Mol Biol Rep. 2023 Mar 15. doi: 10.1007/s11033-023-08345-0. Online ahead of print.

ABSTRACT

Interactomics is a branch of systems biology that deals with the study of protein-protein interactions and how these interactions influence phenotypes. Identifying the interactomes involved during host-pathogen interaction events may bring us a step closer to deciphering the molecular mechanisms underlying plant defence. Here, we conducted a systematic review of plant interactomics studies over the last two decades and found that while a substantial progress has been made in the field, plant-pathogen interactomics remains a less-travelled route. As an effort to facilitate the progress in this field, we provide here a comprehensive research pipeline for an in planta plant-pathogen interactomics study that encompasses the in silico prediction step to the validation step, unconfined to model plants. We also highlight four challenges in plant-pathogen interactomics with plausible solution(s) for each.

PMID:36920596 | DOI:10.1007/s11033-023-08345-0

JAMA Netw Open. 2023 Mar 1;6(3):e233086. doi: 10.1001/jamanetworkopen.2023.3086.

NO ABSTRACT

PMID:36920398 | DOI:10.1001/jamanetworkopen.2023.3086

Adv Mater. 2023 Mar 15:e2211915. doi: 10.1002/adma.202211915. Online ahead of print.

ABSTRACT

Unprecedented advances in metal nanoparticle synthesis have paved the way for broad applications in sensing, imaging, catalysis, diagnosis and therapy by tuning optical properties, enhancing catalytic performance, and improving chemical and biological properties of metal nanoparticles. The central guiding concept for regulating the size and morphology of metal nanoparticles has been identified as the precise manipulation of nucleation and subsequent growth, often known as seed-mediated growth methods. However, since the growth process is sensitive not only to the metal seeds but also to capping agents, metal precursors, growth solution, growth/incubation time, reductant and other influencing factors, the precise control of metal nanoparticle morphology is multifactorial. Further, multiple reaction parameters are entangled with each other, so it is necessary to clarify the mechanism by which each factor precisely regulates the morphology of metal nanoparticles. In this review, to exploit the generality and extendibility of metal nanoparticle synthesis, we systematically summarized the mechanism of growth influencing factors in seed-mediated growth methods. Second, we focus on a variety of critical properties and applications enabled by grown metal nanoparticles. Finally, we review the current progress and offer insights on the challenges, opportunities, and future directions for the growth and applications of grown metal nanoparticles. This article is protected by copyright. All rights reserved.

PMID:36920232 | DOI:10.1002/adma.202211915

Mol Syst Biol. 2023 Mar 15:e11361. doi: 10.15252/msb.202211361. Online ahead of print.

ABSTRACT

DNA methylation comprises a cumulative record of lifetime exposures superimposed on genetically determined markers. Little is known about methylation dynamics in humans following an acute perturbation, such as infection. We characterized the temporal trajectory of blood epigenetic remodeling in 133 participants in a prospective study of young adults before, during, and after asymptomatic and mildly symptomatic SARS-CoV-2 infection. The differential methylation caused by asymptomatic or mildly symptomatic infections was indistinguishable. While differential gene expression largely returned to baseline levels after the virus became undetectable, some differentially methylated sites persisted for months of follow-up, with a pattern resembling autoimmune or inflammatory disease. We leveraged these responses to construct methylation-based machine learning models that distinguished samples from pre-, during-, and postinfection time periods, and quantitatively predicted the time since infection. The clinical trajectory in the young adults and in a diverse cohort with more severe outcomes was predicted by the similarity of methylation before or early after SARS-CoV-2 infection to the model-defined postinfection state. Unlike the phenomenon of trained immunity, the postacute SARS-CoV-2 epigenetic landscape we identify is antiprotective.

PMID:36919946 | DOI:10.15252/msb.202211361

ACS Infect Dis. 2023 Mar 15. doi: 10.1021/acsinfecdis.3c00025. Online ahead of print.

ABSTRACT

Protein kinases have proven to be a very productive class of therapeutic targets, and over 90 inhibitors are currently in clinical use primarily for the treatment of cancer. Repurposing these inhibitors as antimalarials could provide an accelerated path to drug development. In this study, we identified BI-2536, a known potent human polo-like kinase 1 inhibitor, with low nanomolar antiplasmodial activity. Screening of additional PLK1 inhibitors revealed further antiplasmodial candidates despite the lack of an obvious orthologue of PLKs in Plasmodium. A subset of these inhibitors was profiled for their in vitro killing profile, and commonalities between the killing rate and inhibition of nuclear replication were noted. A kinase panel screen identified PfNEK3 as a shared target of these PLK1 inhibitors; however, phosphoproteome analysis confirmed distinct signaling pathways were disrupted by two structurally distinct inhibitors, suggesting PfNEK3 may not be the sole target. Genomic analysis of BI-2536-resistant parasites revealed mutations in genes associated with the starvation-induced stress response, suggesting BI-2536 may also inhibit an aminoacyl-tRNA synthetase.

