Plant Cell. 2023 Apr 29:koad118. doi: 10.1093/plcell/koad118. Online ahead of print.

ABSTRACT

Rhizoctonia solani is a devastating soil-borne pathogen that seriously threatens the cultivation of economically important crops. Multiple strains with a very broad host range have been identified, but only one (AG1-IA, which causes rice sheath blight disease) has been examined in detail. Here, we analyzed AG4-HGI 3 originally isolated from Tartary buckwheat (Fagopyrum tataricum), but with a host range comparable to AG1-IA. Genome comparison reveals abundant pathogenicity genes in this strain. We used multi-omics approaches to improve the efficiency of screening for disease resistance genes. Transcriptomes of the plant-fungi interaction identified differentially expressed genes associated with virulence in Rhizoctonia and resistance in Tartary buckwheat. Integration with jasmonate-mediated transcriptome and metabolome changes revealed a negative regulator of jasmonate signaling, cytochrome P450 (FtCYP94C1), as increasing disease resistance probably via accumulation of resistance-related flavonoids. The integration of resistance data for 320 Tartary buckwheat accessions identified a gene homologous to aspartic proteinase (FtASP), with peak expression following R. solani inoculation. FtASP exhibits no proteinase activity but functions as an antibacterial peptide that slows fungal growth. This work reveals a potential mechanism behind pathogen virulence and host resistance, which should accelerate the molecular breeding of resistant varieties in economically essential crops.

PMID:37119263 | DOI:10.1093/plcell/koad118

Clin Epigenetics. 2023 Apr 28;15(1):69. doi: 10.1186/s13148-023-01488-8.

ABSTRACT

BACKGROUND: Over the past decade, DNA methylation (DNAm)-based deconvolution methods that leverage cell-specific DNAm markers of immune cell types have been developed to provide accurate estimates of the proportions of leukocytes in peripheral blood. Immune cell phenotyping using DNAm markers, termed immunomethylomics or methylation cytometry, offers a solution for determining the body's immune cell landscape that does not require fresh blood and is scalable to large sample sizes. Despite significant advances in DNAm-based deconvolution, references at the population level are needed for clinical and research interpretation of these additional immune layers. Here we aim to provide some references for immune populations in a group of multi-ethnic post-menopausal American women.

RESULTS: We applied DNAm-based deconvolution to a large sample of post-menopausal women enrolled in the Women's Health Initiative (baseline, N = 58) or the ancillary Long Life Study (WHI-LLS, N = 1237) to determine the reference ranges of 58 immune parameters, including proportions and absolute counts for 19 leukocyte subsets and 20 derived cell ratios. Participants were 50-94 years old at the time of blood draw, and N = 898 (69.3%) self-identified as White. Using linear regression models, we observed significant associations between age at blood draw and absolute counts and proportions of naïve B, memory CD4+, naïve CD4+, naïve CD8+, memory CD8+ memory, neutrophils, and natural killer cells. We also assessed the same immune profiles in a subset of paired longitudinal samples collected 14-18 years apart across N = 52 participants. Our results demonstrate high inter-individual variability in rates of change of leukocyte subsets over this time. And, when conducting paired t tests to test the difference in counts and proportions between the baseline visit and LLS visit, there were significant changes in naïve B, memory CD4+, naïve CD4+, naïve CD8+, memory CD8+ cells and neutrophils, similar to the results seen when analyzing the association with age in the entire cohort.

CONCLUSIONS: Here, we show that derived cell counts largely reflect the immune profile associated with proportions and that these novel methods replicate the known immune profiles associated with age. Further, we demonstrate the value this methylation cytometry approach can add as a potential application in epidemiological studies.

PMID:37118842 | DOI:10.1186/s13148-023-01488-8

Sci China Life Sci. 2023 Apr 11. doi: 10.1007/s11427-023-2309-1. Online ahead of print.

