N-staging is a determining factor for prognostic assessment and decision-making for stage-based cancer therapeutic strategies. Visual inspection of whole-slides of intact lymph nodes is currently the ...main method used by pathologists to calculate the number of metastatic lymph nodes (MLNs). Moreover, even at the same N stage, the outcome of patients varies dramatically. Here, we propose a deep-learning framework for analyzing lymph node whole-slide images (WSIs) to identify lymph nodes and tumor regions, and then to uncover tumor-area-to-MLN-area ratio (T/MLN). After training, our model's tumor detection performance was comparable to that of experienced pathologists and achieved similar performance on two independent gastric cancer validation cohorts. Further, we demonstrate that T/MLN is an interpretable independent prognostic factor. These findings indicate that deep-learning models could assist not only pathologists in detecting lymph nodes with metastases but also oncologists in exploring new prognostic factors, especially those that are difficult to calculate manually.
Novel metabolites distinct from canonical pathways can be identified through the integration of three cheminformatics tools: BinVestigate, which queries the BinBase gas chromatography-mass ...spectrometry (GC-MS) metabolome database to match unknowns with biological metadata across over 110,000 samples; MS-DIAL 2.0, a software tool for chromatographic deconvolution of high-resolution GC-MS or liquid chromatography-mass spectrometry (LC-MS); and MS-FINDER 2.0, a structure-elucidation program that uses a combination of 14 metabolome databases in addition to an enzyme promiscuity library. We showcase our workflow by annotating N-methyl-uridine monophosphate (UMP), lysomonogalactosyl-monopalmitin, N-methylalanine, and two propofol derivatives.
Understanding the molecular mechanisms underlying human cartilage degeneration and regeneration is helpful for improving therapeutic strategies for treating osteoarthritis (OA). Here, we report the ...molecular programmes and lineage progression patterns controlling human OA pathogenesis using single-cell RNA sequencing (scRNA-seq).
We performed unbiased transcriptome-wide scRNA-seq analysis, computational analysis and histological assays on 1464 chondrocytes from 10 patients with OA undergoing knee arthroplasty surgery. We investigated the relationship between transcriptional programmes of the OA landscape and clinical outcome using severity index and correspondence analysis.
We identified seven molecularly defined populations of chondrocytes in the human OA cartilage, including three novel phenotypes with distinct functions. We presented gene expression profiles at different OA stages at single-cell resolution. We found a potential transition among proliferative chondrocytes, prehypertrophic chondrocytes and hypertrophic chondrocytes (HTCs) and defined a new subdivision within HTCs. We revealed novel markers for cartilage progenitor cells (CPCs) and demonstrated a relationship between CPCs and fibrocartilage chondrocytes using computational analysis. Notably, we derived predictive targets with respect to clinical outcomes and clarified the role of different cell types for the early diagnosis and treatment of OA.
Our results provide new insights into chondrocyte taxonomy and present potential clues for effective and functional manipulation of human OA cartilage regeneration that could lead to improved health.
The heart is the central organ of the circulatory system, and its proper development is vital for maintaining human life. Here, we used single-cell RNA sequencing to profile the gene expression ...landscapes of ∼4,000 cardiac cells from human embryos and identified four major types of cells: cardiomyocytes (CMs), cardiac fibroblasts, endothelial cells (ECs), and valvar interstitial cells (VICs). Atrial and ventricular CMs acquired distinct features early in heart development. Furthermore, both CMs and fibroblasts show stepwise changes in gene expression. As development proceeds, VICs may be involved in the remodeling phase, and ECs display location-specific characteristics. Finally, we compared gene expression profiles between humans and mice and identified a series of unique features of human heart development. Our study lays the groundwork for elucidating the mechanisms of in vivo human cardiac development and provides potential clues to understand cardiac regeneration.
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•Systematic mapping of the transcriptomic landscape of the human fetal heart•Critical biological features of cardiomyocytes and cardiac fibroblasts are revealed•Synergistic activation of NOTCH and BMP signaling pathways during heart development•Human-specific marker genes are revealed by comparing with mouse heart data
Cui et al. reveal the transcriptional landscapes of human fetal heart development at single-cell resolution and identify critical biological features of different cell types, providing insights into the molecular mechanisms of human heart development.
Molecular mechanisms of ovarian aging and female age-related fertility decline remain unclear. We surveyed the single-cell transcriptomic landscape of ovaries from young and aged non-human primates ...(NHPs) and identified seven ovarian cell types with distinct gene-expression signatures, including oocyte and six types of ovarian somatic cells. In-depth dissection of gene-expression dynamics of oocytes revealed four subtypes at sequential and stepwise developmental stages. Further analysis of cell-type-specific aging-associated transcriptional changes uncovered the disturbance of antioxidant signaling specific to early-stage oocytes and granulosa cells, indicative of oxidative damage as a crucial factor in ovarian functional decline with age. Additionally, inactivated antioxidative pathways, increased reactive oxygen species, and apoptosis were observed in granulosa cells from aged women. This study provides a comprehensive understanding of the cell-type-specific mechanisms underlying primate ovarian aging at single-cell resolution, revealing new diagnostic biomarkers and potential therapeutic targets for age-related human ovarian disorders.
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•Single-cell transcriptomic roadmap of NHP ovarian aging•Molecular signatures revealed for NHP oocytes at stepwise developmental stages•Cell-type-specific inactivation of antioxidant genes in aged monkey and human ovaries
Single-cell transcriptomic analysis in ovaries of young and old cynomolgus monkeys identifies aging-associated and cell-type-specific dysregulation of antioxidative pathways.
