Summary
The continuing nitrogen (N) deposition observed worldwide alters ecosystem nutrient cycling and ecosystem functioning. Litter decomposition is a key process contributing to these changes, but ...the numerous mechanisms for altered decomposition remain poorly identified.
We assessed these different mechanisms with a decomposition experiment using litter from four abundant species (Achnatherum sibiricum, Agropyron cristatum, Leymus chinensis and Stipa grandis) and litter mixtures representing treatment‐specific community composition in a semi‐arid grassland under long‐term simulation of six different rates of N deposition.
Decomposition increased consistently with increasing rates of N addition in all litter types. Higher soil manganese (Mn) availability, which apparently was a consequence of N addition‐induced lower soil pH, was the most important factor for faster decomposition. Soil C : N ratios were lower with N addition that subsequently led to markedly higher bacterial to fungal ratios, which also stimulated litter decomposition.
Several factors contributed jointly to higher rates of litter decomposition in response to N deposition. Shifts in plant species composition and litter quality played a minor role compared to N‐driven reductions in soil pH and C : N, which increased soil Mn availability and altered microbial community structure. The soil‐driven effect on decomposition reported here may have long‐lasting impacts on nutrient cycling, soil organic matter dynamics and ecosystem functioning.
Boron‐doped fused heterocycles have shown great potential in the field of functional materials. This study reports on the synthesis of a new class of bis‐diazidoboranes and the discovery of their ...cycloaddition reaction with isonitriles. Triply fused boron‐doped heterocyclic compounds were constructed in a one‐pot process through a domino cycloaddition, providing an effective route for constructing complex boron‐doped heterocyclic systems.
The room temperature domino cyclization reaction of bis‐diazidoboranes with isonitriles was reported for the first time. This one‐step reaction leads to complex boron‐doped fused heterocycles and provides a new strategy for the construction of boron‐doped heterocyclic systems.
Gastric cancer (GC) is a common malignancy and frequent cause of cancer-related death. Long non-coding RNAs (lncRNAs) have emerged as important regulators and tissue-specific biomarkers of multiple ...cancers, including GC. Recent evidence has indicated that the novel lncRNA LINC01133 plays an important role in cancer progression and metastasis. However, its function and molecular mechanism in GC remain largely unknown.
LINC01133 expression was detected in 200 GC and matched non-cancerous tissues by quantitative reverse transcription PCR. Gain- and loss-of-function experiments were conducted to investigate the biological functions of LINC01133 both in vitro and in vivo. Insights into the underlying mechanisms of competitive endogenous RNAs (ceRNAs) were determined by bioinformatics analysis, dual-luciferase reporter assays, quantitative PCR arrays, TOPFlash/FOPFlash reporter assay, luciferase assay, and rescue experiments.
LINC01133 was downregulated in GC tissues and cell lines, and its low expression positively correlated with GC progression and metastasis. Functionally, LINC01133 depletion promoted cell proliferation, migration, and the epithelial-mesenchymal transition (EMT) in GC cells, whereas LINC01133 overexpression resulted in the opposite effects both in vitro and in vivo. Bioinformatics analysis and luciferase assays revealed that miR-106a-3p was a direct target of LINC01133, which functioned as a ceRNA in regulating GC metastasis. Mechanistic analysis demonstrated that miR-106a-3p specifically targeted the adenomatous polyposis coli (APC) gene, and LINC01133/miR-106a-3p suppressed the EMT and metastasis by inactivating the Wnt/β-catenin pathway in an APC-dependent manner.
Our findings suggest that reduced expression of LINC01133 is associated with aggressive tumor phenotypes and poor patient outcomes in GC. LINC01133 inhibits GC progression and metastasis by acting as a ceRNA for miR-106a-3p to regulate APC expression and the Wnt/β-catenin pathway, suggesting that LINC01133 may serve as a potential prognostic biomarker and anti-metastatic therapeutic target for GC.
The histone demethylase lysine‐specific demethylase 4A (KDM4A) is reported to be overexpressed and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of ...H3K9 or H3K36 methylation marks. However, the biological role and mechanism of KDM4A in prostate cancer (PC) remain unclear. Herein, we reported KDM4A expression was upregulation in phosphatase and tensin homolog knockout mouse prostate tissue. Depletion of KDM4A in PC cells inhibited their proliferation and survival in vivo and vitro. Further studies reveal that USP1 is a deubiquitinase that regulates KDM4A K48‐linked deubiquitin and stability. Interestingly, we found c‐Myc was a key downstream effector of the USP1‐KDM4A/androgen receptor axis in driving PC cell proliferation. Notably, upregulation of KDM4A expression with high USP1 expression was observed in most prostate tumors and inhibition of USP1 promotes PC cells response to therapeutic agent enzalutamide. Our studies propose USP1 could be an anticancer therapeutic target in PC.
