Dietary 5-hydroxytryptophan improves sheep growth performance by enhancing ruminal functions, antioxidant capacity, and tryptophan metabolism: in vitro and in vivo studies.

Background: Hydroxytryptophan (5-HTP) can regulate the synthesis of 5-Hydroxytryptamine (5-HT) and melatonin (MT). In a previous metabolome analysis, we found that 5-HTP is an effective ingredient in yeast culture for regulating rumen fermentation. However, research on the effect of this microbial product (5-HTP) as a functional feed additive in sheep production is still not well explained. Therefore, this study examined the effects of 5-HTP on sheep rumen function and growth performance using in vitro and in vivo models. Methods: A two-factor in vitro experiment involving different 5-HTP doses and fermentation times was conducted. Then, in the in vivo experiment, 10 sheep were divided into a control group which was fed a basal diet, and a 5-HTP group supplemented with 8 mg/kg 5-HTP for 60 days. Results: The results showed that 5-HTP supplementation had a significant effect on in vitro DMD, pH, NH3-N, acetic acid, propionic acid, and TVFA concentrations. 5-HTP altered rumen bacteria composition and diversity indices including Chao1, Shannon, and Simpson. Moreover, the in vivo study on sheep confirmed that supplementing with 8 mg/kg of 5-HTP improved rumen fermentation efficiency and microbial composition. This led to enhanced sheep growth performance and increased involvement in the tryptophan metabolic pathway, suggesting potential benefits. Conclusion: Dietary 5-HTP (8 mg/kg DM) improves sheep growth performance by enhancing ruminal functions, antioxidant capacity, and tryptophan metabolism. This study can provide a foundation for the development of 5-HTP as a functional feed additive in ruminants' production.

Sodium Silicate/Urea/Melamine Ternary Synergistic Waterborne Acrylic Acid Flame-Retardant Coating and Its Flame-Retardant Mechanism.

Waterborne acrylic coatings, the largest market share of predominant environmentally friendly coatings, face limitations in their extensive application due to their flammability. The flame-retardant properties of the coatings could be significantly enhanced by incorporate inorganic flame retardants. However, inorganic flame retardants tend to aggregate and unevenly disperse in waterborne acrylic coatings, causing a substantial decrease in flame retardancy. In this work, sodium silicate was utilized as a flame retardant, with urea and melamine serving as modifiers and synergistic agents. This combination resulted in the preparation of a sodium silicate/urea/melamine ternary synergistic waterborne acrylic flame-retardant coating. This coating was applied to the surface of poplar veneer to create flame-retardant poplar veneer. Subsequently, various instruments, including a scanning electron microscope (SEM), a limiting oxygen index meter (LOI), a thermogravimetric analyzer (TG), and a cone calorimeter (CONE), were employed to investigate the relevant properties and mechanisms of both the flame-retardant coating and poplar veneer. The results demonstrated that the sodium silicate/urea/melamine ternary synergistic flame retardant did not exhibit aggregation and could be uniformly dispersed in waterborne acrylic coatings. The physical and mechanical properties of the ternary synergistic flame-retardant poplar veneer coating were satisfactory. Melamine and urea, acting as modifiers, not only greatly enhanced the dispersibility of sodium silicate in waterborne acrylic coatings, but also assisted in the formation of a silicon-containing char layer through the generation of nitrogen, achieving ternary synergistic flame retardancy. In conclusion, this work explores a novel method to efficiently and uniformly disperse inorganic flame retardants in organic coatings. It significantly improves the dispersibility and uniformity of inorganic flame retardants in organic polymers, thereby substantially enhancing the flame-retardant performance of coatings. This work provides a theoretical basis for the research and application of new flame-retardant coatings in the field of chemistry and materials.

Uncertainty-boosted Robust Video Activity Anticipation.

