Abstract
Squamous cell carcinomas (SCCs) comprise one of the most common histologic types of human cancer. Transcriptional dysregulation of SCC cells is orchestrated by
tumor protein p63 (TP63)
, a ...master transcription factor (TF) and a well-researched SCC-specific oncogene. In the present study, both Gene Set Enrichment Analysis (GSEA) of SCC patient samples and in vitro loss-of-function assays establish fatty-acid metabolism as a key pathway downstream of TP63. Further studies identify
sterol regulatory element binding transcription factor 1 (SREBF1)
as a central mediator linking TP63 with fatty-acid metabolism, which regulates the biosynthesis of fatty-acids, sphingolipids (SL), and glycerophospholipids (GPL), as revealed by liquid chromatography tandem mass spectrometry (LC-MS/MS)-based lipidomics. Moreover, a feedback co-regulatory loop consisting of SREBF1/TP63/
Kruppel like factor 5 (KLF5)
is identified, which promotes overexpression of all three TFs in SCCs. Downstream of SREBF1, a non-canonical, SCC-specific function is elucidated: SREBF1 cooperates with TP63/KLF5 to regulate hundreds of cis-regulatory elements across the SCC epigenome, which converge on activating cancer-promoting pathways. Indeed, SREBF1 is essential for SCC viability and migration, and its overexpression is associated with poor survival in SCC patients. Taken together, these data shed light on mechanisms of transcriptional dysregulation in cancer, identify specific epigenetic regulators of lipid metabolism, and uncover SREBF1 as a potential therapeutic target and prognostic marker in SCC.
Abstract
Porous organic polymers (POPs) have emerged as a novel class of porous materials that are synthesized by the polymerization of various organic monomers with different geometries and ...topologies. The molecular tunability of organic building blocks allows the incorporation of functional units for photocatalytic organic transformations. Here, we report the synthesis of two POP‐based photocatalysts via homopolymerization of vinyl‐functionalized diaryl dihydrophenazine (DADHP) monomer (
POP1
) and copolymerization of vinyl‐functionalized DADHP and 2,2′‐bipyridine monomers (
POP2
). The fluorescence lifetimes of DADHP units in the POPs significantly increased, resulting in enhanced photocatalytic performances over homogeneous controls.
POP1
is highly effective in catalysing visible‐light‐driven C−N bond forming cross‐coupling reactions. Upon coordination with Ni
2+
ions,
POP2‐Ni
shows strong synergy between photocatalytic and Ni catalytic cycles due to the confinement effect within the POP framework, leading to high efficiency in energy, electron, and organic radical transfer.
POP2‐Ni
displays excellent activity in catalysing C−P bond forming reactions between diarylphosphine oxides and aryl iodides. They increased the photocatalytic activities by more than 30‐fold in C−N and C−P cross‐coupling reactions. These POP catalysts were readily recovered via centrifugal separation and reused in six catalytic cycles without loss of activities. Thus, photosensitizer‐based POPs provide a promising platform for heterogeneous photocatalytic organic transformations.
Squamous cell carcinomas (SCCs) are aggressive malignancies. Previous report demonstrated that master transcription factors (TFs) TP63 and SOX2 exhibited overlapping genomic occupancy in SCCs. ...However, functional consequence of their frequent co-localization at super-enhancers remains incompletely understood. Here, epigenomic profilings of different types of SCCs reveal that TP63 and SOX2 cooperatively and lineage-specifically regulate long non-coding RNA (lncRNA) CCAT1 expression, through activation of its super-enhancers and promoter. Silencing of CCAT1 substantially reduces cellular growth both in vitro and in vivo, phenotyping the effect of inhibiting either TP63 or SOX2. ChIRP analysis shows that CCAT1 forms a complex with TP63 and SOX2, which regulates EGFR expression by binding to the super-enhancers of EGFR, thereby activating both MEK/ERK1/2 and PI3K/AKT signaling pathways. These results together identify a SCC-specific DNA/RNA/protein complex which activates TP63/SOX2-CCAT1-EGFR cascade and promotes SCC tumorigenesis, advancing our understanding of transcription dysregulation in cancer biology mediated by master TFs and super-enhancers.
The significance of the liver-microbiome axis has been increasingly recognised as a major modulator of autoimmunity. The aim of this study was to take advantage of a large well-defined ...corticosteroids treatment-naïve group of patients with autoimmune hepatitis (AIH) to rigorously characterise gut dysbiosis compared with healthy controls.