ABSTRACT

Sexual reproduction is prevalent in eukaryotic organisms and plays a critical role in the evolution of new traits and in the generation of genetic diversity. Environmental factors often have a direct impact on the occurrence and frequency of sexual reproduction in fungi. The regulatory effects of atmospheric relative humidity (RH) on sexual reproduction and pathogenesis in plant fungal pathogens and in soil fungi have been extensively investigated. However, the knowledge of how RH regulates the lifecycles of human fungal pathogens is limited. In this study, we report that low atmospheric RH promotes the development of mating projections and same-sex (homothallic) mating in the human fungal pathogen Candida albicans. Low RH causes water loss in C. albicans cells, which results in osmotic stress and the generation of intracellular reactive oxygen species (ROS) and trehalose. The water transporting aquaporin Aqy1, and the G-protein coupled receptor Gpr1 function as cell surface sensors of changes in atmospheric humidity. Perturbation of the trehalose metabolic pathway by inactivating trehalose synthase or trehalase promotes same-sex mating in C. albicans by increasing osmotic or ROS stresses, respectively. Intracellular trehalose and ROS signal the Hog1-osmotic and Hsf1-Hsp90 signaling pathways to regulate the mating response. We, therefore, propose that the cell surface sensors Aqy1 and Gpr1, intracellular trehalose and ROS, and the Hog1-osmotic and Hsf1-Hsp90 signaling pathways function coordinately to regulate sexual mating in response to low atmospheric RH conditions in C. albicans.

PMID:37118508 | DOI:10.1007/s11427-023-2309-1

Environ Sci Pollut Res Int. 2023 Apr 28. doi: 10.1007/s11356-023-26968-5. Online ahead of print.

ABSTRACT

Phytoremediation is a cost-effective nature-based solution for brownfield reclamation. The choice of phytoextraction or phytostabilization strategies is highly relevant when planning full-scale treatments. A suitable approach to identify such species involves the evaluation of plants that grow spontaneously on the contaminated sites. Here, we sought to determine the phytoremediation potential of three spontaneous plant species, namely the trees Acer pseudoplatanus L (A. pseudoplatanus) and Betula celtiberica Rothm. & Vasc (B. celtiberica), and the shrub Buddleja davidii Franch (B. davidii), for the recovery of an urban brownfield. To determine the response of the species to the degree of contamination, we conducted soil and vegetation sampling inside and outside the site. The concentrations of As, Cu, and Zn in soil and plant samples were measured, and then various indexes related to phytoremediation were calculated. The translocation factor and transfer coefficient indicated that vegetation outside the brownfield had phytoextraction capacity while the same plants inside the brownfield revealed phytostabilization properties. Given our results, we propose that the selected species are suitable for phytostabilization strategies in areas with high concentrations of contaminants, whereas they could be used for phytoextraction only in soils with low or moderate levels of pollution.

PMID:37118389 | DOI:10.1007/s11356-023-26968-5

Nat Aging. 2022 Oct;2(10):869-871. doi: 10.1038/s43587-022-00294-w.

NO ABSTRACT

PMID:37118282 | DOI:10.1038/s43587-022-00294-w

Nat Aging. 2022 Nov;2(11):1008-1023. doi: 10.1038/s43587-022-00304-x. Epub 2022 Nov 10.

ABSTRACT

Aging is characterized by an accumulation of myeloid-biased hematopoietic stem cells (HSCs) with reduced developmental potential. Genotoxic stress and epigenetic alterations have been proposed to mediate age-related HSC loss of regenerative and self-renewal potential. However, the mechanisms underlying these changes remain largely unknown. Genetic inactivation of the plant homeodomain 6 (Phf6) gene, a nucleolar and chromatin-associated factor, antagonizes age-associated HSC decline. Immunophenotyping, single-cell transcriptomic analyses and transplantation assays demonstrated markedly decreased accumulation of immunophenotypically defined HSCs, reduced myeloid bias and increased hematopoietic reconstitution capacity with preservation of lymphoid differentiation potential in Phf6-knockout HSCs from old mice. Moreover, deletion of Phf6 in aged mice rejuvenated immunophenotypic, transcriptional and functional hallmarks of aged HSCs. Long-term HSCs from old Phf6-knockout mice showed epigenetic rewiring and transcriptional programs consistent with decreased genotoxic stress-induced HSC aging. These results identify Phf6 as an important epigenetic regulator of HSC aging.