Video activity anticipation aims to predict what will happen in the future, embracing a broad application prospect ranging from robot vision and autonomous driving. Despite the recent progress, the data uncertainty issue, reflected as the content evolution process and dynamic correlation in event labels, has been somehow ignored. This reduces the model generalization ability and deep understanding on video content, leading to serious error accumulation and degraded performance. In this paper, we address the uncertainty learning problem and propose an uncertainty-boosted robust video activity anticipation framework, which generates uncertainty values to indicate the credibility of the anticipation results. The uncertainty value is used to derive a temperature parameter in the softmax function to modulate the predicted target activity distribution. To guarantee the distribution adjustment, we construct a reasonable target activity label representation by incorporating the activity evolution from the temporal class correlation and the semantic relationship. Moreover, we quantify the uncertainty into relative values by comparing the uncertainty among sample pairs and their temporal-lengths. This relative strategy provides a more accessible way in uncertainty modeling than quantifying the absolute uncertainty values on the whole dataset. Experiments on multiple backbones and benchmarks show our framework achieves promising performance and better robustness/interpretability. Source codes are available at https://github.com/qzhb/UbRV2A.

Mechanistic insights into inositol-mediated rumen function promotion and metabolic alteration using in vitro and in vivo models.

Inositol is a bioactive factor that is widely found in nature; however, there are few studies on its use in ruminant nutrition. This study investigated the effects of different inositol doses and fermentation times on rumen fermentation and microbial diversity, as well as the levels of rumen and blood metabolites in sheep. Rumen fermentation parameters, microbial diversity, and metabolites after different inositol doses were determined in vitro. According to the in vitro results, six small-tailed Han sheep fitted with permanent rumen fistulas were used in a 3 × 3 Latin square feeding experiment where inositol was injected into the rumen twice a day and rumen fluid and blood samples were collected. The in vitro results showed that inositol could increase in vitro dry matter digestibility, in vitro crude protein digestibility, NH3-N, acetic acid, propionic acid, and rumen microbial diversity and affect rumen metabolic pathways (p < 0.05). The feeding experiment results showed that inositol increased the blood concentration of high-density lipoprotein and IgG, IgM, and IL-4 levels. The rumen microbial composition was significantly affected (p < 0.05). Differential metabolites in the rumen were mainly involved in ABC transporters, biotin metabolism, and phenylalanine metabolism, whereas those in the blood were mainly involved in arginine biosynthesis and glutathione and tyrosine metabolism. In conclusion, inositol improves rumen function, affects rumen microorganisms and rumen and blood metabolites and may reduce inflammation, improving animal health.

Membranal Expression of Calreticulin Induced by Unfolded Protein Response in Melanocytes: A Mechanism Underlying Oxidative Stress-Induced Autoimmunity in Vitiligo.

Calreticulin (CRT), a damage-associated molecular pattern molecule, is reported to translocate from the endoplasmic reticulum to the membrane in melanocytes under oxidative stress. To investigate the potential role of CRT in the pathogenesis of vitiligo, we analyzed the correlation between CRT and ROS in serum and lesions of vitiligo, detected CRT and protein kinase RNA-like endoplasmic reticulum kinase (PERK) expression in vitiligo lesions, and studied the production of CRT and mediators of unfolded protein response (UPR) pathway and then tested the chemotactic migration of CD8+ T cells or CD11c+ CD86+ cells. Initially, we verified the overexpression of CRT in perilesional epidermis that was positively correlated with the disease severity of vitiligo. Furthermore, the PERK branch of UPR was confirmed to be responsible for the overexpression and membranal translocation of CRT in melanocytes under oxidative stress. We also found that oxidative stress-induced membranal translocation of CRT promoted the activation and migration of CD8+ T cells in vitiligo. In addition, dendritic cells from patients with vitiligo were also prone to maturation with the coincubation of melanocytes harboring membranal CRT. CRT could be induced on the membrane of melanocytes through UPR and might play a role in oxidative stress-triggered CD8+ T-cell response in vitiligo.

