Integrin αvß6 mediates the immune escape through regulation of PD-L1 and serves as a novel marker for immunotherapy of colon carcinoma.

The immune escape of colon cancer and its role in the response to immunotherapies such as PD-1/PD-L1 checkpoint inhibitors have long been of great interest. The positive outcomes of immunotherapy are limited by the immunosuppressive nature of the tumor microenvironment. Integrin αvß6, which can regulate the progression of colon cancer, was recently reported to be involved in the immune suppression of colon cancer. In the present study, we explored the correlation between αvß6 and PD-L1 expression by immunohistochemistry of colon cancer tissues. Then, the regulation of PD-L1 signaling by αvß6 in colon cancer cells was demonstrated. We constructed an in vivo model and performed immunophenotyping experiments to analyze further the regulation of the immune response by αvß6. The role of αvß6 in the response to anti-PD-1 therapy in colon cancer was also verified. αvß6-positive tissues exhibited increased PD-L1 expression. Inhibition of αvß6 not only downregulated constitutive PD-L1 expression but also decreased IFN-γ-induced PD-L1 expression. In addition, αvß6-induced PD-L1 expression was suppressed by the ERK inhibitor PD98059, and knockdown of the ß6-ERK2 binding site had the equivalent effect. αvß6 decreased CD8+ T cell infiltration and granzyme B expression in CD8+ T cells in colon cancer patients. Furthermore, mice engrafted with αvß6-expressing colon cancer cells exhibited an unsatisfactory response to anti-PD-1 therapy, and anti-PD-1-induced increases in CD4+ and CD8+ T cell infiltration could be inhibited by αvß6. These results indicate that αvß6 mediates immune escape in colon cancer by upregulating PD-L1 through the ERK/MAPK pathway. Moreover, αvß6 could serve as a marker for the efficacy of anti-PD-1 therapy in colon cancer.

Establishment of a prognostic model for hypoxia-associated genes in OPSCC and revelation of intercellular crosstalk.

Hypoxia exerts a profound influence on the tumor microenvironment and immune response, shaping treatment outcomes and prognosis. Utilizing consistency clustering, we discerned two hypoxia subtypes in OPSCC bulk sequencing data from GEO. Key modules within OPSCC were identified through weighted gene correlation network analysis (WGCNA). Core modules underwent CIBERSORT immune infiltration analysis and GSEA functional enrichment. Univariate Cox and LASSO analyses were employed to construct prognostic models for seven hypoxia-related genes. Further investigation into clinical characteristics, the immune microenvironment, and TIDE algorithm prediction for immunotherapy response was conducted in high- and low-risk groups. scRNA-seq data were visually represented through TSNE clustering, employing the scissors algorithm to map hypoxia phenotypes. Interactions among cellular subpopulations were explored using the Cellchat package, with additional assessments of metabolic and transcriptional activities. Integration with clinical data unveiled a prevalence of HPV-positive patients in the low hypoxia and low-risk groups. Immunohistochemical validation demonstrated low TDO2 expression in HPV-positive (P16-positive) patients. Our prediction suggested that HPV16 E7 promotes HIF-1α inhibition, leading to reduced glycolytic activity, ultimately contributing to better prognosis and treatment sensitivity. The scissors algorithm effectively segregated epithelial cells and fibroblasts into distinct clusters based on hypoxia characteristics. Cellular communication analysis illuminated significant crosstalk among hypoxia-associated epithelial, fibroblast, and endothelial cells, potentially fostering tumor proliferation and metastasis.

Photo-induced phosphorylation/cyclization of N-homoallyl and N-allyl aldehyde hydrazones to access phosphorylated tetrahydropyridazines and dihydropyrazoles.

A photocatalytic radical carbophosphorylation/cyclization of N-homoallyl aldehyde hydrazones with phosphine oxides was developed under metal-free conditions, achieving phosphorylated tetrahydropyridazines in yields up to 95%. Phosphorylated dihydropyrazoles were also constructed, by reacting N-allyl aldehyde hydrazones with phosphine oxides under the same conditions.

Photocatalytic redox-neutral α-C(sp3)-H pyridination of glycine derivatives and N-arylamines with cyanopyridines.

