetic stock deciphering (mutant map). A range of bioinformatics tools is also provided for data visualization and retrieval. The large batch of omics data and tools were integrated in twelve functional modules that provide useful strategies and data for comparative and functional genomics research. The interactive bioinformatics platform SilkMeta will benefit not only the silkworm but also the insect biology communities.

PMID:37941143 | DOI:10.1093/nar/gkad956

Nucleic Acids Res. 2023 Nov 6:gkad960. doi: 10.1093/nar/gkad960. Online ahead of print.

ABSTRACT

WikiPathways (wikipathways.org) is an open-source biological pathway database. Collaboration and open science are pivotal to the success of WikiPathways. Here we highlight the continuing efforts supporting WikiPathways, content growth and collaboration among pathway researchers. As an evolving database, there is a growing need for WikiPathways to address and overcome technical challenges. In this direction, WikiPathways has undergone major restructuring, enabling a renewed approach for sharing and curating pathway knowledge, thus providing stability for the future of community pathway curation. The website has been redesigned to improve and enhance user experience. This next generation of WikiPathways continues to support existing features while improving maintainability of the database and facilitating community input by providing new functionality and leveraging automation.

PMID:37941138 | DOI:10.1093/nar/gkad960

Nucleic Acids Res. 2023 Nov 6:gkad1024. doi: 10.1093/nar/gkad1024. Online ahead of print.

ABSTRACT

The widespread Pseudomonas genus comprises a collection of related species with remarkable abilities to degrade plastics and polluted wastes and to produce a broad set of valuable compounds, ranging from bulk chemicals to pharmaceuticals. Pseudomonas possess characteristics of tolerance and stress resistance making them valuable hosts for industrial and environmental biotechnology. However, efficient and high-throughput genetic engineering tools have limited metabolic engineering efforts and applications. To improve their genome editing capabilities, we first employed a computational biology workflow to generate a genus-specific library of potential single-stranded DNA-annealing proteins (SSAPs). Assessment of the library was performed in different Pseudomonas using a high-throughput pooled recombinase screen followed by Oxford Nanopore NGS analysis. Among different active variants with variable levels of allelic replacement frequency (ARF), efficient SSAPs were found and characterized for mediating recombineering in the four tested species. New variants yielded higher ARFs than existing ones in Pseudomonas putida and Pseudomonas aeruginosa, and expanded the field of recombineering in Pseudomonas taiwanensisand Pseudomonas fluorescens. These findings will enhance the mutagenesis capabilities of these members of the Pseudomonas genus, increasing the possibilities for biotransformation and enhancing their potential for synthetic biology applications. .

PMID:37941137 | DOI:10.1093/nar/gkad1024

Metabolomics. 2023 Nov 8;19(11):93. doi: 10.1007/s11306-023-02060-4.

ABSTRACT

INTRODUCTION: The Metabolomics Quality Assurance and Quality Control Consortium (mQACC) organized a workshop during the Metabolomics 2022 conference.

OBJECTIVES: The goal of the workshop was to disseminate recent findings from mQACC community-engagement efforts and to solicit feedback about a living guidance document of QA/QC best practices for untargeted LC-MS metabolomics.

METHODS: Four QC-related topics were presented.

RESULTS: During the discussion, participants expressed the need for detailed guidance on a broad range of QA/QC-related topics accompanied by use-cases.

CONCLUSIONS: Ongoing efforts will continue to identify, catalog, harmonize, and disseminate QA/QC best practices, including outreach activities, to establish and continually update QA/QC guidelines.

PMID:37940740 | DOI:10.1007/s11306-023-02060-4

Trends Cell Biol. 2023 Nov 6:S0962-8924(23)00212-X. doi: 10.1016/j.tcb.2023.10.008. Online ahead of print.

ABSTRACT

Adaptation enables cells to change their behavior in response to transient stimuli. While adaptive programs of immune cells have been widely described, it has recently emerged that epithelial cells also acquire memories in vivo. Here, we discuss and classify the adaptations identified in epithelia and describe the associated long-term consequences.

PMID:37940416 | DOI:10.1016/j.tcb.2023.10.008

J Am Coll Cardiol. 2023 Nov 14;82(20):1921-1931. doi: 10.1016/j.jacc.2023.08.053.