TRPM2-dependent autophagy inhibition exacerbates oxidative stress-induced CXCL16 secretion by keratinocytes in vitiligo.

Vitiligo is a depigmented skin disease due to the destruction of melanocytes. Under oxidative stress, keratinocyte-derived chemokine C-X-C motif ligand 16 (CXCL16) plays a critical role in recruiting CD8+ T cells, which kill melanocytes. Autophagy serves as a protective cell survival mechanism and impairment of autophagy has been linked to increased secretion of the proinflammatory cytokines. However, the role of autophagy in the secretion of CXCL16 under oxidative stress has not been investigated. Herein, we initially found that autophagy was suppressed in both keratinocytes of vitiligo lesions and keratinocytes exposed to oxidative stress in vitro. Autophagy inhibition also promoted CXCL16 secretion. Furthermore, upregulated transient receptor potential cation channel subfamily M member 2 (TRPM2) functioned as an upstream oxidative stress sensor to inhibit autophagy. Moreover, TRPM2-mediated Ca2+ influx activated calpain to shear autophagy related 5 (Atg5) and Atg12-Atg5 conjugate formation was blocked to inhibit autophagy under oxidative stress. More importantly, Atg5 downregulation enhanced the binding of interferon regulatory factor 3 (IRF3) to the CXCL16 promoter region by activating Tank-binding kinase 1 (TBK1), thus promoting CXCL16 secretion. These findings suggested that TRPM2-restrained autophagy promotes CXCL16 secretion via the Atg5-TBK1-IRF3 signaling pathway under oxidative stress. Inhibition of TRPM2 may serve as a potential target for the treatment of vitiligo. © 2024 The Pathological Society of Great Britain and Ireland.

Gemcitabine Inhibits the Progression of Pancreatic Cancer by Restraining the WTAP/MYC Chain in an m6A-Dependent Manner.

PURPOSE: Pancreatic cancer (PC) is a common malignant tumor of the digestive system, and its 5-year survival rate is only 4%. N6-methyladenosine (m6A) RNA methylation is the most common post-transcriptional modification and dynamically regulates cancer development, while its role in PC treatment remains unclear. MATERIALS AND METHODS: We treated PC cells with gemcitabine and quantified the overall m6A level with m6A methylation quantification. Real-time quantitative reverse transcription polymerase chain reaction and Western blot analyses were used to detect expression changes of m6A regulators. We verified the m6A modification on the target genes through m6A-immunoprecipitation (IP), and further in vivo experiments and immunofluorescence (IF) assays were applied to verify regulation of gemcitabine on Wilms' tumor 1-associated protein (WTAP) and MYC. RESULTS: Gemcitabine inhibited the proliferation and migration of PC cells and reduced the overall level of m6A modification. Additionally, the expression of the "writer" WTAP was significantly downregulated after gemcitabine treatment. We knocked down WTAP in cells and found target gene MYC expression was significantly downregulated, m6A-IP also confirmed the m6A modification on MYC. Our experiments showed that m6A-MYC may be recognized by the "reader" IGF2BP1. In vivo experiments revealed gemcitabine inhibited the tumorigenic ability of PC cells. IF analysis also showed that gemcitabine inhibited the expression of WTAP and MYC, which displayed a significant trend of co-expression. CONCLUSION: Our study confirmed that gemcitabine interferes with WTAP protein expression in PC, reduces m6A modification on MYC and RNA stability, thereby inhibiting the downstream pathway of MYC, and inhibits the progression of PC.

Photoredox-catalyzed stereo- and regioselective vicinal fluorosulfonyl-borylation of unsaturated hydrocarbons.

