Very long-chain fatty acids (VLCFAs) are crucial for lipid homeostasis and physiological functions. The elongation of VLCFAs, which is mediated by four consecutive enzymes in the endoplasmic reticulum (ER), has been implicated in tumor progression. However, the molecular mechanisms underlying VLCFA elongation enzymes and their specific contributions to tumorigenesis remain largely elusive. Here, we demonstrate that trans-2-enoyl-CoA reductase (TECR) is upregulated in colorectal cancer (CRC). Structural and biochemical analyses revealed a conserved catalytic mechanism for TECR-mediated trans-2-enoyl-CoA reduction. Moreover, we show that TECR forms a stable complex with 3-hydroxyacyl-CoA dehydratase (HACD), to cooperatively drive VLCFA elongation. A unique U-shaped loop in HACD is critical for recognizing TECR. Disruption of the HACD–TECR interaction interface significantly suppresses CRC cell growth. Collectively, these findings elucidate the molecular mechanism of HACD–TECR-mediated VLCFA elongation and suggest a potential therapeutic strategy for CRC treatment by modulating VLCFA metabolism.

Remodeling of fatty acid metabolism is increasingly recognized as a critical feature of tumor progression, yet the contribution of very long-chain fatty acid (VLCFA) remains incompletely understood. The elongation of VLCFAs, which is mediated by four consecutive enzymes in the endoplasmic reticulum (ER), has been implicated in tumor progression. However, the molecular mechanisms underlying VLCFA elongation enzymes and their specific contributions to tumorigenesis remain largely elusive. Here, we demonstrate that trans-2-enoyl-CoA reductase (TECR) is upregulated in colorectal cancer (CRC). Structural and biochemical analyses revealed a conserved catalytic mechanism for TECR-mediated trans-2-enoyl-CoA reduction. Moreover, we show that TECR forms a stable complex with 3-hydroxyacyl-CoA dehydratase (HACD), to cooperatively drive VLCFA elongation. A unique U-shaped loop in HACD is critical for recognizing TECR. Disruption of the HACD-TECR interaction interface significantly suppresses CRC cell growth. Collectively, these findings elucidate the molecular mechanism of HACD-TECR-mediated VLCFA elongation and suggest a potential therapeutic strategy for CRC treatment by modulating VLCFA metabolism.

The Toll-like receptor (TLR) family are critical components of the innate immune system, acting as pattern recognition receptors that detect microbial components and initiate immune responses. In humans, 10 TLRs have been identified, each recognizing distinct pathogen-associated molecular patterns. Among these, TLR9 is unique in its ability to sense CpG motifs, playing a crucial role in the detection of bacterial and viral DNA. Despite its significance, targeting TLR9 for therapeutics has proven to be challenging. Herein we describe the discovery of a series of potent and selective TLR9 antagonists, represented by 5-(hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)quinoline (38), with an IC50 value of 0.1 nM against hTLR9 and >10,000-fold selectivity over hTLR2/4/5/7/8. Compound 38 demonstrated good pharmacokinetic and excellent pharmacodynamic features, indicating its potential utility as a pharmacological tool and a therapeutic candidate for TLR9 related disorders.

The transcription factor MSX1, typically expressed in early development but not in most adult tissues, is often re-activated in various cancers, although its underlying oncogenic mechanisms remain elusive. Here, we found that MSX1 promotes the degradation of FBXW7, an E3 ligase and tumor suppressor, through the CDK1-mediated phosphorylation of MSX1 at Ser136. The phosphorylation mimic MSX1 S136D mutant, but not the dephosphorylated S136A mutant, degrades FBXW7 and results in the accumulation of its substrates, including c-MYC and MCL1, ultimately leading to gastric cancer growth and resistance to apoptosis. As the pMSX1-FBXW7 oncogenic axis was validated in clinical gastric cancer samples, we then developed a therapeutic strategy combining chemotherapy with CDK1 inhibition, which synergistically inhibited the gastric cancer growth. Remarkably, the generated S136A knock-in mouse model showed significant protection against carcinogen-induced gastric tumorigenesis, while also exhibited defective limb and skull dysraphism. Collectively, these findings unraveled the importance of pMSX1-FBXW7 axis for both cancer and mammalian development.