We performed a cross-sectional study of individuals with AIH (n=91) and matched healthy controls (n=98) by 16S rRNA gene sequencing. An independent cohort of 28 patients and 34 controls was analysed to validate the results. All the patients were collected before corticosteroids therapy.
The gut microbiome of steroid treatment-naïve AIH was characterised with lower alpha-diversity (Shannon and observed operational taxonomic units, both p<0.01) and distinct overall microbial composition compared with healthy controls (p=0.002). Depletion of obligate anaerobes and expansion of potential pathobionts including
were associated with disease status. Of note,
, the most strongly disease-associated taxa (p=8.85E-8), positively correlated with serum level of aspartate aminotransferase and liver inflammation. Furthermore, the combination of four patients with AIH-associated genera distinguished AIH from controls with an area under curves of approximately 0.8 in both exploration and validation cohorts. In addition, multiple predicted functional modules were altered in the AIH gut microbiome, including lipopolysaccharide biosynthesis as well as metabolism of amino acids that can be processed by bacteria to produce immunomodulatory metabolites.
Our study establishes compositional and functional alterations of gut microbiome in AIH and suggests the potential for using gut microbiota as non-invasive biomarkers to assess disease activity.
Different fertilization regimes can substantially influence soil fungal community composition, yet fewer studies try to control for the effects of nitrogen input. Here, we investigated the impact of ...fertilization with equal nitrogen upon soil properties and soil fungal diversity and community composition in the North China Plain in a long-term field experiment. Long-term (32 years) fertilization regimes were applied with equal amounts of nitrogen: no chemical fertilizer or organic manure; chemical fertilization only; organic manure fertilization only, and; combination of 1/2 chemical fertilizer and 1/2 organic manure. Then we investigated the influence of these four fertilization regimes to soil properties, fungal diversity and community composition. The results showed that applying organic manure significantly influenced soil properties. Illumina MiSeq sequencing and its analysis revealed that organic manure fertilization significantly changed soil fungal alpha diversity, but chemical fertilization did not. Although soil fungal community composition did not differ significantly among all the fertilization regimes at the phylum and class levels, they did show differences in the abundance of dominant fungi. Yet at the genus level, soil fungal community composition, abundance, and beta diversity was affected by all fertilization regimes. Application of organic manure also reduced the abundance of soil-born fungal pathogens such as Fusarium. Our results suggest that long-term application of organic manure could markedly improve soil properties, altering soil fungal community composition and its diversity. Moreover, organic manure fertilization could limit soil-born fungal diseases, to further contribute to soil ecosystem sustainability.
Rational exploration of efficient, inexpensive, and robust electrocatalysts is critical for the efficient water splitting. Conjugated conductive metal–organic frameworks (cMOFs) with multicomponent ...layered double hydroxides (LDHs) to construct bifunctional heterostructure catalysts are considered as an efficient but complicated strategy. Here, the fabrication of a cMOF/LDH hetero‐nanotree array catalyst (CoNiRu‐NT) coupled with monodispersed ruthenium (Ru) sites via a controllable grafted‐growth strategy is reported. Rich‐amino hexaiminotriphenylene linkers coordinate with the LDH nanotrunk to form cMOF nanobranches, providing numerous anchoring sites to precisely confine and stabilize RuN4 sites. Moreover, monodispersed and reduced Ru moieties facilitate H2O adsorption and dissociation, and the heterointerface between the cMOF and the LDH further modifies the chemical and electronic structures. Optimized CoNiRu‐NT displays a significant increase in electrochemical water‐splitting properties in alkaline media, affording low overpotentials of 22 mV at 10 mA cm−2 and 255 mV at 20 mA cm−2 for the hydrogen evolution reaction and oxygen evolution reaction, respectively. In an actual electrochemical system, CoNiRu‐NT drives an overall water splitting at a low cell voltage of 1.47 V to reach 10 mA cm−2. This performance is comparable to that of pure noble‐metal‐based materials and superior to most reported MOF‐based catalysts.
A conductive metal–organic framework (cMOF)/layered double hydroxide (LDH) hetero‐nanotree structure coupled with monodisperse Ru sites is constructed via a controllable grafted‐growth strategy. Based on a competitive coordination process, RuN sites are precisely anchored by rich‐amino organic linkers. The chemical and electronic structure of the hetero‐nanotree catalysts are well modified and lead to a superior overall water‐splitting performance in alkaline media.
