Regioselective Condensation Polymerization of Propargylic Electrophiles Enabled by Catalytic Element-Cupration.

Here, we report a set of new polymerization reactions enabled by the 1,2-regioselective hydro- and silylcupration of enyne-type propargylic electrophiles. Highly regioregular head-to-tail poly(2-butyne-1,4-diyl)s (HT-PBD), bearing either methyl or silylmethyl side chains, are synthesized for the first time. A rapid entry into carbon-rich copolymers with adjustable silicon content is developed via in situ monomer bifurcation. Furthermore, a one-pot polymerization/semireduction sequence is developed to access a cis-poly(butadiene)-derived backbone by a ligand swap on copper hydride species. Interestingly, borocupration, typically exhibiting identical regioselectivity with its hydro- and silyl analogues, seems to proceed in a 3,4-selective manner. Computational studies suggest the possible role of the propargylic leaving group in this selectivity switch. This work presents a new class of regioregular sp-carbon-rich polymers and meanwhile a novel approach to organosilicon materials.

Interleukin-7 expression by CAR-T cells improves CAR-T cell survival and efficacy in chordoma.

Chordoma is a rare bone tumor that frequently recurs after surgery, and the prognosis is poor with current treatments. This study aimed to identify potential novel immunotherapeutic targets for chordomas by identifying target proteins in clinical samples as well as tumor microenvironmental factors to enhance efficacy. Fourteen chordoma samples were analyzed by single-cell RNA sequencing, and B7-H3 and IL-7 were identified as potential targets and potentiators, respectively. B7-H3-targeted chimeric antigen receptor T (CAR-T) cells and B7-H3 CAR-T cells expressing IL-7 were synthesized and their anti-tumor activity evaluated in vitro, including in primary chordoma organoid models. The B7-H3 CAR-T/IL-7 therapy showed enhanced cytotoxicity and prolonged duration of action against tumor cells. Additionally, IL-7 modulated favorable subpopulations of cultured CAR-T cells, diminished immune checkpoint expression on T-cell surfaces, and enhanced T-cell functionality. The incorporation of IL-7 molecules into the B7-H3 CAR structure augmented CAR-T-cell function and improved CAR-T-cell efficacy, thus providing a novel dual therapeutic strategy for chordoma treatment.

A High-Entropy Prussian Blue Analog for Aqueous Potassium-Ion Batteries.

Aqueous potassium-ion batteries (AKIBs) are considered promising electrochemical energy storage systems owing to their high safety and cost-effectiveness. However, the structural degradation resulting from the repeated accommodation of large K-ions and the dissolution of active electrode materials in highly dielectric aqueous electrolytes often lead to unsatisfactory electrochemical performance. This study introduces a high-entropy Prussian blue analog (HEPBA) cathode material for AKIBs, demonstrating significantly enhanced structural stability and reduced dissolution. The HEPBA exhibits a highly reversible specific capacity of 102.4 mAh g-1, with 84.4% capacity retention after undergoing 3448 cycles over a duration of 270 days. Mechanistic insights derived from comprehensive experimental investigations, supported by theoretical calculations, reveal that the HEPBA features a robust structure resistant to dissolution, a solid-solution reaction pathway with negligible volume variation during charge-discharge, and efficient ion transport kinetics characterized by a reduced band gap and a low energy barrier. This study represents a measurable step forward in the development of long-lasting electrode materials for aqueous AKIBs.

Robust machine-learning based prognostic index using cytotoxic T lymphocyte evasion genes highlights potential therapeutic targets in colorectal cancer.