Background:Current targeted therapies for gastric cancer have limited efficacy, and recently discovered markers have not significantly improved survival rates in patients with gastric cancer. Therefore, it is imperative to identify more specific genes associated with the occurrence and progression of gastric cancer to achieve prevention and treatment. The aim of this study is to discover high-risk genes for gastric cancer by integrating single-cell transcriptomics and Mendelian randomization (MR) analysis. Methods:This study integrates gastric cancer genome-wide association study (GWAS) data, single-cell transcriptomics (sc-RNA-seq), and expression quantitative trait loci (eQTL) data for analysis, and employs two-sample MR to elucidate the causal relationships between genes and gastric cancer, thereby identifying high-risk genes for gastric cancer. Subsequently, in vitro cellular experiments are conducted to validate the transcriptional expression levels of these genes. Results:After quality control of the sc-RNA-seq data, we identified 2463 markers for gastric cancer cell subtypes. Subsequently, we utilized eQTL data and GWAS data for gastric cancer to perform MR analysis, yielding 149 genes with a causal relationship with gastric cancer. By applying log2FC filtering, we ultimately identified 5 high-risk gastric cancer genes: SORBS3, RMND5A, FBXO6, LPGAT1, and EPHB4. Finally, in vitro validation confirmed the differential expression of these 5 high-risk genes between normal gastric epithelial cell lines and gastric cancer cell lines. Conclusions:Our study reveals previously unattended high-risk gastric cancer genes, potentially offering new directions and evidence for the molecular diagnosis and treatment of gastric cancer.

BackgroundThere is no standardized and effective treatment modality for Riehl's melanosis.AimsTo compare the efficacy and safety of oral tranexamic acid (TXA) combined with intense pulsed light (IPL) versus TXA alone in the treatment of refractory Riehl's melanosis.MethodsA prospective study of 28 subjects with refractory Riehl's melanosis and Fitzpatrick Skin Types III or IV was conducted. All subjects received oral TXA 500 mg daily and 11 of them were treated in combination with monthly IPL therapy for 6 months. The primary outcome measure was mean melanin index (MI), erythema index (EI) and acquired dermal macular hyperpigmentation area and severity index (DPASI). The Physician Global Assessment (PGA) and patient satisfaction scale were documented.ResultsAfter treatment, DPASI, mean MI, and EI were significantly reduced in both groups. The group treated with combination therapy showed better improvement according to MI (p = 0.0032) and DPASI (p = 0.00468). PGA and patient satisfaction scale showed superior efficacy in the combination group. No significant difference was observed in treatment-related side effects.ConclusionThe combination of oral TXA and IPL proves to be a safe and satisfactory treatment strategy for refractory Riehl's melanosis.

Cobalt-based oxide CuCo2O4-loaded CuCo2O4/carbon felt (CF) composite cathodes were synthesized by hydrothermal deposition of a precursor of Cu/Fe oxides on CF followed by roasting in air. The material serves both catalytic and cathodic dual functions in the heterogeneous electro-Fenton (EF) process. Through XRD (X-ray diffraction), FTIR (Fourier transform infrared spectroscopy), XPS (X-ray photoelectron spectroscopy), SEM (scanning electron microscope), and catalytic experiments, it was concluded that CuCo2O4 loading was successful and the highest hydrophilic 180-CuCo2O4/CF was obtained by varying the hydrothermal temperature without destroying the original structure. 180-CuCo2O4/CF accomplished 98.03 % degradation in 60 min, and it was found to maintain high degradation capacity in the pH 3 similar to 9 range in experiments where the experimental parameters were varied. Compared to monometallic oxides, Cu and Co dual active centers are integrated in CuCo2O4, giving it diverse redox properties and oxidation states. As a result, the CuCo2O4/CF material can realize the dual function of catalytic and cathodic, which provides a new development direction in practical wastewater treatment.