PMID:37118089 | DOI:10.1038/s43587-022-00304-x

Nat Rev Chem. 2023 Apr;7(4):234-255. doi: 10.1038/s41570-023-00468-z. Epub 2023 Feb 21.

ABSTRACT

The ability to manipulate the chemical composition of proteins and peptides has been central to the development of improved polypeptide-based therapeutics and has enabled researchers to address fundamental biological questions that would otherwise be out of reach. Protein ligation, in which two or more polypeptides are covalently linked, is a powerful strategy for generating semisynthetic products and for controlling polypeptide topology. However, specialized tools are required to efficiently forge a peptide bond in a chemoselective manner with fast kinetics and high yield. Fortunately, nature has addressed this challenge by evolving enzymatic mechanisms that can join polypeptides using a diverse set of chemical reactions. Here, we summarize how such nature-inspired protein ligation strategies have been repurposed as chemical biology tools that afford enhanced control over polypeptide composition.

PMID:37117416 | DOI:10.1038/s41570-023-00468-z

ISME J. 2023 Apr 28. doi: 10.1038/s41396-023-01403-2. Online ahead of print.

NO ABSTRACT

PMID:37117330 | DOI:10.1038/s41396-023-01403-2

Commun Biol. 2023 Apr 28;6(1):465. doi: 10.1038/s42003-023-04820-3.

ABSTRACT

Single-cell transcriptomics datasets from the same anatomical sites generated by different research labs are becoming increasingly common. However, fast and computationally inexpensive tools for standardization of cell-type annotation and data integration are still needed in order to increase research inclusivity. To standardize cell-type annotation and integrate single-cell transcriptomics datasets, we have built a fast model-free integration method, named MASI (Marker-Assisted Standardization and Integration). We benchmark MASI with other well-established methods and demonstrate that MASI outperforms other methods, in terms of integration, annotation, and speed. To harness knowledge from single-cell atlases, we demonstrate three case studies that cover integration across biological conditions, surveyed participants, and research groups, respectively. Finally, we show MASI can annotate approximately one million cells on a personal laptop, making large-scale single-cell data integration more accessible. We envision that MASI can serve as a cheap computational alternative for the single-cell research community.

PMID:37117305 | DOI:10.1038/s42003-023-04820-3

Commun Biol. 2023 Apr 28;6(1):470. doi: 10.1038/s42003-023-04818-x.

NO ABSTRACT

PMID:37117264 | DOI:10.1038/s42003-023-04818-x

Nat Commun. 2023 Apr 28;14(1):2453. doi: 10.1038/s41467-023-38206-0.

NO ABSTRACT

PMID:37117182 | DOI:10.1038/s41467-023-38206-0

Trends Plant Sci. 2023 Apr 27:S1360-1385(23)00129-2. doi: 10.1016/j.tplants.2023.04.003. Online ahead of print.

ABSTRACT

The Salt Overly Sensitive (SOS) pathway plays a central role in plant salinity tolerance. Since the discovery of the SOS pathway, transcriptional and post-translational regulations of its core components have garnered considerable attention. To date, several proteins that regulate these core components, either positively or negatively at the protein and transcript levels, have been identified. Here, we review recent advances in the understanding of the functional regulation of the core proteins of the SOS pathway and an expanding spectrum of their upstream effectors in plants. Furthermore, we also discuss how these novel regulators act as key signaling nodes of multilayer control of plant development and stress adaptation through modulation of the SOS core proteins at the transcriptional and post-translational levels.

PMID:37117077 | DOI:10.1016/j.tplants.2023.04.003

Genome Res. 2023 Apr 28. doi: 10.1101/gr.277177.122. Online ahead of print.