This study identifies USP1 as a critical deubiquitinase for stabilizing KDM4A, thereby promoting prostate cancer growth and tumorigenesis. Targeting KDM4A stabilization through pharmacological inhibition of USP1 by ML323 could thus open an avenue for therapeutic intervention in prostate cancer patients.
Candida albicans can switch from commensal to pathogenic mode, causing mucosal or disseminated candidiasis. The host relies on pattern-recognition receptors including Toll-like receptors (TLRs) and ...C-type lectin receptors (CLRs) to sense invading fungal pathogens and launch immune defense mechanisms. However, the complex interplay between fungus and host innate immunity remains incompletely understood. Here we report that C. albicans upregulates expression of a small secreted cysteine-rich protein Sel1 upon encountering limited nitrogen and abundant serum. Sel1 activates NF-κB and MAPK signaling pathways, leading to expression of proinflammatory cytokines and chemokines. Comprehensive genetic and biochemical analyses reveal both TLR2 and TLR4 are required for the recognition of Sel1. Further, SEL1-deficient C. albicans display an impaired immune response in vivo, causing increased morbidity and mortality in a bloodstream infection model. We identify a critical component in the Candida-host interaction that opens a new avenue to tackle Candida infection and inflammation.
As crucial antigen presenting cells, dendritic cells (DCs) play a vital role in tumor immunotherapy. Taking into account the many recent advances in DC biology, we discuss how DCs (1) recognize ...pathogenic antigens with pattern recognition receptors through specific phagocytosis and through non-specific micropinocytosis, (2) process antigens into small peptides with proper sizes and sequences, and (3) present MHC-peptides to CD4
and CD8
T cells to initiate immune responses against invading microbes and aberrant host cells. During anti-tumor immune responses, DC-derived exosomes were discovered to participate in antigen presentation. T cell microvillar dynamics and TCR conformational changes were demonstrated upon DC antigen presentation. Caspase-11-driven hyperactive DCs were recently reported to convert effectors into memory T cells. DCs were also reported to crosstalk with NK cells. Additionally, DCs are the most important sentinel cells for immune surveillance in the tumor microenvironment. Alongside DC biology, we review the latest developments for DC-based tumor immunotherapy in preclinical studies and clinical trials. Personalized DC vaccine-induced T cell immunity, which targets tumor-specific antigens, has been demonstrated to be a promising form of tumor immunotherapy in patients with melanoma. Importantly, allogeneic-IgG-loaded and HLA-restricted neoantigen DC vaccines were discovered to have robust anti-tumor effects in mice. Our comprehensive review of DC biology and its role in tumor immunotherapy aids in the understanding of DCs as the mentors of T cells and as novel tumor immunotherapy cells with immense potential.
Bioactive macromolecular peptides and oligonucleotides have significant therapeutic potential. However, due to their size, they have no ability to enter the cytoplasm of cells. Peptide/Protein ...transduction domains (PTDs), also called cell-penetrating peptides (CPPs), can promote uptake of macromolecules via endocytosis. However, overcoming the rate-limiting step of endosomal escape into the cytoplasm remains a major challenge. Hydrophobic amino acid R groups are known to play a vital role in viral escape from endosomes. Here we utilize a real-time, quantitative live cell split-GFP fluorescence complementation phenotypic assay to systematically analyze and optimize a series of synthetic endosomal escape domains (EEDs). By conjugating EEDs to a TAT-PTD/CPP spilt-GFP peptide complementation assay, we were able to quantitatively measure endosomal escape into the cytoplasm of live cells via restoration of GFP fluorescence by intracellular molecular complementation. We found that EEDs containing two aromatic indole rings or one indole ring and two aromatic phenyl groups at a fixed distance of six polyethylene glycol (PEG) units from the TAT-PTD-cargo significantly enhanced cytoplasmic delivery in the absence of cytotoxicity. EEDs address the critical rate-limiting step of endosomal escape in delivery of macromolecular biologic peptide, protein and siRNA therapeutics into cells.