BACKGROUND: A minute fraction of patients stands to derive substantial benefits from immunotherapy, primarily attributable to immune evasion. Our objective was to formulate a predictive signature rooted in genes associated with cytotoxic T lymphocyte evasion (CERGs), with the aim of predicting outcomes and discerning immunotherapeutic response in colorectal cancer (CRC). METHODS: 101 machine learning algorithm combinations were applied to calculate the CERGs prognostic index (CERPI) under the cross-validation framework, and patients with CRC were separated into high- and low-CERPI groups. Relationship between immune cell infiltration levels, immune-related scores, malignant phenotypes and CERPI were further analyzed. Various machine learning methods were used to identify key genes related to both patient survival and immunotherapy benefits. Expression of HOXC6, G0S2, and MX2 was evaluated and the effects of HOXC6 and G0S2 on the viability and migration of a CRC cell line were in-vitro verified. RESULTS: The CERPI demonstrated robust prognostic efficacy in predicting the overall survival of CRC patients, establishing itself as an independent predictor of patient outcomes. The low-CERPI group exhibited elevated levels of immune cell infiltration and lower scores for tumor immune dysfunction and exclusion, indicative of a greater potential benefit from immunotherapy. Moreover, there was a positive correlation between CERPI levels and malignant tumor phenotypes, suggesting that heightened CERPI expression contributes to both the occurrence and progression of tumors. Thirteen key genes were identified, and their expression patterns were scrutinized through the analysis of single-cell datasets. Notably, HOXC6, G0S2, and MX2 exhibited upregulation in both CRC cell lines and tissues. Subsequent knockdown experiments targeting G0S2 and HOXC6 resulted in a significant suppression of CRC cell viability and migration. CONCLUSION: We developed the CERPI for effectively predicting survival and response to immunotherapy in patients, and these results may provide guidance for CRC diagnosis and precise treatment.

Alkyne Polymers from Stable Butatriene Homologues: Controlled Radical Polymerization of Vinylidenecyclopropanes.

Controlled polymerization of cumulenic monomers represents a promising yet underdeveloped strategy toward well-defined alkyne polymers. Here we report a stereoelectronic effect-inspired approach using simple vinylidenecyclopropanes (VDCPs) as butatriene homologues in controlled radical ring-opening polymerizations. While being thermally stable, VDCPs mimic butatrienes via conjugation of the cyclopropane ring. This leads to exclusive terminal-selective propagation that affords a highly structurally regular alkyne-based backbone, featuring complete ring-opening and no backbiting regardless of polymerization conditions.

Four-Component Reaction Access to Nitrile-Substituted All-Carbon Quaternary Centers.

A four-component reaction strategy for access to acyclic nitrile-substituted all-carbon quaternary centers is disclosed. In the presence of a DABCO-based ionic liquid catalyst, the reactions proceed smoothly with a wide range of substrates efficiently to deliver nitrile-substituted all-carbon quaternary centers under mild reaction conditions. This protocol is further demonstrated as an efficient method for the construction of contiguous all-carbon quaternary centers. All the reactions are easily operated in a green manner, producing water as the only byproduct. Some of the products show excellent activity against specific fungi.

Integrate analysis of the promote function of Cell division cycle-associated protein family to pancreatic adenocarcinoma.

Background: The cell division cycle-associated (CDCA) protein family plays a pivotal role in the regulation of the cell cycle during tumorigenesis and predicts the prognosis of tumors, but an analysis of these proteins in pancreatic adenocarcinoma (PAAD) is still lacking. Methods: Oncomine and GEPIA were used to observe the expression and prognostic value of eight CDCAs in pan-cancer. Univariate Cox analysis of single CDCAs and multivariate Cox analysis of all eight CDCAs were performed to evaluate the integrated prognostic value of CDCAs, and the results are displayed as hazard ratios (HRs) and 95% confidence intervals (95% CIs). K-M plots and receiver operating characteristics curves were used to display the predicted function and accuracy of CDCAs to determine the risk score. Annotation of CDCA-related genes, gene sets enrichment analysis (GSEA) and gene sets variation analysis (GSVA) were performed to reveal the CDCAs that impact biological processes. Results: CDCAs expression in most tumors is higher than that in normal tissues and is associated with a poor prognosis. Regarding PAAD, increased CDCA expression along with advanced PAAD tumor stage, NUF2, CDCA2, CDCA3, CDCA4 and CDCA5 expression are risk factors for poor prognosis, while CBX2 expression is a protective factor (P < 0.05). The integrated prognostic value of CDCAs in PAAD patients was validated by SurvExpress in the TCGA-PAAD cohort (P < 0.001, HR = 2.16, 95% CI = 1.41-3.3) and the ICGC-PACA cohort (P < 0.001, HR = 2.56, 95% CI = 1.73-3.79). Genetic alteration and DNA methylation of CDCAs might not affect the prognosis of PAAD patients. After comparing high- and low-risk groups separated by CDCA risk scores, the activated pathways were revealed and included the cell cycle, DNA repair, P53, MYC-targets, E2F-targets and PI3K pathways. Conclusion: CDCAs can predict the OS prognosis of PAAD patients. The cell cycle, DNA repair, E2F, P53 and PI3K signaling pathways, in which CDCAs are involved, impact the tumorigenesis of PAAD.