There has been considerable research on sulfur(vi) fluoride exchange (SuFEx) chemistry, which is considered to be a next-generation click reaction, and relies on the unique balance between reactivity and stability inherent in high valent organosulfur. The synthetic versatility of the bifunctional handles containing the fluorosulfonyl group presents great synthetic value and opportunity for drug discovery. However, the direct photoredox-catalyzed fluorosulfonyl-borylation process remains unexplored and challenging due to its system incompatibility and limited synthetic strategies. Herein, we developed a sequential photocatalytic radical difunctionalization strategy for the highly efficient stereoselective synthesis of vicinal fluorosulfonyl borides (VFSBs) with an integrated redox-active SO2F radical reagent. The VFSBs acted as orthogonal synthons, and were subjected to a range of convenient transformations via the cleavage of the C-B and S(vi)-F bonds, including halogenation, Suzuki coupling, hydrogenation, and the SuFEX click reaction, which demonstrated the great potential of the VFSB moieties for use in skeleton linkage and drug modification.

Advanced Glycation End Products-Induced Activation of Keratinocytes: A Mechanism Underlying Cutaneous Immune Response in Psoriasis.

Psoriasis is a common inflammatory skin disease, in which epidermal keratinocytes play a vital role in its pathogenesis by acting both as the responder and as the accelerator to the cutaneous psoriatic immune response. Advanced glycation end products (AGEs) are a class of proinflammatory metabolites that are commonly accumulating in cardiometabolic disorders. Recent studies have also observed the increased level of AGEs in the serum and skin of psoriasis patients, but the role of AGEs in psoriatic inflammation has not been well investigated. In the present study, we initially detected abnormal accumulation of AGEs in epidermal keratinocytes of psoriatic lesions collected from psoriasis patients. Furthermore, AGEs promoted the proliferation of keratinocytes via upregulated Keratin 17 (K17)-mediated p27KIP1 inhibition followed by accelerated cell cycle progression. More importantly, AGEs facilitated the production of interleukin-36 alpha (IL-36α) in keratinocytes, which could enhance T helper 17 (Th17) immune response. In addition, the induction of both K17 and IL-36α by AGEs in keratinocytes was dependent on the activation of signal transducer and activator of transcription 1/3 (STAT1/3) signaling pathways. At last, the effects of AGEs on keratinocytes were mediated by the receptor for AGEs (RAGE). Taken together, these findings support that AGEs potentiate the innate immune function of keratinocytes, which contributes to the formation of psoriatic inflammation. Our study implicates AGEs as a potential pathogenic link between psoriasis and cardiometabolic comorbidities.

Modular and Practical 1,2-Aryl(Alkenyl) Heteroatom Functionalization of Alkenes through Iron/Photoredox Dual Catalysis.

Efficient methods for synthesizing 1,2-aryl(alkenyl) heteroatomic cores, encompassing heteroatoms such as nitrogen, oxygen, sulfur, and halogens, are of significant importance in medicinal chemistry and pharmaceutical research. In this study, we present a mild, versatile and practical photoredox/iron dual catalytic system that enables access to highly privileged 1,2-aryl(alkenyl) heteroatomic pharmacophores with exceptional efficiency and site selectivity. Our approach exhibits an extensive scope, allowing for the direct utilization of a wide range of commodity or commercially available (hetero)arenes as well as activated and unactivated alkenes with diverse functional groups, drug scaffolds, and natural product motifs as substrates. By merging iron catalysis with the photoredox cycle, a vast array of alkene 1,2-aryl(alkenyl) functionalization products that incorporate a neighboring azido, amino, halo, thiocyano and nitrooxy group were secured. The scalability and ability to rapid synthesize numerous bioactive small molecules from readily available starting materials highlight the utility of this protocol.

Unsupervised Low-Light Video Enhancement With Spatial-Temporal Co-Attention Transformer.