ABSTRACT

BACKGROUND: Despite major advances in pharmacological treatment for patients with heart failure, residual mortality remains high. This suggests that important pathways are not yet targeted by current heart failure therapies.

OBJECTIVES: We sought integration of genetic, transcriptomic, and proteomic data in a large cohort of patients with heart failure to detect major pathways related to progression of heart failure leading to death.

METHODS: We used machine learning methodology based on stacked generalization framework and gradient boosting algorithms, using 54 clinical phenotypes, 403 circulating plasma proteins, 36,046 transcript expression levels in whole blood, and 6 million genomic markers to model all-cause mortality in 2,516 patients with heart failure from the BIOSTAT-CHF (Systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study. Results were validated in an independent cohort of 1,738 patients.

RESULTS: The mean age of the patients was 70 years (Q1-Q3: 61-78 years), 27% were female, median N-terminal pro-B-type natriuretic peptide was 4,275 ng/L (Q1-Q3: 2,360-8,486 ng/L), and 7% had heart failure with preserved ejection fraction. During a median follow-up of 21 months, 657 (26%) of patients died. The 4 major pathways with a significant association to all-cause mortality were: 1) the PI3K/Akt pathway; 2) the MAPK pathway; 3) the Ras signaling pathway; and 4) epidermal growth factor receptor tyrosine kinase inhibitor resistance. Results were validated in an independent cohort of 1,738 patients.

CONCLUSIONS: A systems biology approach integrating genomic, transcriptomic, and proteomic data identified 4 major pathways related to mortality. These pathways are related to decreased activation of the cardioprotective ERBB2 receptor, which can be modified by neuregulin.

PMID:37940229 | DOI:10.1016/j.jacc.2023.08.053

Math Biosci. 2023 Nov 6:109102. doi: 10.1016/j.mbs.2023.109102. Online ahead of print.

ABSTRACT

Modeling biological systems holds great promise for speeding up the rate of discovery in systems biology by predicting experimental outcomes and suggesting targeted interventions. However, this process is dogged by an identifiability issue, in which network models and their parameters are not sufficiently constrained by coarse and noisy data to ensure unique solutions. In this work, we evaluated the capability of a simplified yeast cell-cycle network model to reproduce multiple observed transcriptomic behaviors under genomic mutations. We matched time-series data from both cycling and checkpoint arrested cells to model predictions using an asynchronous multi-level Boolean approach. We showed that this single network model, despite its simplicity, is capable of exhibiting dynamical behavior similar to the datasets in most cases, and we demonstrated the drop in severity of the identifiability issue that results from matching multiple datasets.

PMID:37939998 | DOI:10.1016/j.mbs.2023.109102

Cell Rep Methods. 2023 Oct 30:100639. doi: 10.1016/j.crmeth.2023.100639. Online ahead of print.

ABSTRACT

For studies using microbiome data, the ability to robustly combine data from technically and biologically distinct microbiome studies is a crucial means of supporting more robust and clinically relevant inferences. Formidable technical challenges arise when attempting to combine data from technically diverse 16S rRNA gene variable region amplicon sequencing (16S) studies. Closed operational taxonomic units and taxonomy are criticized as being heavily dependent upon reference sets and with limited precision relative to the underlying biology. Phylogenetic placement has been demonstrated to be a promising taxonomy-free manner of harmonizing microbiome data, but it has lacked a validated count-based feature suitable for use in machine learning and association studies. Here we introduce a phylogenetic-placement-based, taxonomy-independent, compositional feature of microbiota: phylotypes. Phylotypes were predictive of clinical outcomes such as obesity or pre-term birth on technically diverse independent validation sets harmonized post hoc. Thus, phylotypes enable the rigorous cross-validation of 16S-based clinical prognostic models and associative microbiome studies.

PMID:37939711 | DOI:10.1016/j.crmeth.2023.100639

J Proteome Res. 2023 Nov 8. doi: 10.1021/acs.jproteome.3c00425. Online ahead of print.