PMID:36919909 | DOI:10.1021/acsinfecdis.3c00025

Nucleic Acids Res. 2023 Mar 15:gkad145. doi: 10.1093/nar/gkad145. Online ahead of print.

ABSTRACT

Genome-scale engineering enables rational removal of dispensable genes in chassis genomes. Deviating from this approach, we applied greedy accumulation of deletions of large dispensable regions in the Bacillus subtilis genome, yielding a library of 298 strains with genomes reduced up to 1.48 Mb in size. High-throughput physiological phenotyping of these strains confirmed that genome reduction is associated with substantial loss of cell fitness and accumulation of synthetic-sick interactions. Transcriptome analysis indicated that <15% of the genes conserved in our genome-reduced strains exhibited a twofold or higher differential expression and revealed a thiol-oxidative stress response. Most transcriptional changes can be explained by loss of known functions and by aberrant transcription at deletion boundaries. Genome-reduced strains exhibited striking new phenotypes relative to wild type, including a very high resistance (increased >300-fold) to the DNA-damaging agent mitomycin C and a very low spontaneous mutagenesis (reduced 100-fold). Adaptive laboratory evolution failed to restore cell fitness, except when coupled with a synthetic increase of the mutation rate, confirming low evolvability. Although mechanisms underlying this emergent phenotype are not understood, we propose that low evolvability can be leveraged in an engineering strategy coupling reductive cycles with evolutive cycles under induced mutagenesis.

PMID:36919610 | DOI:10.1093/nar/gkad145

Genome Biol. 2023 Mar 14;24(1):49. doi: 10.1186/s13059-023-02886-0.

ABSTRACT

BACKGROUND: The epidermis of cotton ovule produces fibers, the most important natural cellulose source for the global textile industry. However, the molecular mechanism of fiber cell growth is still poorly understood.

RESULTS: Here, we develop an optimized protoplasting method, and integrate single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) to systematically characterize the cells of the outer integument of ovules from wild type and fuzzless/lintless (fl) cotton (Gossypium hirsutum). By jointly analyzing the scRNA-seq data from wildtype and fl, we identify five cell populations including the fiber cell type and construct the development trajectory for fiber lineage cells. Interestingly, by time-course diurnal transcriptomic analysis, we demonstrate that the primary growth of fiber cells is a highly regulated circadian rhythmic process. Moreover, we identify a small peptide GhRALF1 that circadian rhythmically controls fiber growth possibly through oscillating auxin signaling and proton pump activity in the plasma membrane. Combining with scATAC-seq, we further identify two cardinal cis-regulatory elements (CREs, TCP motif, and TCP-like motif) which are bound by the trans factors GhTCP14s to modulate the circadian rhythmic metabolism of mitochondria and protein translation through regulating approximately one third of genes that are highly expressed in fiber cells.

CONCLUSIONS: We uncover a fiber-specific circadian clock-controlled gene expression program in regulating fiber growth. This study unprecedentedly reveals a new route to improve fiber traits by engineering the circadian clock of fiber cells.

PMID:36918913 | DOI:10.1186/s13059-023-02886-0

Nat Cell Biol. 2023 Mar;25(3):381-389. doi: 10.1038/s41556-023-01095-y. Epub 2023 Mar 13.

ABSTRACT

COVID-19 is a systemic disease involving multiple organs. We previously established a platform to derive organoids and cells from human pluripotent stem cells to model SARS-CoV-2 infection and perform drug screens1,2. This provided insight into cellular tropism and the host response, yet the molecular mechanisms regulating SARS-CoV-2 infection remain poorly defined. Here we systematically examined changes in transcript profiles caused by SARS-CoV-2 infection at different multiplicities of infection for lung airway organoids, lung alveolar organoids and cardiomyocytes, and identified several genes that are generally implicated in controlling SARS-CoV-2 infection, including CIART, the circadian-associated repressor of transcription. Lung airway organoids, lung alveolar organoids and cardiomyocytes derived from isogenic CIART-/- human pluripotent stem cells were significantly resistant to SARS-CoV-2 infection, independently of viral entry. Single-cell RNA-sequencing analysis further validated the decreased levels of SARS-CoV-2 infection in ciliated-like cells of lung airway organoids. CUT&RUN, ATAC-seq and RNA-sequencing analyses showed that CIART controls SARS-CoV-2 infection at least in part through the regulation of NR4A1, a gene also identified from the multi-organoid analysis. Finally, transcriptional profiling and pharmacological inhibition led to the discovery that the Retinoid X Receptor pathway regulates SARS-CoV-2 infection downstream of CIART and NR4A1. The multi-organoid platform identified the role of circadian-clock regulation in SARS-CoV-2 infection, which provides potential therapeutic targets for protection against COVID-19 across organ systems.

