Comprehensive integration of single-cell transcriptomic data illuminates the regulatory network architecture of plant cell fate specification.

Plant morphogenesis relies on precise gene expression programs at the proper time and position which is orchestrated by transcription factors (TFs) in intricate regulatory networks in a cell-type specific manner. Here we introduced a comprehensive single-cell transcriptomic atlas of Arabidopsis seedlings. This atlas is the result of meticulous integration of 63 previously published scRNA-seq datasets, addressing batch effects and conserving biological variance. This integration spans a broad spectrum of tissues, including both below- and above-ground parts. Utilizing a rigorous approach for cell type annotation, we identified 47 distinct cell types or states, largely expanding our current view of plant cell compositions. We systematically constructed cell-type specific gene regulatory networks and uncovered key regulators that act in a coordinated manner to control cell-type specific gene expression. Taken together, our study not only offers extensive plant cell atlas exploration that serves as a valuable resource, but also provides molecular insights into gene-regulatory programs that varies from different cell types.

Single cell transcriptomic analyses implicate an immunosuppressive tumor microenvironment in pancreatic cancer liver metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease refractory to all targeted and immune therapies. However, our understanding of PDAC microenvironment especially the metastatic microenvironment is very limited partly due to the inaccessibility to metastatic tumor tissues. Here, we present the single-cell transcriptomic landscape of synchronously resected PDAC primary tumors and matched liver metastases. We perform comparative analysis on both cellular composition and functional phenotype between primary and metastatic tumors. Tumor cells exhibit distinct transcriptomic profile in liver metastasis with clearly defined evolutionary routes from cancer cells in primary tumor. We also identify specific subtypes of stromal and immune cells critical to the formation of the pro-tumor microenvironment in metastatic lesions, including RGS5+ cancer-associated fibroblasts, CCL18+ lipid-associated macrophages, S100A8+ neutrophils and FOXP3+ regulatory T cells. Cellular interactome analysis further reveals that the lack of tumor-immune cell interaction in metastatic tissues contributes to the formation of the immunosuppressive microenvironment. Our study provides a comprehensive characterization of the transcriptional landscape of PDAC liver metastasis.

Cellular Membrane-Engineered Nanovesicles as a Three-Stage Booster to Target the Lesion Core.

The lesion core is the area with the most serious injury and vigorous repair. Existing nanocarriers are difficult to break through the targeted delivery to the lesion core for precise treatment in the intracellular and extracellular microenvironment. Herein, a cellular membrane-engineered nanovesicle (CMEV) with a hierarchical structure is constructed using the double emulsion-extrusion method by integrating a neutrophil membrane, functional antibody, and gelled drug-loaded core as a three-stage booster to target the lesion core and deliver catestatin (CST), a small therapeutic peptide, for ischemic cardiomyopathy therapy. By coating the neutrophil membrane outside the shell, CMEV is endowed with the function of neutrophil-like migration to achieve the first stage of tissue targeting. Based on the specific anchoring to injured myocardium, a myosin light chain 3 (MLC3) antibody is embedded to fulfill the second stage of CMEV accumulation in the lesion core. The gelled core containing CST-sodium alginate (NaAlg) with a pH-responsive shell is prepared by ionic cross-linking to accomplish the third stage of precise CST administration. Triggered by the microenvironment, NaAlg electrostatically adheres to the lesion core for sustained release, enhancing the efficacy of CST in improving cardiomyocyte apoptosis, excessive fibrosis, macrophage polarization, and angiogenesis. Thus, the "three-stage booster" nanovesicle significantly ameliorates cardiac function and adverse remodeling to treat ischemic cardiomyopathy.

Association between insulin resistance and cardiac remodeling in HER2-positive breast cancer patients: a real-world study.

BACKGROUND: Insulin resistance is an overlapping risk factor for both heart and breast cancer, while its interaction with cardiotoxicity in breast cancer (BC) patients is not clear. This study investigated the impact of insulin resistance on cardiac remodeling in patients with human epidermal growth factor receptor 2 (HER2)-positive BC during and after trastuzumab therapy in real-world clinical practice. METHODS: HER2-positive BC patients who received trastuzumab treatment between December 2012 and December 2017 were reviewed and 441 patients with baseline metabolic indices and serial echocardiographic measurements (baseline, 6, 12, and 18 months) after trastuzumab therapy initiation were included. Repeated measurement analysis of variance was used to evaluate temporal trends in multiparameter echocardiography. Linear mixed model was applied to further evaluate the role of insulin resistance in forementioned changes. Correlation of homeostasis model assessment-estimated insulin resistance (HOMA-IR) and triglyceride-glucose index (TyG) levels to changes in echocardiography parameters was explored. RESULTS: Of 441 patients (mean age 54 ± 10 [SD] years), 61.8% received anthracycline-based chemotherapy, 33.5% received left-sided radiotherapy, 46% received endocrine therapy. No symptomatic cardiac dysfunction was observed over the therapy course. A total of 19 (4.3%) participants experienced asymptomatic cancer therapy-related cardiac dysfunction (CTRCD), and the peak onset time was 12 months after the initiation of trastuzumab. Albeit relatively low CTRCD incidence, cardiac geometry remodeling, especially left atrial (LA) dilation over therapy was notable and was more severe in high HOMA-IR and TyG level groups (P < 0.01). Noteworthy, a partial reversibility of cardiac remodeling was observed with treatment cessation. Additionally, HOMA-IR level positively correlated to changes in LA diameter from baseline to 12 months (r = 0.178, P = 0.003). No significant association (all P > 0.10) was detected between HOMA-IR or TyG level and dynamic left ventricular parameter evaluation. Multivariate linear regression analysis demonstrated that higher HOMA-IR level was an independent determinant for LA enlargement in BC patients during anti-HER2 targeted therapy course after adjusting for confounding risk factors (P = 0.006). CONCLUSION: Insulin resistance was associated with left atrial adverse remodeling (LAAR) in HER2-positive BC patients that received standard trastuzumab therapy, indicating that insulin resistance could be a supplementation to baseline cardiovascular risk stratification proforma for HER2-targeted antitumor therapies.