A photo-induced α-C(sp3)-H decyanative pyridination of N-arylglycine derivatives with cyanopyridines was developed. This reaction was performed under organic photocatalytic and redox-neutral conditions via a radical-radical cross-coupling process. Besides, the protocol was also suitable for the C(sp3)-H pyridination of N-aryl tetrahydroisoquinolines as well as benzylamines.

Photocatalytic cyclization of 3-(2-isocyanophenyl)quinazolin-4(3H)-ones for the construction of quinoxalino[2,1-b]quinazolinones.

A new kind of building unit, 3-(2-isocyanophenyl)quinazolin-4(3H)-ones, was designed and synthesized for the construction of novel quinoxalino[2,1-b]quinazolinones. The radical cyclization of 3-(2-isocyanophenyl)quinazolin-4(3H)-ones with ethers afforded ether-substituted tetracyclic quinoxalino[2,1-b]quinazolinones under photocatalytic and metal-free conditions. In the process, the isocyano accepts a carbon radical to give an imidoyl radical, which adds to the electron-deficient CN bond in quinazolin-4(3H)-one.

SiO2-TiO2 Nanoparticle Aqueous Foam for Volatile Organic Compounds' Suppression.

Volatile organic compounds (VOCs) are prevalent soil contaminants. During the ex situ soil remediation process, VOCs may overflow from the soil and cause gas to diffuse into the atmosphere. Moreover, some VOCs, such as trichloromethane, are categorized by the EPA as emerging contaminants, imparting toxicity to organs, and the endocrine and immune systems, and posing a huge threat to human health and the environment. To reduce VOCs' emissions from contaminated soil, aqueous foam suppression is a prospective method that provides a durable mass transfer barrier for VOCs, and it has been widely used in odor control. Based on an aqueous foam substrate, in order to enhance the foam's stability and efficiency of suppression, SiO2-TiO2-modified nanoparticles have been used as stabilizing agents to improve the mechanical strength of liquid film. The nanoparticles are endowed with the ability to photocatalyze after the introduction of titanium dioxide. From SEM imaging, IR, and a series of morphological characterization experiments, the dispersibility of the SiO2-TiO2-modified nanoparticles was significantly improved under the polar solvent, which, in turn, increased the foam duration. The foam dynamic analysis experiments showed that the foam liquid half-life was increased by 4.08 h, and the volume half-life was increased by 4.44 h after adding the novel synthesized nanoparticles to the bulk foam substrate. From the foam VOC suppression test, foam with modified nanoparticles was more efficient in terms of VOCs' suppression, in contrast with its nanoparticle-free counterparts, due to the longer retention time. Moreover, in a bench-scale experiment, the SiO2-TiO2 nanoparticles foam worked against dichloroethane, n-hexane, and toluene for almost 12 h, with a 90% suppression rate, under UV irradiation, which was 2~6 h longer than that of UV-free SiO2-TiO2 nanoparticles, the KH-570-modified nanosilica foam, and the nanoparticle-free bulk foam. XPS and XRD results indicate that in SiO2-TiO2 nanoparticles, the proportion of titanium valence was changed, providing more oxygen vacancies compared to raw titanium dioxides.

Catalytic hydrolysis of carbonyl sulfide in blast furnace gas over Sm-Ce-Ox@ZrO2 catalyst.

Carbonyl sulfur (COS) is a prominent organic sulfur pollutant commonly found in the by-product gas generated by the steel industry. A series of Sm-doped CeOx@ZrO2 catalysts were prepared for the hydrolysis catalytic removal of COS. The results showed that the addition of Sm resulted in the most significant enhancement of hydrolysis catalytic activity. The 3% Sm2O3-Ce-Ox@ZrO2 catalyst exhibited the highest activity, achieving a hydrolysis catalytic efficiency of 100% and H2S selectivity of 100% within the temperature range of 90-180 °C. The inclusion of Sm had the effect of reducing the acidity of the catalyst while increasing weak basic sites, which facilitated the adsorption and activation of COS molecules at low temperatures. Appropriate doping of Sm proved beneficial in converting active surface chemisorbed oxygen into lattice oxygen, thereby decreasing the oxidation of intermediate products and maintaining the stability of the hydrolysis reaction.