ABSTRACT

Protein tyrosine sulfation (sY) is a post-translational modification (PTM) catalyzed by Golgi-resident tyrosyl protein sulfo transferases (TPSTs). Information on sY in humans is currently limited to ∼50 proteins, with only a handful having verified sites of sulfation. As such, the contribution of sulfation to the regulation of biological processes remains poorly defined. Mass spectrometry (MS)-based proteomics is the method of choice for PTM analysis but has yet to be applied for systematic investigation of the "sulfome", primarily due to issues associated with discrimination of sY-containing from phosphotyrosine (pY)-containing peptides. In this study, we developed an MS-based workflow for sY-peptide characterization, incorporating optimized Zr4+ immobilized metal-ion affinity chromatography (IMAC) and TiO2 enrichment strategies. Extensive characterization of a panel of sY- and pY-peptides using an array of fragmentation regimes (CID, HCD, EThcD, ETciD, UVPD) highlighted differences in the generation of site-determining product ions and allowed us to develop a strategy for differentiating sulfated peptides from nominally isobaric phosphopeptides based on low collision energy-induced neutral loss. Application of our "sulfomics" workflow to a HEK-293 cell extracellular secretome facilitated identification of 21 new sulfotyrosine-containing proteins, several of which we validate enzymatically, and reveals new interplay between enzymes relevant to both protein and glycan sulfation.

PMID:37939282 | DOI:10.1021/acs.jproteome.3c00425

Sci Adv. 2023 Nov 10;9(45):eadg5296. doi: 10.1126/sciadv.adg5296. Epub 2023 Nov 8.

ABSTRACT

Owing to the nondeterministic and nonlinear nature of gene expression, the steady-state intracellular protein abundance of a clonal population forms a distribution. The characteristics of this distribution, including expression strength and noise, are closely related to cellular behavior. However, quantitative description of these characteristics has so far relied on arrayed methods, which are time-consuming and labor-intensive. To address this issue, we propose a deep-learning-assisted Sort-Seq approach (dSort-Seq) in this work, enabling high-throughput profiling of expression properties with high precision. We demonstrated the validity of dSort-Seq for large-scale assaying of the dose-response relationships of biosensors. In addition, we comprehensively investigated the contribution of transcription and translation to noise production in Escherichia coli, from which we found that the expression noise is strongly coupled with the mean expression level. We also found that the transcriptional interference caused by overlapping RpoD-binding sites contributes to noise production, which suggested the existence of a simple and feasible noise control strategy in E. coli.

PMID:37939173 | DOI:10.1126/sciadv.adg5296

Eur J Hum Genet. 2023 Nov 8. doi: 10.1038/s41431-023-01462-1. Online ahead of print.

ABSTRACT

COVID-19, the disease caused by SARS-CoV-2, has caused significant morbidity and mortality worldwide. The betacoronavirus continues to evolve with global health implications as we race to learn more to curb its transmission, evolution, and sequelae. The focus of this review, the second of a three-part series, is on the biological effects of the SARS-CoV-2 virus on post-acute disease in the context of tissue and organ adaptations and damage. We highlight the current knowledge and describe how virological, animal, and clinical studies have shed light on the mechanisms driving the varied clinical diagnoses and observations of COVID-19 patients. Moreover, we describe how investigations into SARS-CoV-2 effects have informed the understanding of viral pathogenesis and provide innovative pathways for future research on the mechanisms of viral diseases.

PMID:37938797 | DOI:10.1038/s41431-023-01462-1

Nature. 2023 Nov 8. doi: 10.1038/s41586-023-06701-5. Online ahead of print.

ABSTRACT

Microsatellite repeat expansions within genes contribute to a number of neurological diseases1,2. The accumulation of toxic proteins and RNA molecules with repetitive sequences, and/or sequestration of RNA-binding proteins by RNA molecules containing expanded repeats are thought to be important contributors to disease aetiology3-9. Here we reveal that the adenosine in CAG repeat RNA can be methylated to N1-methyladenosine (m1A) by TRMT61A, and that m1A can be demethylated by ALKBH3. We also observed that the m1A/adenosine ratio in CAG repeat RNA increases with repeat length, which is attributed to diminished expression of ALKBH3 elicited by the repeat RNA. Additionally, TDP-43 binds directly and strongly with m1A in RNA, which stimulates the cytoplasmic mis-localization and formation of gel-like aggregates of TDP-43, resembling the observations made for the protein in neurological diseases. Moreover, m1A in CAG repeat RNA contributes to CAG repeat expansion-induced neurodegeneration in Caenorhabditis elegans and Drosophila. In sum, our study offers a new paradigm of the mechanism through which nucleotide repeat expansion contributes to neurological diseases and reveals a novel pathological function of m1A in RNA. These findings may provide an important mechanistic basis for therapeutic intervention in neurodegenerative diseases emanating from CAG repeat expansion.