Existing low-light video enhancement methods are dominated by Convolution Neural Networks (CNNs) that are trained in a supervised manner. Due to the difficulty of collecting paired dynamic low/normal-light videos in real-world scenes, they are usually trained on synthetic, static, and uniform motion videos, which undermines their generalization to real-world scenes. Additionally, these methods typically suffer from temporal inconsistency (e.g., flickering artifacts and motion blurs) when handling large-scale motions since the local perception property of CNNs limits them to model long-range dependencies in both spatial and temporal domains. To address these problems, we propose the first unsupervised method for low-light video enhancement to our best knowledge, named LightenFormer, which models long-range intra- and inter-frame dependencies with a spatial-temporal co-attention transformer to enhance brightness while maintaining temporal consistency. Specifically, an effective but lightweight S-curve Estimation Network (SCENet) is first proposed to estimate pixel-wise S-shaped non-linear curves (S-curves) to adaptively adjust the dynamic range of an input video. Next, to model the temporal consistency of the video, we present a Spatial-Temporal Refinement Network (STRNet) to refine the enhanced video. The core module of STRNet is a novel Spatial-Temporal Co-attention Transformer (STCAT), which exploits multi-scale self- and cross-attention interactions to capture long-range correlations in both spatial and temporal domains among frames for implicit motion estimation. To achieve unsupervised training, we further propose two non-reference loss functions based on the invertibility of the S-curve and the noise independence among frames. Extensive experiments on the SDSD and LLIV-Phone datasets demonstrate that our LightenFormer outperforms state-of-the-art methods.

Melanin inspired microcapsules delivering immune metabolites for hepatic fibrosis management.

Patients with hepatic fibrosis (HF) have a high risk of developing liver cirrhosis and hepatocellular carcinoma, and there is an urgent need for preventive strategies to block this process. Previous studies have found that disordered inflammation and oxidative damage play important roles in HF progression, suggesting two attractive therapeutic targets. Herein, a new kind of bioinspired microcapsules with a core-shell structure is generated using microfluidics. Polydopamine nanoparticles (PDANPs), a synthetic analogue of natural melanin, are embedded in the polymer shell to provide antioxidative properties for these microcapsules. The aqueous core is used to encapsulate ketone body ß-hydroxybutyrate (BHB), an energy metabolite recently known to have regulating effects of cellular signals involved in chronic inflammation. In a HF mouse model, the BHB-encapsulated PDANPs-embedded microcapsules (BHB-PDA-MCs) can not only decrease the severity of inflammatory response, but also the level of oxidative stress. As a result, this combinational strategy is demonstrated to prevent the activation of hepatic stellate cells, the accumulation of extracellular matrix, and the damage of hepatic lobules. These findings indicate that BHB-PDA-MCs can be a promising drug delivery system and have a synergistic effect on HF management.

Prognostic evaluation of pancreatic cancer based on the model of chemo-radiotherapy resistance-related genes.

Background: The incidence and mortality of pancreatic cancer are almost the same, and the 5-year survival rate is less than 10%. The high mortality of pancreatic cancer is related to chemo-radiotherapy. The present study aimed to establish a prognostic signature of pancreatic cancer based on chemo-radiotherapy resistant-related genes (CRRGs). Methods: In this study, we explored the radiation-resistant and chemotherapy-resistant pancreatic cancer cell lines by colony formation and a subcutaneous tumor model in nude mice. Next, we obtained CRRGs from radiation- and gemcitabine-resistant pancreatic cancer cell lines in the Gene Expression Omnibus (GEO) database. Based on univariate Cox and least absolute shrinkage and selection operator (LASSO) Cox regression analyses, a prognostic model of the pancreatic adenocarcinoma (PAAD) cohort in The Cancer Genome Atlas (TCGA) database (N=177) was established and verified using the GEO cohort data set (N=112). Finally, the functions of candidate target genes were verified by a methyl thiazolyl tetrazolium (MTT) assay, a colony formation assay, and a subcutaneous tumor model in nude mice. Results: Through the in vitro and in vivo experiments, we found that radiotherapy- and chemotherapy-resistant pancreatic cancer cells were cross-resistant to chemotherapy and radiotherapy. We constructed a risk model consisting of nine CRRGs (SNAP25, GPR87, DLL1, LAD1, WASF3, ARHGAP29, ZBED2, GAD1, and JAG1) by using public databases. According to the Kaplan-Meier curve analysis, the survival of the high-risk group was worse than that of the low-risk group. We then used nomograms to predict the 1/3/5-year overall survival (OS) in pancreatic cancer patients. We chose JAG1 as a candidate target since it has been proven to be involved in the stemness maintenance of cancer cells, and found that JAG1 silencing inhibited the proliferation and chemo-radiotherapy tolerance of pancreatic cancer cells. Conclusions: This study established and validated a prognostic signature of pancreatic cancer using nine CRRGs. The in vitro and in vivo experiments showed that JAG1 could promote the proliferation and chemoradiotherapy tolerance of pancreatic cancer cell lines. These findings may offer new insights into the role of CRRGs in pancreatic cancer and provide novel prognostic biomarkers for the treatment of pancreatic cancer.