PMID:36918693 | DOI:10.1038/s41556-023-01095-y

Sci Rep. 2023 Mar 14;13(1):4253. doi: 10.1038/s41598-023-31191-w.

NO ABSTRACT

PMID:36918662 | DOI:10.1038/s41598-023-31191-w

Nat Commun. 2023 Mar 14;14(1):1411. doi: 10.1038/s41467-023-36997-w.

ABSTRACT

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

PMID:36918541 | DOI:10.1038/s41467-023-36997-w

Gut. 2023 Mar 14:gutjnl-2022-328332. doi: 10.1136/gutjnl-2022-328332. Online ahead of print.

ABSTRACT

OBJECTIVE: Gastric cancer (GC) is a leading cause of cancer mortality, with ARID1A being the second most frequently mutated driver gene in GC. We sought to decipher ARID1A-specific GC regulatory networks and examine therapeutic vulnerabilities arising from ARID1A loss.

DESIGN: Genomic profiling of GC patients including a Singapore cohort (>200 patients) was performed to derive mutational signatures of ARID1A inactivation across molecular subtypes. Single-cell transcriptomic profiles of ARID1A-mutated GCs were analysed to examine tumour microenvironmental changes arising from ARID1A loss. Genome-wide ARID1A binding and chromatin profiles (H3K27ac, H3K4me3, H3K4me1, ATAC-seq) were generated to identify gastric-specific epigenetic landscapes regulated by ARID1A. Distinct cancer hallmarks of ARID1A-mutated GCs were converged at the genomic, single-cell and epigenomic level, and targeted by pharmacological inhibition.

RESULTS: We observed prevalent ARID1A inactivation across GC molecular subtypes, with distinct mutational signatures and linked to a NFKB-driven proinflammatory tumour microenvironment. ARID1A-depletion caused loss of H3K27ac activation signals at ARID1A-occupied distal enhancers, but unexpectedly gain of H3K27ac at ARID1A-occupied promoters in genes such as NFKB1 and NFKB2. Promoter activation in ARID1A-mutated GCs was associated with enhanced gene expression, increased BRD4 binding, and reduced HDAC1 and CTCF occupancy. Combined targeting of promoter activation and tumour inflammation via bromodomain and NFKB inhibitors confirmed therapeutic synergy specific to ARID1A-genomic status.

CONCLUSION: Our results suggest a therapeutic strategy for ARID1A-mutated GCs targeting both tumour-intrinsic (BRD4-assocatiated promoter activation) and extrinsic (NFKB immunomodulation) cancer phenotypes.

PMID:36918265 | DOI:10.1136/gutjnl-2022-328332

Virus Res. 2023 Mar 12:199091. doi: 10.1016/j.virusres.2023.199091. Online ahead of print.

ABSTRACT

AIM: This study investigated the prophylactic and therapeutic role of ultradiluted preparation of the Delta variant of SARS-CoV-2 recombinant spike (S) protein during S antigen-induced inflammatory process of disease progression along with the probable mechanism of action.

MAIN METHODS: Ultradiluted S protein (UDSP) was prepared and administered orally to adult BALB/c mice before and after administration of S antigen intranasally. After an observation period of 72 h, animals were sacrificed and expression level of ferritin was assayed through ELISA. The genetic expressions of cytokines, IL-6, IL-10, IL-1β, TNFα, IL-17, MMP-9, TIMP-1, ferritin light and heavy chains, and mitochondrial ferritin from lung tissues were investigated through RT-PCR. Formalin-fixed lung tissue sections were stained with hematoxylin and eosin to observe the degree of pathological changes. The activity of MMP-9 in lung tissues was investigated through gelatin zymography and immunofluorescence of MMP-9 in lung tissue sections was performed to revalidate the finding from gelatin zymography. Systems biology approach was used to elucidate a probable pathway where UDSP attenuated the inflammation through the regulation of pro- and anti-inflammatory cytokines.