Osteoarthritis (OA) has been recognized as the most common chronic age-related disease. Cartilage degeneration influences OA therapy. Here we report that hematopoietic pre-B cell leukemia ...transcription factor-interacting protein (HPIP) is essential for OA development. Elevated HPIP levels are found in OA patients. Col2a1-CreER
/HPIP
mice exhibit obvious skeletal abnormalities compared with their HPIP
littermates. HPIP deficiency in mice protects against developing OA. Moreover, intra-articular injection of adeno-associated virus carrying HPIP-specific short hairpin RNA in vivo attenuates OA histological signs. Notably, in vitro RNA-sequencing and chromatin immunoprecipitation sequencing profiles identify that HPIP modulates OA cartilage degeneration through transcriptional activation of Wnt target genes. Mechanistically, HPIP promotes the transcription of Wnt targets by interacting with lymphoid enhancer binding factor 1 (LEF1). Furthermore, HPIP potentiates the transcriptional activity of LEF1 and acetylates histone H3 lysine 56 in the promoters of Wnt targets, suggesting that HPIP is an attractive target in OA regulatory network.
In present study, novel nitrogen doped carbon dots (NCDs) are synthesized using a green material—dopamine—as a precursor and studied as corrosion inhibitors for Q235 carbon steel in 1 M HCl solution. ...According to the electrochemical results, it is found that NCDs acting as a mixed-type corrosion inhibitor can effectively retard the acid corrosion of carbon steel, and their inhibition efficiency increases with the concentration increasing from 50 to 400 ppm. The highest inhibition efficiency is 96.1% in the presence of 400 ppm NCDs at room temperature. Additionally, the adsorption of NCDs obeys the Langmuir adsorption isotherm. In addition, weight loss results show that the inhibition efficiency in the presence of 400 ppm NCDs increases with prolonged exposure time and rising temperature (298–328 K), owing to the strong adsorption of NCDs on the steel surface, and the η value is 92.2% at 60 h of immersion and 86.2%, 89.1%, 90.6% and 92.9% at 298, 308, 318 and 328 K, respectively. Surface analysis by scanning electron microscope (SEM), laser scanning confocal microscope (LSCM) and X-ray photoelectron spectroscopy (XPS) further proves the formation of a protective NCD film on the steel surface.
Adenosine deaminases acting on RNA (ADARs) are editing enzymes that convert adenosine to inosine in duplex RNA, a modification reaction with wide-ranging consequences in RNA function. Understanding ...of the ADAR reaction mechanism, the origin of editing-site selectivity, and the effect of mutations is limited by the lack of high-resolution structural data for complexes of ADARs bound to substrate RNAs. Here we describe four crystal structures of the human ADAR2 deaminase domain bound to RNA duplexes bearing a mimic of the deamination reaction intermediate. These structures, together with structure-guided mutagenesis and RNA-modification experiments, explain the basis of the ADAR deaminase domain's dsRNA specificity, its base-flipping mechanism, and its nearest-neighbor preferences. In addition, we identified an ADAR2-specific RNA-binding loop near the enzyme active site, thus rationalizing differences in selectivity observed between different ADARs. Finally, our results provide a structural framework for understanding the effects of ADAR mutations associated with human disease.
Purpose
To evaluate the effect and mechanism of 1,25(OH)
2
D
3
on pancreatic stellate cells (PSCs) in type 2 diabetes mellitus (T2DM).
Methods
A mouse model of T2DM was successfully established by ...high-fat diet (HFD) /streptozotocin (STZ) and administered 1,25(OH)
2
D
3
for 3 weeks. Fasting blood glucose (FBG), glycated hemoglobin A1c (GHbA1c), insulin (INS) and glucose tolerance were measured. Histopathology changes and fibrosis of pancreas were examined by hematoxylin and eosin staining and Masson staining. Mouse PSCs were extracted, co-cultured with mouse insulinoma β cells (MIN6 cells) and treated with 1,25(OH)
2
D
3
. ELISA detection of inflammatory factor expression. Tissue reactive oxygen species (ROS) levels were also measured. Immunofluorescence or Western blotting were used to measure fibrosis and inflammation-related protein expression.
Results
PSCs activation and islets fibrosis in T2DM mice. Elevated blood glucose was accompanied by significant increases in serum inflammatory cytokines and tissue ROS levels. 1,25(OH)
2
D
3
attenuated islet fibrosis by reducing hyperglycemia, ROS levels, and inflammatory factors expression. Additionally, the co-culture system confirmed that 1,25(OH)
2
D
3
inhibited PSCs activation, reduced the secretion of pro-inflammatory cytokines, down-regulated the expression of fibrosis and inflammation-related proteins, and promoted insulin secretion.
Conclusion
Our findings identify that PSCs activation contributes to islet fibrosis and β-cell dysfunction. 1,25(OH)
2
D
3
exerts beneficial effects on T2DM potentially by inhibiting PSCs activation and inflammatory response, highlighting promising control strategies of T2DM by vitamin D.
Graphical Abstract
Fig. 7 Molecular mechanism of 1,25(OH)
2
D
3
in β cell damage following PSCs activation in T2DM mice.
Highlights
PSCs activation leads to islet fibrosis in T2DM mice.
TGF- β, IL-1 β, TNF-α, ROS induce PSCs activation, thereby inhibiting MIN6 cell proliferation and function.
1,25(OH)
2
D
3
inhibits PSCs activation by downregulating the expression of factors such as TGF-β, protecting β cell function.
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