A bioinformatics analysis and an experimental validation of the hypoxia-related prognostic model.

Background: Hypoxia plays an important role in the development of pancreatic cancer (PCA). However, there is few research on the application of hypoxia molecules in predicting the prognosis of PCA. We aimed to establish a prognostic model based on hypoxia-related genes (HRGs) for PCA to discover new biomarkers, and to reveal the potential of this prognostic model for evaluating the tumor microenvironment (TME). Methods: Univariate Cox regression analysis was used to identify HRGs associated with overall survival (OS) of PCA samples. A hypoxia-related prognostic model was established based on least absolute shrinkage and selection operator (LASSO) regression analysis in The Cancer Genome Atlas (TCGA) cohort. The model was validated in the Gene Expression Omnibus (GEO) datasets. The Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to estimate the infiltration of immune cells. A wound healing assay and transwell invasion assay were used to explore the biological functions of target genes in PCA. Results: A total of 18 HRGs were differentially expressed between the tumor and normal pancreatic tissue, 4 (BHLHE40, ENO1, SDC4, and TGM2) of which were selected to construct a prognostic model. According to this model, patients in the high-risk group had a less favorable prognosis. Furthermore, the proportion of M0 macrophages was significantly higher in high-risk tissue-type patients, whereas naïve B cells, plasma cells, CD8+ T cells, and activated CD4+ memory T cells were significantly lower. The expression of BHLHE40 in PCA cells was significantly up-regulated under hypoxic conditions. Moreover, BHLHE40 was shown to regulate the transcription and expression of the downstream target gene TLR3. The wound healing assay and transwell invasion assay indicated that BHLHE40 mediated PCA cell migration and invasion by targeting the downstream gene TLR3. Conclusions: The hypoxia-related prognostic model established by the expression pattern of 4 HRGs can be used to predict the prognosis and assess the TME of PCA patients. Mechanically, activation of the BHLHE40/TLR3 axis is responsible for the promoted invasion and migration of PCA cells in a hypoxic environment.

Pharmacological inhibition of demethylzeylasteral on JAK-STAT signaling ameliorates vitiligo.