Necroptosis inhibitors: mechanisms of action and therapeutic potential.

Necroptosis is a type of programmed cell death that is morphologically similar to necrosis. This type of cell death is involved in various pathophysiological disorders, including inflammatory, neurodegenerative, infectious, and malignant diseases. Receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) pseudokinase constitute the core components of the necroptosis signaling pathway and are considered the most promising targets for therapeutic intervention. The discovery and characterization of necroptosis inhibitors not only accelerate our understanding of the necroptosis signaling pathway but also provide important drug candidates for the treatment of necroptosis-related diseases. Here, we will review recent research progress on necroptosis inhibitors, mechanisms of action and their potential applications for disease treatment.

Photocatalytic Carbosulfonylation/Cyclization of N-Homoallyl and N-Allyl Aldehyde Hydrazones toward Sulfonylated Tetrahydropyridazines and Dihydropyrazoles.

N'-Benzylidene-N-homoallylacetohydrazides were designed and synthesized as novel skeletons for the construction of functionalized tetrahydropyridazines. A series of aryl- and alkylsulfonylated tetrahydropyridazines were obtained in yields of up to 94% employing sulfonyl chlorides as the sulfonyl radical sources under visible-light irradiation. Besides, sulfonylated dihydropyrazoles were also produced from N-allyl-N'-benzylideneacetohydrazides. Mechanistic investigations indicated that both energy transfer and single electron transfer processes were involved in accomplishing the radical 6/5-endo-trig cyclization to the C═N bond.

Precessing jet nozzle connecting to a spinning black hole in M87.

The nearby radio galaxy M87 offers a unique opportunity to explore the connections between the central supermassive black hole and relativistic jets. Previous studies of the inner region of M87 revealed a wide opening angle for the jet originating near the black hole1-4. The Event Horizon Telescope resolved the central radio source and found an asymmetric ring structure consistent with expectations from general relativity5. With a baseline of 17 years of observations, there was a shift in the jet's transverse position, possibly arising from an 8- to 10-year quasi-periodicity3. However, the origin of this sideways shift remains unclear. Here we report an analysis of radio observations over 22 years that suggests a period of about 11 years for the variation in the position angle of the jet. We infer that we are seeing a spinning black hole that induces the Lense-Thirring precession of a misaligned accretion disk. Similar jet precession may commonly occur in other active galactic nuclei but has been challenging to detect owing to the small magnitude and long period of the variation.

Metal-free polychloromethylation/cyclization of unactivated alkenes towards ring-fused tricyclic indolones and benzoimidazoles.

Polychloromethylative cyclization of N-alkenyl indoles was developed under metal-free conditions to afford tricyclic pyridoindolones and pyrroloindolones in moderate to good yields. In the reaction, commercially available CHCl3 and CH2Cl2 were employed as tri- and dichloromethyl radical sources. Moreover, tri- and dichloromethylated polycyclic benzoimidazoles can also be obtained under standard conditions.

Photocatalytic chemo-, regio- & stereoselective olefinic ß-C-H decarboxylative alkylation of enamides with diacyl peroxides.

A decarboxylative alkylation of enamides with alkyl diacyl peroxides induced by visible-light is described. The chemo-, regio- and stereoselective olefinic ß-C-H alkylation generates a series of primary- and secondary alkylated enamides in yields up to 95%. This transformation bears the advantages of operational simplicity, good functional group compatibility and mild conditions.

A simulation study of 1D U-Net-based inter-crystal scatter event recovery of PET detectors.

To achieve high spatial resolution of reconstructed images in positron emission tomography (PET), the size of the scintillation crystal element is set small in current PET systems, which greatly increases the inter-crystal scattering (ICS) frequency. The ICS is a type of Compton scattering of the gamma photons from one crystal element to its neighborhood element, which obscures the determination of the first interaction position. In this study, we propose a 1D U-Net convolutional neural network to predict the first interaction position, which provides a universal way to efficiently solve the ICS recovery problem. The network is trained using the dataset collected from the GATE Monte Carlo simulation. The 1D U-Net structure is applied due to its capability of synthesizing both low-level and high-level information, which shows superiority in solving the ICS recovery problem. After being well trained, the 1D U-Net can generate a prediction accuracy of 78.1%. Compared to the coincidence events only composed from two photoelectric gamma photons, the sensitivity is improved by 149%. The contrast-to-noise ratio of the reconstructed contrast phantom increases from 6.973 to 10.795 for the 16 mm hot sphere. Compared to the take-energy-centroid method, the spatial resolution of the reconstructed resolution phantom can obtain the best improvement of 33.46%. Compared with the previous deep learning method based on the fully connected network, the proposed 1D U-Net can work more stably with considerably fewer network parameters. The 1D U-Net network model shows good universality when predicting different phantoms, and the computation speed is fast.