Changes in gut flora are associated with liver fibrosis. The interactions of host with intestinal flora are still unknown, with little research investigating such interactions with comprehensive multi-omics data. The present work analyzed and integrated large-scale multi-omics transcriptomics, microbiome, metabolome, and single-cell RNA-sequencing datasets from Kaempferol-treated and untreated control groups by advanced bioinformatics methods. This study concludes that kaempferol dose-dependently improved serum markers (like AST, ALT, TBil, Alb, and PT) and suppressed fibrosis markers (including HA, PC III, LN, α-SMA, and Collagen I), while kaempferol also increased body weight. Mechanistically, kaempferol improved the metabolic levels of intestinal flora dysbiosis and associated lipids. This was achieved by increasing the abundance of g__Robinsoniella, g__Erysipelotrichaceae_UCG-003, g__Coriobacteriaceae_UCG-002, and 5-Methylcytidine, all-trans-5,6- Epoxyretinoic acid, LPI (18:0), LPI (20:4), etc. to achieve this. Kaemferol exerts anti-inflammatory and immune-enhancing effects by down-regulating the Th17/IL-17 signaling pathway in PDGF-induced LX2 cells. In addition, kaempferol administration remarkably elevated CD4 + T and CD8 + T cellular proportions, thereby activating immune cells for protecting the body and controlling inflammatory conditions. The combined interaction of multiple data may explain how Kaempferol modulates the intestinal flora thereby remodeling the hepatocyte population and alleviating liver fibrosis.

Precise synthesis of topologically predictable and discrete molecular crystals with permanent porosities remains a long-term challenge. Here, we report the first successful synthesis of a series of 11 isoreticular multivariate hydrogen-bonded organic frameworks (MTV-HOFs) from pyrene-based derivatives bearing −H, −CH 3 , −NH 2 and −F groups achieved by a shape-fitted, π–π stacking self-assembly strategy. These MTV-HOFs are single-crystalline materials composed of tecton, as verified by single-crystal diffraction, nuclear magnetic resonance (NMR) spectra, Raman spectra, water sorption isotherms and density functional theory (DFT) calculations. These MTV-HOFs exhibit tunable hydrophobicity with water uptake starting from 50 to 80 % relative humidity, by adjusting the combinations and ratios of functional groups. As a proof of application, the resulting MTV-HOFs were shown to be capable of capturing a mustard gas simulant, 2-chloroethyl ethyl sulfide (CEES) from moisture. The location of different functional groups within the pores of the MTV-HOFs leads to a synergistic effect, which resulted in a superior CEES/H 2 O selectivity (up to 94 %) compared to that of the HOFs with only pure component and enhanced breakthrough performance (up to 4000 min/g) when compared to benchmark MOF materials. This work is an important advance in the synthesis of MTV-HOFs, and provides a platform for the development of porous molecular materials for numerous applications.

The self-healing behavior has been extensively used in intelligent sensing systems capable of molecular recognition. However, most rigid crystalline frameworks, once collapsed under external stimuli like pressure, heat, or vacuum, could hardly recover to their crystalline phases under ambient conditions. Here, we report the self-healing of a new microporous hydrogen-bonded organic framework, FDU-HOF-3 (FDU = Fudan University), for ammonia (NH3) capture and compared it with the established mesoporous HOF-101. With the introduction of low-concentration NH3 into the pores, the HOFs became disordered but were then simply heated under a vacuum to return to their original crystalline states after NH3 removal. Close characterizations revealed that the repeatable self-healing behavior of these HOFs was achieved due to the COOH-NH3 acid-base interactions accompanied by the breaking and regeneration of complementary COOH-COOH hydrogen bonds. FDU-HOF-3 showed a record-capturing capability for low-concentration NH3 (8.13 mmol/g at 25 mbar) among all HOFs and displayed a quick photocurrent decrease after exposure to 250 ppm NH3 for less than 10 s. These self-healing HOFs were used to capture and release NH3 for over 10 cycles without any decrease in the adsorption capacities.

Human meridian (Jingluo) system was hypothesized by traditional Chinese medicine (TCM) for thousands of years, suggesting 12 normal meridian channels going through respective organs, carrying fluid and energy, and laying thermal effects. Some treatments based on meridians have been proved effective. However, existence of meridians has never been confirmed, let alone the lack of measurement for meridian phenotypes. Thermal effect is one of the major phenotypes of meridian metabolism. Infrared photograph was employed to display the picture of meridians since 1970. Unfortunately, no satisfactory results have been obtained. It is possible that only when a certain meridian is activated will there be thermal effect for successful infrared photograph. In this study, 13 types of tea were selected out of the herbs to activate the hypothesized 12 meridians for imagery taking. Forty-two volunteers took part in the experiment lasted for 13 days. Different tea was tested in different day. Infrared imageries of the human bodies were taken immediately after each tea was drunk. The highest temperatures of the fingers, palms, and above the organs were derived from the imageries and analyzed. The temperatures of the organs and fingers possibly connected by 12 hypothesized meridians rose together significantly following the meridian hypothesis. Infrared imageries showed quite clear shapes of the organs activated by different kinds of tea, e.g., heart and kidneys by yellow tea, etc. Some high temperature lines also matched the hypothetic meridians. Our work displayed the probable imageries of all the 12 hypothetic meridians for the first time, and proved with data that different foods may activate different organs following the meridian hypothesis, shedding light on a possible new method of targeted drug designs. Measurements of meridian phenotypes can be developed based on this method of activation.