BACKGROUND: The activation of CD8+ T cells and their trafficking to the skin through JAK-STAT signaling play a central role in the development of vitiligo. Thus, targeting this key disease pathway with innovative drugs is an effective strategy for treating vitiligo. Natural products isolated from medicinal herbs are a useful source of novel therapeutics. Demethylzeylasteral (T-96), extracted from Tripterygium wilfordii Hook F, possesses immunosuppressive and anti-inflammatory properties. METHODS: The efficacy of T-96 was tested in our mouse model of vitiligo, and the numbers of CD8+ T cells infiltration and melanocytes remaining in the epidermis were quantified using whole-mount tail staining. Immune regulation of T-96 in CD8+ T cells was evaluated using flow cytometry. Pull-down assay, mass spectrum analysis, molecular docking, knockdown and overexpression approaches were utilized to identify the target proteins of T-96 in CD8+ T cells and keratinocytes. RESULTS: Here, we found that T-96 reduced CD8+ T cell infiltration in the epidermis using whole-mount tail staining and alleviated the extent of depigmentation to a comparable degree of tofacitinib (Tofa) in our vitiligo mouse model. In vitro, T-96 decreased the proliferation, CD69 membrane expression, and IFN-γ, granzyme B, (GzmB), and perforin (PRF) levels in CD8+ T cells isolated from patients with vitiligo. Pull-down assays combined with mass spectrum analysis and molecular docking showed that T-96 interacted with JAK3 in CD8+ T cell lysates. Furthermore, T-96 reduced JAK3 and STAT5 phosphorylation following IL-2 treatment. T-96 could not further reduce IFN-γ, GzmB and PRF expression following JAK3 knockdown or inhibit increased immune effectors expression upon JAK3 overexpression. Additionally, T-96 interacted with JAK2 in IFN-γ-stimulated keratinocytes, inhibiting the activation of JAK2, decreasing the total and phosphorylated protein levels of STAT1, and reducing the production and secretion of CXCL9 and CXCL10. T-96 did not significantly inhibit STAT1 and CXCL9/10 expression following JAK2 knockdown, nor did it suppress upregulated STAT1-CXCL9/10 signaling upon JAK2 overexpression. Finally, T-96 reduced the membrane expression of CXCR3, and the culture supernatants pretreated with T-96 under IFN-γ stressed keratinocytes markedly blocked the migration of CXCR3+CD8+ T cells, similarly to Tofa in vitro. CONCLUSION: Our findings demonstrated that T-96 might have positive therapeutic responses to vitiligo by pharmacologically inhibiting the effector functions and skin trafficking of CD8+ T cells through JAK-STAT signaling.

Identification and characterization of a novel molecular classification based on disulfidptosis-related genes to predict prognosis and immunotherapy efficacy in hepatocellular carcinoma.

BACKGROUND: Disulfidptosis has been discovered as a mechanism of cell death mediating by SLC7A11. Nonetheless, little is known about the relationship between disulfidptosis-related genes (DRG) and hepatocellular carcinoma (HCC). METHODS: 7 datasets including 1,302 HCC patients and 62,530 cells were downloaded. We adopted consensus clustering algorithm to construct the consensus matrix and cluster the samples' DRG related expression profile data. Then, weighted gene co-expression network analysis (WGCNA) was conducted to identify hub gene modules associated with the identified clusters and determine the correlation between modules. A DRG.score was constructed based on genes through differential analysis and WGCNA of the 2 clusters. RESULTS: Univariate and multivariate Cox regression analysis show that SLC7A11 and LRPPRC can be used as an independent factor in HCC. Then, two molecular subgroups with significantly different survival were identified based on 10 DRG. The cluster.A showed a worse prognosis, higher immune infiltration, and higher immune checkpoint expression. Then, by differential analysis and WGCNA of the 2 clusters, we identified 5 hub genes, and constructed a DRG.score. Univariate and multivariate Cox regression analysis show that DRG.score can be used as an independent factor to predict the prognosis in HCC. Furthermore, high DRG.score group had a worse prognosis, and was validated in TCGA-LIHC, LIRI-JP, GSE14520, GSE36376, and GSE76427. Preclinically, patients with higher DRG.score demonstrated significant immunotherapy therapeutic advantages and transcatheter arterial chemoembolization clinical benefits. CONCLUSIONS: SLC7A11 and LRPPRC play an essential role in HCC prognosis prediction. The DRG.score might become useful biomarkers for novel therapeutic targets.

Parabolic-Index Ring-Core Fiber Supporting High-Purity Orbital Angular Momentum Modes.