Tongqiao Huoxue Decoction ameliorates traumatic brain injury-induced gastrointestinal dysfunction by regulating CD36/15-LO/NR4A1 signaling, which fails when CD36 and CX3CR1 are deficient.

AIMS: Gastrointestinal (GI) dysfunction, as a common peripheral-organ complication after traumatic brain injury (TBI), is primarily characterized by gut inflammation and damage to the intestinal mucosal barrier (IMB). Previous studies have confirmed that TongQiao HuoXue Decoction (TQHXD) has strong anti-inflammatory properties and protects against gut injury. However, few have reported on the therapeutic effects of TQHXD in a TBI-induced GI dysfunction model. We aimed to explore the effects of TQHXD on TBI-induced GI dysfunction and the underlying mechanism thereof. METHODS: We assessed the protective effects and possible mechanism of TQHXD in treating TBI-induced GI dysfunction via gene engineering, histological staining, immunofluorescence (IF), 16S ribosomal ribonucleic acid (rRNA) sequencing, real-time polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), Western blot (WB), and flow cytometry (FCM). RESULTS: TQHXD administration ameliorated TBI-induced GI dysfunction by modulating the abundance and structure of bacteria; reconstructing the destroyed epithelial and chemical barriers of the IMB; and improving M1/M2 macrophage, T-regulatory cell (Treg)/T helper 1 cell (Th1 ), as well as Th17 /Treg ratios to preserve homeostasis of the intestinal immune barrier. Notably, Cluster of Differentiation 36 (CD36)/15-lipoxygenase (15-LO)/nuclear receptor subfamily 4 group A member 1 (NR4A1) signaling was markedly stimulated in colonic tissue of TQHXD-treated mice. However, insufficiency of both CD36 and (C-X3-C motif) chemokine receptor 1 (CX3CR1) worsened GI dysfunction induced by TBI, which could not be rescued by TQHXD. CONCLUSION: TQHXD exerted therapeutic effects on TBI-induced GI dysfunction by regulating the intestinal biological, chemical, epithelial, and immune barriers of the IMB, and this effect resulted from the stimulation of CD36/NR4A1/15-LO signaling; however, it could not do so when CX3CR1 and CD36 were deficient. TQHXD might therefore be a potential drug candidate for treating TBI-induced GI dysfunction.

Metal-Free Photoinduced Hydrocyclization of Unactivated Alkenes toward Ring-Fused Quinazolin-4(3H)-ones via Intermolecular Hydrogen Atom Transfer.

A visible-light-induced hydrocyclization of unactivated alkenes was developed using 3CzClIPN as the photocatalyst to generate substituted α-methyldeoxyvasicinones and α-methylmackinazolinones in moderate to good yields. An intermolecular hydrogen atom transfer with THF as the hydrogen source was involved. Mechanism studies indicated that the intramolecular addition of the in situ formed aminal radical to the unactivated alkene generated the polycyclic quinazolinone.

Therapy of traumatic brain injury by modern agents and traditional Chinese medicine.

Traumatic brain injury (TBI) is the leading cause of disability and death, and the social burden of mortality and morbidity caused by TBI is significant. Under the influence of comprehensive factors, such as social environment, lifestyle, and employment type, the incidence of TBI continues to increase annually. Current pharmacotherapy of TBI mainly focuses on symptomatic supportive treatment, aiming to reduce intracranial pressure, ease pain, alleviate irritability, and fight infection. In this study, we summarized numerous studies covering the use of neuroprotective agents in different animal models and clinical trials after TBI. However, we found that no drug has been approved as specifically effective for the treatment of TBI. Effective therapeutic strategies for TBI remain an urgent need, and attention is turning toward traditional Chinese medicine. We analyzed the reasons why existing high-profile drugs had failed to show clinical benefits and offered our views on the research of traditional herbal medicine for treating TBI.