ABSTRACT

Alternative polyadenylation (APA) enables a gene to generate multiple transcripts with different 3' ends, which is dynamic across different cell types or conditions. Many computational methods have been developed to characterize sample-specific APA using the corresponding RNA-seq data, but suffered from high error rate on both polyadenylation site (PAS) identification and quantification of PAS usage (PAU), and bias toward 3' untranslated regions. Here we developed a tool for APA identification and quantification (APAIQ) from RNA-seq data, which can accurately identify PAS and quantify PAU in a transcriptome-wide manner. Using 3' end-seq data as the benchmark, we showed that APAIQ outperforms current methods on PAS identification and PAU quantification, including DaPars2, Aptardi, mountainClimber, SANPolyA, and QAPA. Finally, applying APAIQ on 421 RNA-seq samples from liver cancer patients, we identified >540 tumor-associated APA events and experimentally validated two intronic polyadenylation candidates, demonstrating its capacity to unveil cancer-related APA with a large-scale RNA-seq data set.

PMID:37117035 | DOI:10.1101/gr.277177.122

Cancer Cell. 2023 Apr 25:S1535-6108(23)00129-0. doi: 10.1016/j.ccell.2023.04.003. Online ahead of print.

ABSTRACT

Due to their immunosuppressive role, tumor-infiltrating regulatory T cells (TI-Tregs) represent attractive immuno-oncology targets. Analysis of TI vs. peripheral Tregs (P-Tregs) from 36 patients, across four malignancies, identified 17 candidate master regulators (MRs) as mechanistic determinants of TI-Treg transcriptional state. Pooled CRISPR-Cas9 screening in vivo, using a chimeric hematopoietic stem cell transplant model, confirmed the essentiality of eight MRs in TI-Treg recruitment and/or retention without affecting other T cell subtypes, and targeting one of the most significant MRs (Trps1) by CRISPR KO significantly reduced ectopic tumor growth. Analysis of drugs capable of inverting TI-Treg MR activity identified low-dose gemcitabine as the top prediction. Indeed, gemcitabine treatment inhibited tumor growth in immunocompetent but not immunocompromised allografts, increased anti-PD-1 efficacy, and depleted MR-expressing TI-Tregs in vivo. This study provides key insight into Treg signaling, specifically in the context of cancer, and a generalizable strategy to systematically elucidate and target MR proteins in immunosuppressive subpopulations.

PMID:37116491 | DOI:10.1016/j.ccell.2023.04.003

Biomater Adv. 2023 Apr 18;150:213431. doi: 10.1016/j.bioadv.2023.213431. Online ahead of print.

ABSTRACT

Biomechanical inputs are ubiquitously present in biological systems and are known to regulate various cell functions. In particular, neural cell development is sensitive to mechanical regulation, as these cells reside in one of the softest microenvironments in the body. To fully characterize and comprehend how mechanical force modulates early neuronal processes, we prepared substrates functionalized with DNA probes displaying integrin ligands, including cRGD and laminin, to quantify integrin-mediated molecular tension during neurite initiation in primary cortical neurons. Our live-cell imaging analysis reveals that integrin-mediated tension force is highly dynamic and distributed across the cell body, with the overall tension signal gradually increasing during neurite outgrowth. Notably, we detected a consistent level of mechanical force (amplitude = 4.7-12 piconewtons, pN) for cell integrin-ligand interactions. Further quantifications reveal that neurons exhibit faster cell spreading and neurite outgrowth upon interacting with ligands functionalized with 4.7 pN relative to 12 pN probes. These findings indicate that the magnitude of integrin-mediated mechanical feedback regulates neuronal activity during early neuritogenesis. Additionally, we observed that mechanical tension is correlated with calcium signaling, since inhibiting calcium influx substantially reduced mechanical tension. Thus, our findings support that the magnitude of integrin-mediated mechanical feedback regulates neuronal activity during early neuritogenesis and that mechanical force is an essential element complementing well-known biochemical regulatory mechanisms orchestrating the integrin activation machinery and controlled neurite outgrowth in cortical neurons.