PMID:37938769 | DOI:10.1038/s41586-023-06701-5

Nature. 2023 Nov 8. doi: 10.1038/s41586-023-06704-2. Online ahead of print.

ABSTRACT

Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are understudied. For example, we lack a comprehensive understanding of the mechanisms of toxicities observed in patients receiving T cell therapies, including recent reports of encephalitis caused by reactivation of human herpesvirus 6 (HHV-6)1. Here, through petabase-scale viral genomics mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in cultures of human CD4+ T cells. Using single-cell sequencing, we identify a rare population of HHV-6 'super-expressors' (about 1 in 300-10,000 cells) that possess high viral transcriptional activity, among research-grade allogeneic chimeric antigen receptor (CAR) T cells. By analysing single-cell sequencing data from patients receiving cell therapy products that are approved by the US Food and Drug Administration2 or are in clinical studies3-5, we identify the presence of HHV-6-super-expressor CAR T cells in patients in vivo. Together, the findings of our study demonstrate the utility of comprehensive genomics analyses in implicating cell therapy products as a potential source contributing to the lytic HHV-6 infection that has been reported in clinical trials1,6-8 and may influence the design and production of autologous and allogeneic cell therapies.

PMID:37938768 | DOI:10.1038/s41586-023-06704-2

Nature. 2023 Nov;623(7986):274-282. doi: 10.1038/s41586-023-06686-1. Epub 2023 Nov 8.

ABSTRACT

Neuroscience research has entered a phase of key discoveries in the realm of neurogenomics owing to strong financial and intellectual support for resource building and tool development. The previous challenge of tissue heterogeneity has been met with the application of techniques that can profile individual cells at scale. Moreover, the ability to perturb genes, gene regulatory elements and neuronal activity in a cell-type-specific manner has been integrated with gene expression studies to uncover the functional underpinnings of the genome at a systems level. Although these insights have necessarily been grounded in model systems, we now have the opportunity to apply these approaches in humans and in human tissue, thanks to advances in human genetics, brain imaging and tissue collection. We acknowledge that there will probably always be limits to the extent to which we can apply the genomic tools developed in model systems to human neuroscience; however, as we describe in this Perspective, the neuroscience field is now primed with an optimal foundation for tackling this ambitious challenge. The application of systems-level network analyses to these datasets will facilitate a deeper appreciation of human neurogenomics that cannot otherwise be achieved from directly observable phenomena.

PMID:37938705 | DOI:10.1038/s41586-023-06686-1

Nat Commun. 2023 Nov 8;14(1):7193. doi: 10.1038/s41467-023-43065-w.

ABSTRACT

Artificial RNA translation modulation usually relies on multiple components, such as RNA binding proteins (RBPs) or microRNAs (miRNAs) for off-switches and double-inverter cascades for on-switches. Recently, translational circular RNAs (circRNAs) were developed as promising alternatives for linear messenger RNAs (mRNAs). However, circRNAs still lack straightforward and programmable translation control strategies. Here, we rationally design a programmable miRNA-responsive internal ribosome entry site (IRES) translation activation and repression (PROMITAR) platform capable of implementing miRNA-based translation upregulation and downregulation in a single RNA construct. Based on the PROMITAR platform, we construct logic gates and cell-type classifier circRNAs and successfully identify desired mammalian cell types. We also demonstrate the potential therapeutic application of our platform for targeted cancer cell killing by encoding a cytotoxic protein in our engineered circRNAs. We expect our platform to expand the toolbox for RNA synthetic biology and provide an approach for potential biomedical applications in the future.

PMID:37938567 | DOI:10.1038/s41467-023-43065-w

Biol Trace Elem Res. 2023 Nov 8. doi: 10.1007/s12011-023-03932-5. Online ahead of print.