Upregulation of microRNA-143-3p induces apoptosis and suppresses proliferation, invasion, and migration of papillary thyroid carcinoma cells by targeting MSI2.

As a tumor-associated biological molecule, microRNA-143-3p (miR-143-3p) is implicated in the progression of papillary thyroid carcinoma (PTC). We conducted this study to elucidate the effects of miR-143-3p mediated by Musashi RNA binding protein 2 (MSI2) on the biological activities of PTC cells. The K1 cells with the lowest miR-143-3p expression were selected for the experiments. The targeting relationship between miR-143-3p and MSI2 was verified. The biological functions of miR-143-3p and MSI2 with respect to K1 cell proliferation, cycle distribution, apoptosis, invasion, migration, and tumorigenesis were studied using gain- and loss-of-function assays both in vitro and in vivo. MSI2 was verified to be a target gene of miR-143-3p. Cells treated with upregulation of miR-143-3p or silencing of MSI2 exhibited significantly decreased the expression of Bcl-2, PCNA, MCM2, Ki67, MSI2, MMP-2, and MMP-9. This was accompanied by inhibited cell proliferation, cell invasion, and migration, as well as a significant increase in Bax expression, cell cycle arrest, and cell apoptosis. More importantly, the tumor inhibitory effects of upregulated miR-143-3p were also confirmed in the tumor xenografts in nude mice. Our results indicate that upregulation of miR-143-3p suppresses the progression of PTC by impeding cell growth, invasion, and migration via downregulation of MSI2, highlighting the potential of miR-143-3p as a target for future PTC treatment.

CD133 promotes the self-renewal capacity of thyroid cancer stem cells through activation of glutamate aspartate transporter SLC1A3 expression.

CD133+ cancer stem cells are responsible for thyroid cancer initiation. The regulatory pathways essential for sustaining the self-renewal of thyroid cancer stem cells remain largely unknown. Glutamate signaling regulates the self-renewal ability of stem cells. In the present study, we found that the level of glutamate was higher in CD133+ thyroid cancer cells than in CD133- thyroid cancer cells. The transcriptional level of glutamate aspartate transporter SLC1A3 was high in CD133+ thyroid cancer cells. Activation of NF-κB signaling by CD133 was responsible for SLC1A3 high transcription level in CD133+ thyroid cancer cells. Knock down of SLC1A3 significantly reduced the level of glutamate and inhibited the self-renewal activity and tumorigenicity of CD133+ thyroid cancer cells. Overexpression of SLC1A3 rescued the negative effect of CD133 knockdown on the self-renewal capability of CD133+ thyroid cancer cells. Taken together, CD133 promotes the self-renewal capacity of CD133+ thyroid cancer cells at least partly through activation of SLC1A3 expression.

Long non-coding RNA MIAT promotes papillary thyroid cancer progression through upregulating LASP1.