KEY FINDINGS: UDSP attenuated the S antigen-induced hyperinflammation in the lung by regulating pro- and anti-inflammatory cytokines, calming cytokine storm, reducing ferritin level both in transcriptional and translational levels, and restoring critical ratio of MMP-9: TIMP-1.

SIGNIFICANCE: Our findings suggest a probable pathway by which UDSP might have attenuated inflammation through the regulation of cytokines, receptors, and other molecules. This proclaims UDSP as a promising antiviral agent in the treatment of COVID-19-induced immunopathogenesis.

PMID:36918101 | DOI:10.1016/j.virusres.2023.199091

Int J Antimicrob Agents. 2023 Mar 12:106785. doi: 10.1016/j.ijantimicag.2023.106785. Online ahead of print.

ABSTRACT

OBJECTIVES: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is an urgent threat to public health, with the emergence of high-level resistant strains such as the FC428 clone. This study aimed to evaluate the high-resolution melting assay of N. gonorrhoeae AMR (HRM-NG-AMR) for diagnosing of N. gonorrhoeae infection and detecting extended-spectrum cephalosporins and azithromycin resistance.

METHODS: To evaluate the performance of the HRM-NG-AMR assay, we employed a multicentre collection of 1488 samples, including 770 isolates and 718 urogenital swabs. The presence of N. gonorrhoeae was confirmed by culture. Minimum inhibitory concentrations of antibiotics against the tested isolates were determined using the agar dilution method.

RESULTS: Regarding N. gonorrhoeae identification, HRM-NG-AMR had a sensitivity of 95.15% (95% confidence interval [CI], 91.65-97.28) and a specificity of 96.44% (95% CI, 94.17-97.89) using culture as a standard. Regarding AMR detection, the specificity ranged from 96.29% (95% CI, 94.57-97.50) for cefixime to 99.52% (95% CI, 98.68-99.85) for azithromycin. Additionally, the sensitivity ranged from 31.34% (95% CI, 20.87-43.97) for azithromycin to 79.10% (95% CI, 63.52-89.42) for ceftriaxone. We determined that 98.81% (664/672) and 91.52% (615/672) of N. gonorrhoeae isolates were susceptible to ceftriaxone and cefixime, respectively, by detecting non-mosaic penA. Lastly, 40 genotypic FC428-related strains with the penA-60.001 allele were accurately identified.

CONCLUSIONS: The HRM-NG-AMR assay showed promising diagnostic performance for detecting N. gonorrhoeae infection and predicting AMR. Study is being designed to evaluate the application of this assay in the clinical setting to enhance AMR surveillance and treatment intervention.

PMID:36918087 | DOI:10.1016/j.ijantimicag.2023.106785

J Hosp Infect. 2023 Mar 12:S0195-6701(23)00078-6. doi: 10.1016/j.jhin.2023.03.004. Online ahead of print.

ABSTRACT

BACKGROUND: The global COVID-19 pandemic has resulted in a greater interest in improving the ventilation of indoor environments in order to remove aerosolized virus and thus reduce transmission. Air purification systems have been proposed as a solution to improve aerosol removal.

AIM: The aim is to determine the efficacy of air purification systems in reducing the viral load in environmental air of a room.

METHODS: A containment room equipped with HEPA filter on air intake and exhaust was constructed. It was connected via an inlet with the BSL-2 facility. From the BSL-2, Feline Corona virus (FCoV) loaded aerosols were released into the containment room. After nebulization, air sampling was performed to determine the viral load in air prior to assessing the clean air delivery rate of the air purification systems. The infectivity of the captured viruses was also examined.

FINDINGS: The air purification systems realized a 97 to 99% reduction in viral load in air in one hour. Captured infectious FCoV was reduced by 99.9% to 99.99% by use of an ESP technology.

CONCLUSIONS: The air purification systems, using ESP technology or HEPA filter, reduce the viral load in air. The ESP purifiers inactivate captured FCoV viruses. Therefore, air purification systems can be used as an adjunctive infection control measure.

PMID:36918067 | DOI:10.1016/j.jhin.2023.03.004

Immunity. 2023 Mar 7:S1074-7613(23)00092-4. doi: 10.1016/j.immuni.2023.02.018. Online ahead of print.

ABSTRACT

Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.

PMID:36917985 | DOI:10.1016/j.immuni.2023.02.018

Cancer Cell. 2023 Mar 13;41(3):546-572. doi: 10.1016/j.ccell.2023.02.018.