Irritable bowel syndrome (IBS) is a common disorder in gastrointestinal system and impairs the quality of life of the patients. Clostridium butyricum (CB) is a probiotics that has been used in ...several gastrointestinal diseases. The efficacy of CB in treating IBS is still unknown. This prospective, multi-centre, randomized, double-blind, placebo-controlled trial aimed to assess the efficacy and safety of CB in treating diarrhea-predominant IBS (IBS-D) and analyze the fecal microbiota after treatment. Two hundred patients with IBS-D were recruited and were given CB or placebo for 4 weeks. End points included change from baseline in IBS symptoms, quality of life, stool consistency and frequency. Compared with placebo, CB is effective in improving the overall IBS-D symptoms (-62.12 ± 74.00 vs. -40.74 ± 63.67, P = 0.038) as well as quality of life (7.232 ± 14.06 vs. 3.159 ± 11.73, P = 0.032) and stool frequency (-1.602 ± 1.416 vs. -1.086 ± 1.644, P = 0.035). The responder rates are found higher in CB compared with the placebo (44.76% vs. 30.53%, P = 0.042). The change in fecal microbiota was analyzed and function pathways of CB in treating IBS-D were predicted. In conclusion, CB improves overall symptoms, quality of life and stool frequency in IBS-D patients and is considered to be used as a probiotics in treating IBS-D clinically.
Pyrometallurgy technique is usually applied as a pretreatment to enhance the leaching efficiencies in the hydrometallurgy process for recovering valuable metals from spent lithium‐ion batteries. ...However, traditional pyrometallurgy processes are energy and time consuming. Here, we report a carbothermal shock (CTS) method for reducing LiNi0.3Co0.2Mn0.5O2 (NCM325) cathode materials with uniform temperature distribution, high heating and cooling rates, high temperatures, and ultrafast reaction times. Li can be selectively leached through water leaching after CTS process with an efficiency of >90 %. Ni, Co, and Mn are recovered by dilute acid leaching with efficiencies >98 %. The CTS reduction strategy is feasible for various spent cathode materials, including NCM111, NCM523, NCM622, NCM811, LiCoO2, and LiMn2O4. The CTS process, with its low energy consumption and potential scale application, provides an efficient and environmentally friendly way for recovering spent lithium‐ion batteries.
Carbothermal shock (CTS) method with high heating and cooling rates, high temperatures (up to ≈2200 °C), and ultrafast reaction times of ≈20 s is utilized for recycling spent cathode materials. Li can be selectively leached through water leaching with an efficiency of >90 %. Ni, Co, and Mn are recovered by dilute acid leaching with efficiencies >98 %.
Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with extremely skewed ethnic and geographic distributions. Increasing evidence indicates that targeting the tumor microenvironment (TME) ...represents a promising therapeutic approach in NPC, highlighting an urgent need to deepen the understanding of the complex NPC TME. Here, we generated single-cell transcriptome profiles for 7581 malignant cells and 40,285 immune cells from fifteen primary NPC tumors and one normal sample. We revealed malignant signatures capturing intratumoral transcriptional heterogeneity and predicting aggressiveness of malignant cells. Diverse immune cell subtypes were identified, including novel subtypes such as CLEC9A
dendritic cells (DCs). We further revealed transcriptional regulators underlying immune cell diversity, and cell-cell interaction analyses highlighted promising immunotherapeutic targets in NPC. Moreover, we established the immune subtype-specific signatures, and demonstrated that the signatures of macrophages, plasmacytoid dendritic cells (pDCs), CLEC9A
DCs, natural killer (NK) cells, and plasma cells were significantly associated with improved survival outcomes in NPC. Taken together, our findings represent a unique resource providing in-depth insights into the cellular heterogeneity of NPC TME and highlight potential biomarkers for anticancer treatment and risk stratification, laying a new foundation for precision therapies in NPC.
Currently, there is no strong evidence of the well-established biomarkers for immune checkpoint inhibitors (ICIs) in nasopharyngeal carcinoma (NPC). Here, we aimed to reveal the heterogeneity of ...tumour microenvironment (TME) through virtual microdissection of gene expression profiles. An immune-enriched subtype was identified in 38% (43/113) of patients, which was characterized by significant enrichment of immune cells or immune responses. The remaining patients were therefore classified as a non-Immune Subtype (non-IS), which exhibited highly proliferative features. Then we identified a tumour immune evasion state within the immune-enriched subtype (18/43, 42%), in which high expression of exclusion- and dysfunction-related signatures was observed. These subgroups were designated the Evaded and Active Immune Subtype (E-IS and A-IS), respectively. We further demonstrated that A-IS predicted favourable survival and improved ICI response as compared to E-IS and non-IS. In summary, this study introduces the novel immune subtypes and demonstrates their feasibility in tailoring immunotherapeutic strategies.
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