BACKGROUND: Accumulating evidences indicate that long non-coding RNAs (lncRNAs) play an important role in initiation and development of thyroid cancer. However, the underlying molecular mechanism remains elusive. METHODS: To explore potential oncogenic and tumor suppressive lncRNAs in papillary thyroid cancer (PTC), we performed RNA sequencing to discover differentially expression lncRNAs between PTC tissues and matched normal tissues. RT-qPCR was used to validate differentially expressed lncRNAs. Bioinformatic analysis was performed to predicted potential miRNA and gene which might be regulated by MIAT. Cell proliferation, invasion and cycle assay were conducted to study the function of MIAT and LASP1 in PTC. RESULTS: Through analysis of RNA sequencing, we observed that lncRNA-MIAT was overexpressed in PTC tissues. The upregulation of MIAT was further confirmed in 40 pairs of PTC tissues and normal tissues we collected. In the function assays, results suggested that MIAT silencing led to inhibition of cell proliferation, invasion and disruption of cell cycle progression in PTC cells. Mechanistically, MIAT directly bound to miR-324-3p and upregulated LASP1 expression in PTC cells. In addition, expression of MIAT was positively correlated with LASP1 mRNA expression in samples collected from patients with PTC. More importantly, transfection of recombinant LASP1 attenuated MIAT silencing induced inhibition of cell proliferation, invasion and disruption of cell cycle progression in PTC cells. CONCLUSIONS: In conclusion, the findings suggest that lncRNA-MIAT may promote PTC proliferation and invasion through physically binding miR-324-3p and upregulation of LASP1.

Mango Fruit Load Estimation Using a Video Based MangoYOLO-Kalman Filter-Hungarian Algorithm Method.

: Pre-harvest fruit yield estimation is useful to guide harvesting and marketing resourcing, but machine vision estimates based on a single view from each side of the tree ("dual-view") underestimates the fruit yield as fruit can be hidden from view. A method is proposed involving deep learning, Kalman filter, and Hungarian algorithm for on-tree mango fruit detection, tracking, and counting from 10 frame-per-second videos captured of trees from a platform moving along the inter row at 5 km/h. The deep learning based mango fruit detection algorithm, MangoYOLO, was used to detect fruit in each frame. The Hungarian algorithm was used to correlate fruit between neighbouring frames, with the improvement of enabling multiple-to-one assignment. The Kalman filter was used to predict the position of fruit in following frames, to avoid multiple counts of a single fruit that is obscured or otherwise not detected with a frame series. A "borrow" concept was added to the Kalman filter to predict fruit position when its precise prediction model was absent, by borrowing the horizontal and vertical speed from neighbouring fruit. By comparison with human count for a video with 110 frames and 192 (human count) fruit, the method produced 9.9% double counts and 7.3% missing count errors, resulting in around 2.6% over count. In another test, a video (of 1162 frames, with 42 images centred on the tree trunk) was acquired of both sides of a row of 21 trees, for which the harvest fruit count was 3286 (i.e., average of 156 fruit/tree). The trees had thick canopies, such that the proportion of fruit hidden from view from any given perspective was high. The proposed method recorded 2050 fruit (62% of harvest) with a bias corrected Root Mean Square Error (RMSE) = 18.0 fruit/tree while the dual-view image method (also using MangoYOLO) recorded 1322 fruit (40%) with a bias corrected RMSE = 21.7 fruit/tree. The video tracking system is recommended over the dual-view imaging system for mango orchard fruit count.

In Field Fruit Sizing Using A Smart Phone Application.

In field (on tree) fruit sizing has value in assessing crop health and for yield estimation. As the mobile phone is a sensor and communication rich device carried by almost all farm staff, an Android application ("FruitSize") was developed for measurement of fruit size in field using the phone camera, with a typical assessment rate of 240 fruit per hour achieved. The application was based on imaging of fruit against a backboard with a scale using a mobile phone, with operational limits set on camera to object plane angle and camera to object distance. Image processing and object segmentation techniques available in the OpenCV library were used to segment the fruit from background in images to obtain fruit sizes. Phone camera parameters were accessed to allow calculation of fruit size, with camera to fruit perimeter distance obtained from fruit allometric relationships between fruit thickness and width. Phone geolocation data was also accessed, allowing for mapping fruits of data. Under controlled lighting, RMSEs of 3.4, 3.8, 2.4, and 2.0 mm were achieved in estimation of avocado, mandarin, navel orange, and apple fruit diameter, respectively. For mango fruit, RMSEs of 5.3 and 3.7 mm were achieved on length and width, benchmarked to manual caliper measurements, under controlled lighting, and RMSEs of 5.5 and 4.6 mm were obtained in-field under ambient lighting.