Background and Purpose
It is well known that microsatellite instability‐high (MSI‐H) is associated with 5‐fluorouracil (5‐FU) resistance in colorectal cancer. MSI‐H is the phenotype of DNA mismatch ...repair deficiency (MMR‐D), mainly occurring due to hypermethylation of MLH1 promoter CpG island. However, the mechanisms of MMR‐D/MSI‐H are unclear. We aim to investigate the pathway of MMR‐D/MSI‐H involved in 5‐FU resistance.
Experimental Approach
Human colorectal cancer specimens were diagnosed for MSI‐H by immunohistochemistry and western blotting. Proteome microarray interactome assay was performed to screen nuclear proteins interacting with ATG5. Nuclear ATG5 and ATG5‐Mis18α overexpression were analysed in ATG5high colorectal cancer bearing mice. The methylation assay determined the hypermethylation of hMLH1 promoter CpG island in freshly isolated human colorectal cancer tissue samples and HT29atg5 and SW480atg5 cancer cells.
Key Results
In ATG5high colorectal cancer patients, 5‐FU‐based therapy resulted in nuclear translocation of ATG5, leading to MSI‐H. Colorectal cancer in Atg5 Tg mice demonstrated 5‐FU resistance, compared to Atg5+/− and WT mice. Proteome microarray assay identified Mis18α, a protein localized on the centromere and a source for methylation of the underlying chromatin, which responded to the translocated nuclear ATG5 leading to ATG5‐Mis18α conjugate overexpression. This resulted in MLH1 deficiency due to hypermethylation of hMLH1 promoter CpG island, while the deletion of nuclear Mis18α failed to induce ATG5‐Mis18α complex and MMR‐D/MSI‐H.
Conclusions and Implications
Nuclear ATG5 resulted in MMR‐D/MSI‐H through its interaction with Mis18α in ATG5high colorectal cancer cells. We suggest that ATG5‐Mis18α or Mis18α may be a therapeutic target for treating colorectal cancer.
2,5‐Furandicarboxylic acid (FDCA) is considered to be a promising replacement for terephthalic acid since they share similar structures and properties. In contrast to FDCA, 2,5‐furandicarboxylic acid ...methyl (FDCAM) has properties that allow it to be easily purified. In this work, we reported an oxidative esterification of 5‐hydroxymethylfurfural (HMF) and furfural to prepare corresponding esters over CoxOy–N@C catalysts using O2 as benign oxidant. High yield and selectivity of FDCAM and methyl 2‐furoate were obtained under optimized conditions. Factors which influenced the product distribution were examined thoroughly. The CoxOy–N@C catalysts were recycled five times and no significant loss of activity was detected. Characterization of the catalysts could explain such phenomena. Using XPS and TGA, we made a thorough investigation of the effects of ligand and pyrolysis temperature on catalyst activity.
Happy Ester: The oxidative esterification of 5‐hydroxymethylfurfural (HMF) and furfural over CoxOy–N@C catalysts is performed using O2 as benign oxidant, obtaining the corresponding esters. High yield and selectivity of 2,5‐furandicarboxylic acid methyl and methyl 2‐furoate are achieved under optimized conditions.
Constructing ambient‐stable, single‐atom‐layered metal‐based materials with atomic precision and understanding their underlying stability mechanisms are challenging. Here, stable single‐atom‐layered ...nanoclusters of Pd were synthesized and precisely characterized through electrospray ionization mass spectrometry and single‐crystal X‐ray crystallography. A pseudo‐pentalene‐like Pd8 unit was found in the nanocluster, interacting with two syn PPh units through nonmetal‐to‐metal ‐ring coordination. The unexpected coordination, which is distinctly different from the typical organoring‐to‐metal coordination in half‐sandwich‐type organometallic compounds, contributes to the ambient stability of the as‐obtained single‐atom‐layered nanocluster as revealed through theoretical and experimental analyses. Furthermore, quantum chemical calculations revealed dominant electron transition along the horizontal x‐direction of the Pd8 plane, indicating high photothermal conversion efficiency (PCE) of the nanocluster, which was verified by the experimental PCE of 73.3 %. Therefore, this study unveils the birth of a novel type of compound and the finding of the unusual nonmetal‐to‐metal ‐ring coordination and has important implications for future syntheses, structures, properties, and structure–property correlations of single‐atom‐layered metal‐based materials.
Ambient‐stable, single‐atom‐layered Pd nanoclusters are synthesized and precisely characterized. Nonmetal‐to‐metal‐ ring coordination is reported, which contributes to the exceptional stability of the as‐obtained nanocluster, as revealed through theoretical and experimental analyses. Furthermore, the horizontal electron transition induces superb photothermal conversion efficiency of 73.3 %.
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