ABSTRACT

The emergence of conflicting reports on the natural occurrence of Alzheimer's disease (AD) in non-human primates has prompted research on the comparison of the role of diet-associated changes in gene expression between humans and non-human primates. This article analyzes the effects of different human and chimpanzee diets and their link with apolipoproteins, lipid, and iron (Fe) metabolism, starting from available data, to find out any gap in the existing knowledge. By using a system biology approach, we have re-analyzed the liver and brain RNA seq data of mice fed with either human or chimpanzee diet for 2 weeks to look for genetic differences that may explain the differences in AD occurrence between those two classes. In liver samples of mice fed with the chimpanzee diet in comparison to the human diet, apolipoprotein A-1, ceruloplasmin, and 10 other genes were upregulated while 21 genes were downregulated. However, brain apolipoprotein E4 gene expression was not changed upon diet. Genetic, structural, and functional differences in apolipoprotein E protein, along with differences in Fe metabolisms and a longer lifespan of humans during evolution may account for the observed disparity.

PMID:37938458 | DOI:10.1007/s12011-023-03932-5

ISME Commun. 2021 Nov 13;1(1):67. doi: 10.1038/s43705-021-00069-1.

ABSTRACT

Sulfate analog oxyanions that function as selective metabolic inhibitors of dissimilatory sulfate reducing microorganisms (SRM) are widely used in ecological studies and industrial applications. As such, it is important to understand the mode of action and mechanisms of tolerance or adaptation to these compounds. Different oxyanions vary widely in their inhibitory potency and mechanism of inhibition, but current evidence suggests that the sulfate adenylyl transferase/ATP sulfurylase (Sat) enzyme is an important target. We heterologously expressed and purified the Sat from the model SRM, Desulfovibrio alaskensis G20. With this enzyme we determined the turnover kinetics (kcat, KM) for alternative substrates (molybdate, selenate, arsenate, monofluorophosphate, and chromate) and inhibition constants (KI) for competitive inhibitors (perchlorate, chlorate, and nitrate). These measurements enable the first quantitative comparisons of these compounds as substrates or inhibitors of a purified Sat from a respiratory sulfate reducer. We compare predicted half-maximal inhibitory concentrations (IC50) based on Sat kinetics with measured IC50 values against D. alaskensis G20 growth and discuss our results in light of known mechanisms of sensitivity or resistance to oxyanions. This analysis helps with the interpretation of recent adaptive laboratory evolution studies and illustrates the value of interpreting gene-microbe-environment interactions through the lens of enzyme kinetics.

PMID:37938298 | DOI:10.1038/s43705-021-00069-1

Elife. 2023 Nov 8;12:RP86695. doi: 10.7554/eLife.86695.

ABSTRACT

Understanding how the brain encodes behaviour is the ultimate goal of neuroscience and the ability to objectively and reproducibly describe and quantify behaviour is a necessary milestone on this path. Recent technological progresses in machine learning and computational power have boosted the development and adoption of systems leveraging on high-resolution video recording to track an animal pose and describe behaviour in all four dimensions. However, the high temporal and spatial resolution that these systems offer must come as a compromise with their throughput and accessibility. Here, we describe coccinella, an open-source reductionist framework combining high-throughput analysis of behaviour using real-time tracking on a distributed mesh of microcomputers (ethoscopes) with resource-lean statistical learning (HCTSA/Catch22). Coccinella is a reductionist system, yet outperforms state-of-the-art alternatives when exploring the pharmacobehaviour in Drosophila melanogaster.

PMID:37938101 | DOI:10.7554/eLife.86695

EMBO J. 2023 Nov 8:e113595. doi: 10.15252/embj.2023113595. Online ahead of print.

ABSTRACT

Plants often experience recurrent stressful events, for example, during heat waves. They can be primed by heat stress (HS) to improve the survival of more severe heat stress conditions. At certain genes, sustained expression is induced for several days beyond the initial heat stress. This transcriptional memory is associated with hyper-methylation of histone H3 lysine 4 (H3K4me3), but it is unclear how this is maintained for extended periods. Here, we determined histone turnover by measuring the chromatin association of HS-induced histone H3.3. Genome-wide histone turnover was not homogenous; in particular, H3.3 was retained longer at heat stress memory genes compared to HS-induced non-memory genes during the memory phase. While low nucleosome turnover retained H3K4 methylation, methylation loss did not affect turnover, suggesting that low nucleosome turnover sustains H3K4 methylation, but not vice versa. Together, our results unveil the modulation of histone turnover as a mechanism to retain environmentally mediated epigenetic modifications.

PMID:37937667 | DOI:10.15252/embj.2023113595