Folic Acid Has a Protective Effect on Retinal Vascular Endothelial Cells against High Glucose.

Diabetic retinopathy (DR) is a severe complication of diabetes, which seriously affects the life quality of patients. Because of the damage caused by DR, there is an urgent need to develop effective drugs. Folic acid, a water-soluble vitamin, is one of the vitamin B complexes. Folic acid is widely found in the meat and vegetables. In the clinic, low folic acid levels in the body may have a certain correlation with DR. However, there is no relevant basic research proving a relationship between folic acid levels and DR. The purpose of this study was therefore to investigate whether folic acid has a protective effect on the retinal vascular endothelial cells against high glucose levels. Moreover, the molecular mechanism of action of folic acid was further explored. The results showed that folic acid significantly suppressed the cell viability, tube length, migrated cells and the percentage of BrdU⁺ cells compared with the high glucose group. Moreover, folic acid decreased the mRNA expression of TEAD1 and the protein expression of TEAD1 and YAP1. These findings indicate that folic acid can protect retinal vascular endothelial cells from high glucose-induced injury by regulating the proteins in the Hippo signaling pathway.

The Hippo signaling pathway: a potential therapeutic target is reversed by a Chinese patent drug in rats with diabetic retinopathy.

BACKGROUND: The Hippo signaling pathway is reported to be involved in angiogenesis, but the roles of the Hippo pathway in diabetic retinopathy have not been addressed. Fufang Xueshuantong Capsule has been used to treat diabetic retinopathy in China; however, the effect of Fufang Xueshuantong Capsule on the Hippo pathway has not been investigated. METHODS: In this study, diabetes was induced in Sprague-Dawley rats with intraperitoneal injection of streptozotocin. Twenty weeks later, Fufang Xueshuantong Capsule was administered for 12 weeks. When the administration ended, the eyes were isolated for western blot and immunohistochemistry analyses. The levels of P- mammalian sterile 20-like (MST), large tumor suppressor homolog (Lats), P- yes-associated protein (YAP), transcriptional co-activator with PDZ binding motif (TAZ) and TEA domain family members (TEAD) were measured. RESULTS: Diabetic rats had a decreased P-MST level in the inner plexiform layer and reduced expression of P-YAP in the photoreceptor layers of their eyes. In addition, diabetic rats displayed remarkable increases in Lats, TAZ and TEAD in their retinas. Furthermore, Fufang Xueshuantong Capsule restored the changes in the Hippo pathway. CONCLUSIONS: The Hippo signaling pathway is important for the progression of diabetic retinopathy and will hopefully be a targeted therapeutic approach for the prevention of diabetic retinopathy.

On-Tree Mango Fruit Size Estimation Using RGB-D Images.

In-field mango fruit sizing is useful for estimation of fruit maturation and size distribution, informing the decision to harvest, harvest resourcing (e.g., tray insert sizes), and marketing. In-field machine vision imaging has been used for fruit count, but assessment of fruit size from images also requires estimation of camera-to-fruit distance. Low cost examples of three technologies for assessment of camera to fruit distance were assessed: a RGB-D (depth) camera, a stereo vision camera and a Time of Flight (ToF) laser rangefinder. The RGB-D camera was recommended on cost and performance, although it functioned poorly in direct sunlight. The RGB-D camera was calibrated, and depth information matched to the RGB image. To detect fruit, a cascade detection with histogram of oriented gradients (HOG) feature was used, then Otsu's method, followed by color thresholding was applied in the CIE L*a*b* color space to remove background objects (leaves, branches etc.). A one-dimensional (1D) filter was developed to remove the fruit pedicles, and an ellipse fitting method employed to identify well-separated fruit. Finally, fruit lineal dimensions were calculated using the RGB-D depth information, fruit image size and the thin lens formula. A Root Mean Square Error (RMSE) = 4.9 and 4.3 mm was achieved for estimated fruit length and width, respectively, relative to manual measurement, for which repeated human measures were characterized by a standard deviation of 1.2 mm. In conclusion, the RGB-D method for rapid in-field mango fruit size estimation is practical in terms of cost and ease of use, but cannot be used in direct intense sunshine. We believe this work represents the first practical implementation of machine vision fruit sizing in field, with practicality gauged in terms of cost and simplicity of operation.