ABSTRACT

Primary tumors actively and specifically prime pre-metastatic niches (PMNs), the future sites of organotropic metastasis, preparing these distant microenvironments for disseminated tumor cell arrival. While initial studies of the PMN focused on extracellular matrix alterations and stromal reprogramming, it is increasingly clear that the far-reaching effects of tumors are in great part achieved through systemic and local PMN immunosuppression. Here, we discuss recent advances in our understanding of the tumor immune microenvironment and provide a comprehensive overview of the immune determinants of the PMN's spatiotemporal evolution. Moreover, we depict the PMN immune landscape, based on functional pre-clinical studies as well as mounting clinical evidence, and the dynamic, reciprocal crosstalk with systemic changes imposed by cancer progression. Finally, we outline emerging therapeutic approaches that alter the dynamics of the interactions driving PMN formation and reverse immunosuppression programs in the PMN ensuring early anti-tumor immune responses.

PMID:36917952 | DOI:10.1016/j.ccell.2023.02.018

Curr Biol. 2023 Mar 13;33(5):R170-R175. doi: 10.1016/j.cub.2022.12.054.

ABSTRACT

Plants have evolved a remarkable capacity to develop new organs post-embryonically throughout their lifespan. A prime example of this is root branching. Root branching occurs in two ways: dichotomous and lateral branching. The dichotomous branching is the result of the division of the root apical meristem into two daughter meristems, likely through symmetric cell divisions of the root apical cell, as has recently been illustrated in the extant lycophyte Selaginella moellendorffii (Figure 1). Lateral root branching relies on the de novo specification of a subset of founder cells (hereinafter referred to as lateral root stem cells) located in the internal tissues of an existing root. This step is followed by initiation, in which the specified cells re-enter the cell cycle, and subsequently by primordium formation and emergence. In this primer, we summarize recent advances describing the molecular bases underlying lateral root stem cell specification in angiosperms and highlight the important positional signals that fine tune this process. By delving into the evolutionary origins of root branching, we point out that positional control of lateral root stem cell specification has not been the prevailing mechanism among all plants and discuss the process in ferns (i.e., a sister group of seed plants), where it seems to be under the control of lineage-dependent mechanisms.

PMID:36917935 | DOI:10.1016/j.cub.2022.12.054

Adv Med Sci. 2023 Mar 12;68(1):111-120. doi: 10.1016/j.advms.2023.02.003. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive disease caused by defects in the CF transmembrane conductance regulator (CFTR) protein. Due to the genetic nature of the disease, interventions in the genome can target any underlying alterations and potentially provide permanent disease resolution. The current development of gene-editing tools, such as designer nuclease technology capable of genome correction, holds great promise for both CF and other genetic diseases. In recent years, Cas9-based technologies have enabled the generation of genetically defined human stem cell and disease models based on induced pluripotent stem cells (iPSC). In this article, we outline the potential and possibilities of using CRISPR/Cas9-based gene-editing technology in CF modeling.

PMID:36917892 | DOI:10.1016/j.advms.2023.02.003

Microbiol Spectr. 2023 Mar 14:e0016723. doi: 10.1128/spectrum.00167-23. Online ahead of print.

ABSTRACT

Microbiota residing on the urban transit systems (UTSs) can be shared by travelers and have niche-specific assemblage. However, it remains unclear how the assemblages are influenced by city characteristics, rendering city-specific and microbial-aware urban planning challenging. Here, we analyzed 3,359 UTS microbial samples collected from 16 cities around the world. We found the stochastic process dominated in all UTS microbiota assemblages, with the explanation rate (R2) of the neutral community model (NCM) higher than 0.7. Moreover, city characteristics predominantly drove such assemblage, largely responsible for the variation in the stochasticity ratio (50.1%). Furthermore, by utilizing an artificial intelligence model, we quantified the ability of UTS microbes in discriminating between cities and found that the ability was also strongly affected by city characteristics, especially climate and continent. From these, we found that although the NCM R2 of the New York City UTS microbiota was 0.831, the accuracy of the microbial-based city characteristic classifier was higher than 0.9. This is the first study to demonstrate the effects of city characteristics on the UTS microbiota assemblage, paving the way for city-specific and microbial-aware applications. IMPORTANCE We analyzed the urban transit system microbiota assemblage across 16 cities. The stochastic process was dominant in the urban transit system microbiota assemblage. The urban transit system microbe's ability in discriminating between cities was quantified using transfer learning based on random forest (RF) methods. Certain urban transit system microbes were strongly affected by city characteristics.

PMID:36916942 | DOI:10.1128/spectrum.00167-23

Plant Physiol. 2023 Mar 14:kiad161. doi: 10.1093/plphys/kiad161. Online ahead of print.

NO ABSTRACT

PMID:36916496 | DOI:10.1093/plphys/kiad161