Recently,artificial and semi-artificial photosynthesis have attracted extensive attentions in addressing the crisis of energy from fossil fuels and reducing excessive CO2 emission.Metal-organic frameworks(MOFs)have been considered as ideal platforms for con-structing artificial photosynthesis systems due to their unique properties like large specific surface area,high porosity and diverse framework topology,and tunable functionalities.This review discussed the characteristics,superiorities and challenges of MOF-based photocatalysts,and detailed summarization of several common design strategies for MOF-based artificial systems,in-cluding i)enhancement of light absorption,ii)acceleration of the charge separation and transfer,and iii)introduction of additional active units.Particularly,we give examples showing the applications of MOF-based photocatalysts,where the mechanisms of supe-rior photocatalytic activity and selectivity are also analyzed,thereby providing theoretical guidance for rational design of MOF-based photocatalysts.Finally,the challenges and future research directions of MOF-based photocatalysts are prospected.

BACKGROUND:Peritoneal metastasis (PM) is an important factor contributing to poor prognosis in patients with gastric cancer (GC). Transcriptomic sequencing has been used to explore the molecular changes in metastatic cancers, but comparing the bulk RNA-sequencing data between primary tumors and metastases in PM studies is unreasonable due to the small proportion of tumor cells in PM tissues.METHODS:We performed single-cell RNA-sequencing analysis on four gastric adenocarcinoma specimens, including one primary tumor sample (PT), one adjacent nontumoral sample (PN), one peritoneal metastatic sample (MT) and one normal peritoneum sample (MN), from the same patient. Pseudotime trajectory analysis was used to display the process by which nonmalignant epithelial cells transform into tumor cells and then metastasize to the peritoneum. Finally, in vitro and in vivo assays were used to validate one of the selected genes that promote peritoneal metastasis.RESULTS:Single-cell RNA sequencing showed that a development curve was found from normal mucosa to tumor tissues and then into metastatic sites on peritoneum. TAGLN2 was found to trigger this metastasis process. The migration and invasion capability of GC cells were changed by downregulating and upregulating TAGLN2 expression. Mechanistically, TAGLN2 might modulate tumor metastasis via alterations in cell morphology and several signaling pathways, thus promoting epithelial-mesenchymal transition (EMT).CONCLUSIONS:In summary, we identified and validated TAGLN2 as a novel gene involved in GC peritoneal metastasis. This study provided valuable insight into the mechanisms of GC metastasis and developed a potential therapeutic target to prevent GC cell dissemination.

Mas-related G-protein-coupled receptors X1-X4 (MRGPRX1-X4) are 4 primate-specific receptors that are recently reported to be responsible for many biological processes, including itch sensation, pain transmission, and inflammatory reactions. MRGPRX1 is the first identified human MRGPR, and its expression is restricted to primary sensory neurons. Due to its dual roles in itch and pain signaling pathways, MRGPRX1 has been regarded as a promising target for itch remission and pain inhibition. Here, we reported a cryo-electron microscopy (cryo-EM) structure of Gq-coupled MRGPRX1 in complex with a synthetic agonist compound 16 in an active conformation at an overall resolution of 3.0 Å via a NanoBiT tethering strategy. Compound 16 is a new pain-relieving compound with high potency and selectivity to MRGPRX1 over other MRGPRXs and opioid receptor. MRGPRX1 was revealed to share common structural features of the Gq-mediated receptor activation mechanism of MRGPRX family members, but the variable residues in orthosteric pocket of MRGPRX1 exhibit the unique agonist recognition pattern, potentially facilitating to design MRGPRX1-specific modulators. Together with receptor activation and itch behavior evaluation assays, our study provides a structural snapshot to modify therapeutic molecules for itch relieving and analgesia targeting MRGPRX1.