Microbial metabolites in chronic heart failure and its common comorbidities.

This study aimed to identify microbial signatures that contribute to the shared etiologies between chronic heart failure (CHF), type 2 diabetes, and chronic kidney disease. The serum levels of 151 microbial metabolites were measured in 260 individuals from the Risk Evaluation and Management of heart failure cohort, and it was found that those metabolites varied by an order of 105 fold. Out of 96 metabolites associated with the three cardiometabolic diseases, most were validated in two geographically independent cohorts. In all three cohorts, 16 metabolites including imidazole propionate (ImP) consistently showed significant differences. Notably, baseline ImP levels were three times higher in the Chinese compared with the Swedish cohorts and increased by 1.1-1.6 fold with each additional CHF comorbidity in the Chinese population. Cellular experiments further supported a causal link between ImP and distinct CHF relevant phenotypes. Additionally, key microbial metabolite-based risk scores were superior in CHF prognosis than the traditional Framingham or Get with the Guidelines-Heart Failure risk scores. Interactive visualization of these specific metabolite-disease links is available on our omics data server (https://omicsdata.org/Apps/REM-HF/).

Catestatin Protects Against Diastolic Dysfunction by Attenuating Mitochondrial Reactive Oxygen Species Generation.

Background Catestatin has been reported as a pleiotropic cardioprotective peptide. Heart failure with preserved ejection fraction (HFpEF) was considered a heterogeneous syndrome with a complex cause. We sought to investigate the role of catestatin in HFpEF and diastolic dysfunction. METHODS AND RESULTS Administration of recombinant catestatin (1.5 mg/kg/d) improved diastolic dysfunction and left ventricular chamber stiffness in transverse aortic constriction mice with deoxycorticosterone acetate pellet implantation, as reflected by Doppler tissue imaging and pressure-volume loop catheter. Less cardiac hypertrophy and myocardial fibrosis was observed, and transcriptomic analysis revealed downregulation of mitochondrial electron transport chain components after catestatin treatment. Catestatin reversed mitochondrial structural and respiratory chain component abnormality, decreased mitochondrial proton leak, and reactive oxygen species generation in myocardium. Excessive oxidative stress induced by Ru360 abolished catestatin treatment effects on HFpEF-like cardiomyocytes in vitro, indicating the beneficial role of catestatin in HFpEF as a mitochondrial ETC modulator. The serum concentration of catestatin was tested among 81 patients with HFpEF and 76 non-heart failure controls. Compared with control subjects, serum catestatin concentration was higher in patients with HFpEF and positively correlated with E velocity to mitral annular e' velocity ratio, indicating a feedback compensation role of catestatin in HFpEF. Conclusions Catestatin protects against diastolic dysfunction in HFpEF through attenuating mitochondrial electron transport chain-derived reactive oxygen species generation. Serum catestatin concentration is elevated in patients with HFpEF, probably as a relatively insufficient but self-compensatory mechanism.

Pirfenidone-loaded exosomes derived from pancreatic ductal adenocarcinoma cells alleviate fibrosis of premetastatic niches to inhibit liver metastasis.

Given the metastasis-promoting effect of pancreatic ductal adenocarcinoma (PDAC)-derived exosomes through activation of fibrotic premetastatic niches, targeting and intervening in premetastatic organs to inhibit distant metastasis have challenged researchers and clinicians. Herein, a self-biomimetic drug delivery system based on exosomes derived from PDAC (PF@PCCEs) was constructed to precisely deliver an antifibrotic drug (pirfenidone, PF) to fibrotic premetastatic organs. First, PDAC-derived exosomes were confirmed to remarkably promote liver fibrosis. Then the prepared PF@PCCEs were actively internalized by HSCs (hepatic stellate cells) and subsequently alleviated the activation of HSCs. Delivery of PF to the premetastatic liver affected the niche suitable for the colonization of circulating tumour cells, further suppressing liver metastasis of PDAC. Thus, the strategy for intervening in the formation of fibrotic premetastatic niches to inhibit liver metastasis of PDAC using PF@PCCEs might offer inspiration for the treatment of tumour metastasis.

Characterization of the complete chloroplast genome sequence of Chinese endemic species of Aster batangensis (Asteraceae: Astereae) and its phylogenetic implications.

This study was the first report complete chloroplast genome of Aster batangensis (Astereae: Asteraceae), the perennial herb endemic to China. The plastid genome of Aster batangensis include 132 unique genes, with 87 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. Among these genes, 21 duplicate genes, including10 protein-coding genes, 7 tRNA genes, and 4 rRNA genes were detected. The complete genome size of Aster batangensis has a typical quadripartite circular structure with 152,605 bp in total length, consisting a large single copy (LSC) of 84,351 bp and a small single copy (SSC) of 18,212 bp, separated by a pair of invested repeats (IR) of 25,021 bp. The average GC content of whole plastome sequence is 37.3%, and the LSC, SSC and IR regions is 35.3%, 31.3%, and 43.0%, respectively. The phylogenetic analysis by the maximum likelihood method showed that A. batangensis was closely related to the other members of Astereae (e.g. Aztecaster matudae, Conyza bonariensis, Lagenophora cuchumatanica, Baccharis tricuneata, Baccharis genistelloides).