Substituent-Controlled Regioselective Photoinduced Cyclization of N-Allylbenzamides with N-Sulfonylaminopyridinium Salts.

The annulation reactions of N-allylbenzamides with N-sulfonylaminopyridinium salts were developed under metal-free photoinduced mild conditions. Substituent-controlled sulfonaminoarylation and sulfonaminooxylation of benzamides were realized: N-allylbenzamides lead to benzosultams, while N-(2-phenylallyl)benzamides give sulfonamidylated oxazoline derivatives. Control experiments indicated that those reactions undergo a radical pathway with arylsulfonamidyl radicals as the intermediates. The aryl C-H bond functionalization in arylsulfonamidyl was involved for the first time to give benzosultams.

[Effects of Continuous Straw Returning with Chemical Fertilizer on the Carbon Pool and Crop Yield of Rice-Rape Rotation Soils].

According to the positioning experiment of straw returning in the continuous field 7a, the effects of straw returning combined with chemical fertilizer on soil total organic carbon (TOC), dissolved organic carbon (DOC), particulate organic carbon (POC), labile organic carbon (LOC), carbon pool management index (CPMI), and crop yield in farmland soil profiles (0-20, 20-50, and 50-80 cm) in the Chaohu Lake area were studied. There were four treatments:no straw returning+no fertilization (CK), conventional fertilization (F), straw returning+conventional fertilization (SF1), and straw returning+80% conventional fertilization (SF2). The changes in soil total organic carbon and component content, CPMI, and rape rice yield in different soil layers were analyzed. Taking CK as a reference, conventional fertilization and straw returning combined with chemical fertilizer increased the content of total organic carbon and components in the soil vertical profile, and the content of total organic carbon and components in different soil layers decreased gradually with the increase in soil depth. In the 0-20 cm soil layer, compared with that in the F treatment, the SF1 and SF2 treatments significantly increased the contents of TOC, DOC, POC, and LOC by 14.23%-28.97%, 7.86%-27.01%, 16.46%-24.24%, and 5.89%-6.64%, respectively (P<0.05). In the 20-50 cm soil layer, the contents of TOC and LOC in SF1 were significantly increased by 9.43% and 8.34%, respectively, compared with those in the F treatment (P<0.05), and the contents of DOC and POC in SF2 were significantly increased by 17.51% and 65.83% compared with those in the F treatment (P<0.05). In the 50-80 cm soil layer, there was no significant difference in the contents of total organic carbon and components among the treatments. The effect of straw returning and chemical fertilizer on the soil carbon pool management index was significant. SF1 significantly improved the CPMI of the 0-50 cm soil layer compared with that in the F treatment, whereas the CPMI of the F treatment was the largest in the 50-80 cm soil layer; however, there was no significant difference among all treatments. Straw returning combined with chemical fertilizer had a significant effect on crop yield, and the yield of the SF1 treatment was the highest; compared with that of the F treatment, the rice, rape, and annual yields were significantly increased by 6.19%, 7.67%, and 6.54%, respectively (P<0.05). In general, straw returning combined with chemical fertilizer was of great significance to improve the soil carbon pool, soil fertility, and crop yield in the Chaohu Lake area.

Recent advances in C-H functionalization of 2H-indazoles.

2H-Indazoles are one class of the most important nitrogen-containing heterocyclic compounds. The 2H-indazole motif is widely present in bioactive natural products and drug molecules that exhibit distinctive bioactivities. Therefore, much attention has been paid to access diverse 2H-indazole derivatives. Among them, the late-stage functionalization of 2H-indazoles via C-H activation is recognized as an efficient approach for increasing the complexity and diversity of 2H-indazole derivatives. In this review, we summarized recent achievements in the late-stage functionalization of 2H-indazoles, including the C3-functionalization of 2H-indazoles through transition metal-catalyzed C-H activation or a radical pathway, transition metal-catalyzed ortho C2'-H functionalization of 2H-indazoles and remote C-H functionalization at the benzene ring in 2H-indazoles.