PMID:37116456 | DOI:10.1016/j.bioadv.2023.213431

Nat Rev Chem. 2021 Oct;5(10):674-675. doi: 10.1038/s41570-021-00317-x.

NO ABSTRACT

PMID:37118180 | DOI:10.1038/s41570-021-00317-x

Nat Aging. 2021 Sep;1(9):750-752. doi: 10.1038/s43587-021-00115-6.

NO ABSTRACT

PMID:37117626 | DOI:10.1038/s43587-021-00115-6

Sci Adv. 2023 Apr 28;9(17):eade8934. doi: 10.1126/sciadv.ade8934. Epub 2023 Apr 28.

ABSTRACT

Fitness landscapes are models of the sequence space of a genetic element that map how each sequence corresponds to its activity and can be used to guide laboratory evolution. The ribosome is a macromolecular machine that is essential for protein synthesis in all organisms. Because of the prevalence of dominant lethal mutations, a comprehensive fitness landscape of the ribosomal peptidyl transfer center (PTC) has not yet been attained. Here, we develop a method to functionally map an orthogonal tethered ribosome (oRiboT), which permits complete mutagenesis of nucleotides located in the PTC and the resulting epistatic interactions. We found that most nucleotides studied showed flexibility to mutation, and identified epistatic interactions between them, which compensate for deleterious mutations. This work provides a basis for a deeper understanding of ribosome function and malleability and could be used to inform design of engineered ribosomes with applications to synthesize next-generation biomaterials and therapeutics.

PMID:37115918 | DOI:10.1126/sciadv.ade8934

Cell Rep. 2023 Apr 26;42(5):112444. doi: 10.1016/j.celrep.2023.112444. Online ahead of print.

ABSTRACT

The bioenergetic mechanisms by which Mycobacterium tuberculosis survives hypoxia are poorly understood. Current models assume that the bacterium shifts to an alternate electron acceptor or fermentation to maintain membrane potential and ATP synthesis. Counterintuitively, we find here that oxygen itself is the principal terminal electron acceptor during hypoxic dormancy. M. tuberculosis can metabolize oxygen efficiently at least two orders of magnitude below the concentration predicted to occur in hypoxic lung granulomas. Despite a difference in apparent affinity for oxygen, both the cytochrome bcc:aa3 and cytochrome bd oxidase respiratory branches are required for hypoxic respiration. Simultaneous inhibition of both oxidases blocks oxygen consumption, reduces ATP levels, and kills M. tuberculosis under hypoxia. The capacity of mycobacteria to scavenge trace levels of oxygen, coupled with the absence of complex regulatory mechanisms to achieve hierarchal control of the terminal oxidases, may be a key determinant of long-term M. tuberculosis survival in hypoxic lung granulomas.

PMID:37115669 | DOI:10.1016/j.celrep.2023.112444

Bioinformatics. 2023 Apr 28:btad275. doi: 10.1093/bioinformatics/btad275. Online ahead of print.

ABSTRACT

MOTIVATION: Allostery enables changes to the dynamic behavior of a protein at distant positions induced by binding. Here, we present APOP, a new allosteric pocket prediction method, which perturbs the pockets formed in the structure by stiffening pairwise interactions in the elastic network across the pocket, to emulate ligand binding. Ranking the pockets based on the shifts in the global mode frequencies, as well as their mean local hydrophobicities, leads to high prediction success when tested on a dataset of allosteric proteins, composed of both monomers and multimeric assemblages.

RESULTS: Out of the 104 test cases, APOP predicts known allosteric pockets for 92 within the top 3 rank out of multiple pockets available in the protein. In addition, we demonstrate that APOP can also find new alternative allosteric pockets in proteins. Particularly interesting findings are the discovery of previously overlooked large pockets located in the centers of many protein biological assemblages; binding of ligands at these sites would likely be particularly effective in changing the protein's global dynamics.

AVAILABILITY: APOP is freely available as an open-source code (https://github.com/Ambuj-UF/APOP) and as a web server at https://apop.bb.iastate.edu/.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:37115636 | DOI:10.1093/bioinformatics/btad275