The prognostic value of CXC-chemokine receptor 2 (CXCR2) in gastric cancer patients.

BACKGROUND: CXC chemokine receptor 2 (CXCR2) has been reported to play an important role in the proliferation and invasion of gastric cancer cells. The present study aims to investigate the impact of CXCR2 expression on the overall survival (OS) of gastric cancer patients after radical resection. METHODS: Intratumoral CXCR2 expression was evaluated with immunohistochemistry on tissue microarrays containing tumor samples of 357 gastric cancer patients from a single center. CXCR2 expression levels were correlated to clinicopathological variables and OS. RESULTS: CXCR2 expression was mainly located in the cytoplasm of gastric carcinoma cells. High CXCR2 expression was associated with poor tumor differentiation (p = 0.021), increased tumor depth (p < 0.001), lymph node metastasis (p < 0.001), advanced TNM stage (p < 0.001) and short OS (p = 0.001). CXCR2 expression was an independent prognostic factor for OS (p = 0.001) in multivariate analysis, and could be combined with TNM stage to generate a predictive nomogram for clinical outcome in patients with gastric cancer. CONCLUSION: Intratumoral CXCR2 expression is a novel independent predictor for survival in gastric cancer patients. CXCR2 might be a promising therapeutic target of postoperative adjuvant treatment.

Development of a liquid chromatography-mass spectrometry method for determination of agrimol B in rat plasma: application to preclinical pharmacokinetics.

A sensitive and accurate liquid chromatography coupled with mass spectrometry (LC-MS) method was developed for the determination of agrimol B, a main active ingredient isolated from Agrimonia pilosa Ledeb., in rat plasma. Chromatographic separation was achieved on a Zorbax CN column (150 × 4.6 mm, 5 µm), with isocratic elution consisting of acetonitrile and water (15:85, v/v) at a flow rate of 0.6 mL/min. Agrimol B and dryocrassin ABBA, an internal standard (IS), were analyzed by selected ion monitoring at m/z transitions of 681.3 and 819.4, respectively. This assay exhibited a good linearity with a correlation coefficient >0.99 and showed no endogenous interference with the analyte and IS. The limit of quantification of agrimol B was 8.025 ng/mL with acceptable precision and accuracy. The method was successfully applied in the pharmacokinetic study of agrimol B in rats after intravenous (1 mg/kg) and oral (2, 5 and 10 mg/kg) doses of agrimol B. The absolute bioavailability of agrimol B was 16.4-18.0% in rat. Our study clarifies the pharmacokinetic behavior of agrimol B in animals.

DDQ-mediated oxidative coupling: an approach to 2,3-dicyanofuran (thiophene).

A facile oxidative coupling of α-carbonyl radicals to 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) for the synthesis of 2,3-dicyanofurans and thiophenes starting from readily available ß-diketones, simple ketones, and ß-keto thioamides in up to 95% yield in one step was developed. Mechanistic investigations revealed that a radical process could be involved in this transformation, and a water promoted C-C bond cleavage pathway is proposed for the formation of 2,3-dicyanofurans and thiophenes.

Direct synthesis of polysubstituted 2-aminothiophenes by Cu(II)-catalyzed addition/oxidative cyclization of alkynoates with thioamides.

A facile and direct synthetic method was developed for the construction of structurally important 2-aminothiophenes in moderate to excellent yields (up to 91%), via Cu(II)-catalyzed addition/oxidative cyclization of readily available thioamides with alkynoates under an air atmosphere.