When frozen pathological results of suspicious peritoneal nodules found in gastric cancer (GC) patients are negative or indeterminant, whether to perform gastrectomy will always be a dilemma for surgeons. This study aimed to facilitate intraoperative surgical decision-making based on frozen section (FS) results and clinicopathological characteristics. From January 2015 to July 2021, 318 GC patients were enrolled retrospectively. The correlations between frozen and paraffin pathology of peritoneal nodules were examined. Then, predictive factors of positive paraffin section (PS) results were identified, and a nomogram was constructed. The survival significance of gastrectomy was also explored. Of 70 FS-negative patients, 59 (84.3

Wearable personal protective equipment that is decorated with photoactive self-cleaning materials capable of actively neutralizing biological pathogens is in high demand. Here, we developed a series of solution-processable, crystalline porous materials capable of addressing this challenge. Textiles coated with these materials exhibit a broad range of functionalities, including spontaneous reactive oxygen species (ROS) generation upon absorption of daylight, and long-term ROS storage in dark conditions. The ROS generation and storage abilities of these materials can be further improved through chemical engineering of the precursors without altering the three-dimensional assembled superstructures. In comparison with traditional TiO2 or C3 N4 self-cleaning materials, the fluorinated molecular coating material HOF-101-F shows a 10- to 60-fold enhancement of ROS generation and 10- to 20-fold greater ROS storage ability. Our results pave the way for further developing self-cleaning textile coatings for the rapid deactivation of highly infectious pathogenic bacteria under both daylight and light-free conditions.

In the present work, the catalytic co-aquathermolysis of Mackay River bitumen and lignin was performed at the temperature of not higher than 300 degrees C. The heteropoly acid (HPA) catalysts was used as the catalyst for coaquathermolysis. The bitumen to lignin ratio, lignin solvent, and reaction temperature have been optimized. The properties of oil samples before and after reaction including viscosity, API degrees, SARA contents and average relative molecular weight have been determined. The results confirmed the synergistic effect in bitumen and lignin catalytic co-aquathermolysis. Compared with the bitumen aquathermolysis alone, the viscosity-reducing ratio and heavy fraction conversion ratio increased by 42.6 and 9.15 percentages, respectively, API degrees increased by 1.3, and molecular weight of asphaltene decreased by 199. The synergistic mechanism of co-aquathermolysis has been analyzed through Fourier transform infrared spectroscopy (FTIR) and oxygen content changes of aromatics. More oxygen-containing groups have appeared in the FTIR spectra, and the oxygen element content of aromatics increased. The complementation of endothermicity of bitumen thermal cracking and exothermicity of lignin pyrolysis provided the co-aquathermolysis with synergistic viscosity reduction effect. We hope that the results will cast a new light on Mackay River bitumen in situ or ground upgrading for its transportation and refining.

The AlOX tunnel barrier in Josephson junctions prepared by conventional thermal oxidation method is formed by diffusing high-purity oxygen into the surface of Al. But the tunnel barrier fabricated by this method is not completely oxidized, and the thickness of barrier is hard to control accurately. In this work, we use atomic layer deposition to grow Al2O3 tunnel barrier on the surface of Ti. The sandwich structure of Ti/Al2O3/Ti Josephson junction is grown layer by layer. We investigate the corresponding microstructure and electrical properties by adjusting the thickness of the Al2O3 tunnel barrier and the area of the junction. The experimental results show that the monolayer Al2O3 film is about 1.17 Å (1 Å = 10–10 m), which is grown by atomic layer deposition, achieves atomic-level controlled thickness. The resistance is controlled by adjusting the barrier thickness at room temperature. And we obtain a Josephson junction with good resistance uniformity at room temperature by optimizing the junction area.

An effective approach to access dyadic 1,3-oxazinan-2-ones 8a-8c and 4,4a,5,6-tetrahydro-[1,3]oxazino [3,4-a]quinolin-1(3H)-ones 8d-8h was developed through Sc(OTf)(3)-catalyzed intramolecular cyclization from tert-butoxycarbonyl to acyliminium ion 7a-7j. A variety of substituted N,O-acetals, with different ring size, proved to be suitable substrates for this transformation, and a series of (4aS,6S,7R)-6-OTBS-7-substituted-hexahydropyrrolo[1,2-c][1,3]oxazin-1-ones 11a-11j and other chiral dyadic 1,3-oxazinan-2-ones 8i, 8j, 11k were synthesized in moderate yields with excellent diastereoselectivities (dr > 99:1). Moreover, 2,5-trans-products 11a-11j were obtained through this interesting Lewis acid-catalyzed intramolecular cyclization process. (C) 2021 Elsevier Ltd. All rights reserved.