We design a graded-index ring-core fiber with a GeO2-doped silica ring core and SiO2 cladding. This fiber structure can inhibit the effect of spin-orbit coupling to mitigate the power transfer among different modes and eventually enhance the orbital angular momentum (OAM) mode purity. By changing the high-index ring core from the step-index to parabolic graded-index profile, the purity of the OAM1,1 mode can be improved from 86.48% to 94.43%, up by 7.95%. The proposed fiber features a flexible structure, which can meet different requirements for mode order, effective mode area, etc. Simulation results illustrate that the parabolic-index ring-core fiber is promising in enhancing the OAM mode purity, which could potentially reduce the channel crosstalk in mode-division-multiplexed optical communication systems.

Photoredox Microfluidic Synthesis of Trifluoromethylated Amino Acids.

Fluorinated amino acids are a class of highly valuable building blocks that are widely employed in biological science and pharmaceutical industry for improved stability, activity, and folding property of proteins. However, the synthetic approach has conventionally been constrained by harsh conditions and limited substrate range. We demonstrate a general synthetic protocol for photoinduced α-CF3 amino acids using continuous flow technology that benefits from enhanced fusion and precise control of reaction time, making it potentially useful in large-scale peptide synthesis.

Sestrin2 contributes to BRAF inhibitor resistance via reducing redox vulnerability of melanoma cells.

BACKGROUND: Treatment resistance often occurs with BRAF inhibitor (BRAFi) therapy for melanoma, bringing in a great challenge to the treatment of melanoma patients harboring mutant BRAF gene. Recent studies revealed redox vulnerability constitutes a novel opportunity to overcome BRAFi resistance. Previously we found Sestrin2 provided protection to metastatic melanoma cells by detoxifying reactive oxygen species (ROS) induced by anoikis, but its defensive role against redox stimuli elicited by BRAFi was unclear. OBJECTIVE: In-depth explored the role of Sestrin2 in BRAFi-resistant melanoma. METHODS: Vemurafenib-resistant melanoma cells were established using 451Lu and UACC62 cell lines carrying BRAFV600E mutation. Mechanistic studies were subsequently performed by transfection of lentiviral vectors encoding an shRNA against SESN2 or embedded with the coding sequences of SESN2 cDNA. RESULTS: Elevated Sestrin2 expression was found in vemurafenib-resistance melanoma cells. Further mechanistic studies revealed that BRAFi-resistant melanoma cells employ Sestrin2 to adapt to higher oxidative stress under vemurafenib exposure. It was also demonstrated that mTOR signaling was significantly activated following Sestrin2 knockdown. Given the known promoting role of active mTOR signaling in melanoma proliferation and survival, the effects of mTOR blocker and Sestrin2 ablation on BRAFi-resistant melanoma cells were further tested, and the combination was found to result in enhanced inhibition of melanoma cell growth. CONCLUSIONS: Our findings demonstrated the contribution of Sestrin2 to the development of BRAFi resistance and the fact that the combination of mTOR blocker assisted Sestrein2 ablation in eliminating BRAFi resistance of melanoma. Therefore, mTOR and Sestrin2 may be novel combinatorial therapeutic targets to overcome BRAFi resistance of melanoma.

Microstructure and High-Temperature Ablation Behaviour of Hafnium-Doped Tungsten-Yttrium Alloys.

W is a widely used refractory metal with ultra-high melting point up to 3410 °C. However, its applications are limited by poor ablation resistance under high-temperature flame and air flow, which is crucial for aerospace vehicles. To improve the ablation resistance of W under extreme conditions, W-Y alloys doped with different Hf mass fractions (0, 10, 20, and 30) were prepared using the fast hot pressing sintering method. Microstructure and ablation behaviours at 2000 °C were investigated. Results showed that adding an appropriate amount of Hf improved the properties of the W-Y alloy evidently. In particular, the hardness of the alloy increased with the increased content of Hf. The formation of the HfO2 layer on the surface during ablation decreased the mass and linear ablation rates, indicating enhanced ablation resistance. However, excessive Hf addition will result in crack behaviour during ablation. With a Hf content of 20 wt.%, the alloy exhibited high stability and an excellent ablation resistance.