Acylcarnitines promote gallbladder cancer metastasis through lncBCL2L11-THOC5-JNK axis.

BACKGROUND: The progression of gallbladder cancer (GBC) is accompanied by abnormal fatty acid ß-oxidation (FAO) metabolism. Different types of lipids perform various biological functions. This study aimed to determine the role of acyl carnitines in the molecular mechanisms of GBC progression. METHODS: Distribution of lipids in GBC was described by LC-MS-based lipidomics. Cellular localization, expression level and full-length of lncBCL2L11 were detected using fluorescence in situ hybridization (FISH) assays, subcellular fractionation assay and 5' and 3' rapid amplification of the cDNA ends (RACE), respectively. In vitro and in vivo experiments were used to verify the biological function of lncBCL2L11 in GBC cells. Methylated RNA Immunoprecipitation (MeRIP) was performed to detect the methylation levels of lncBCL2L11. RNA pull-down assay and RNA immunoprecipitation (RIP) assay were used to identify lncBCL2L11 interacting proteins. Co-Immunoprecipitation (Co-IP) and Western blot assay were performed to validate the regulatory mechanism of lncBCL2L11 and THO complex. RESULTS: Acylcarnitines were significantly up-regulated in GBC tissues. High serum triglycerides correlated to decreased survival in GBC patients and promoted tumor migration. LncBCL2L11 was identified in the joint analysis of highly metastatic cells and RNA sequencing data. LncBCl2L11 prevented the binding of THOC6 and THOC5 and causes the degradation of THOC5, thus promoting the accumulation of acylcarnitines in GBC cells, leading to the malignant progression of cancer cells. In addition, highly expressed acylcarnitines stabilized the expression of lncBCL2L11 through N6-methyladenosine methylation (m6A), forming a positive feedback regulation in tumor dissemination. CONCLUSIONS: LncBCL2L11 is involved in gallbladder cancer metastasis through FAO metabolism. High lipid intake is associated with poor prognosis of GBC. Therefore, targeting lncBCL2L11 and its pathway-related proteins or reducing lipid intake may be significant for the treatment of GBC patients.

Boron-Intercalation Engineering toward Defected 1T Phase-Rich MoBxS2-x-Supported IrOx Clusters for Acidic OER.

The construction of supported Ir-based catalysts can effectively reduce the amount of Ir and generate a synergistic effect that enhances the oxygen evolution reaction (OER) activity and stability, making it one of the effective solutions for optimizing acidic OER catalysts. However, most reported metal oxide supports suffer from poor acid resistance and low electrical conductivity, which are critical for the OER process. Herein, we synthesized a nanosheet-like defected 1T phase-rich MoBxS2-x via a molten salt calcination process, during which the 1T phase was formed, and B was intercalated into MoS2 to protect the 1T phase structure during annealing procedure. After the wet refluxing process, IrOx clusters were uniformly deposited on the surface of MoBxS2-x to form IrOx@MoBxS2-x, which exhibited an overpotential of 168 mV at a current density of 10 mA cm-2 with an Ir loading amount of 25.8 wt %. By comparing the OER performance of IrOx@MoBxS2-x, IrOx@MoS2(Calcinated), and IrOx@MoS2, it is demonstrated that calcination and B intercalation of MoS2 can significantly increase acidic OER performance. This work digs into the application of 1T-MoS2 as an OER catalyst support, providing strategies for the phase and morphology control of 1T-MoS2.

Theoretical Investigation and Molecular Design: A Series of Tripod-Type Cu(I) Blue Light Thermally Activated Delayed Fluorescence Materials.

The photophysical properties and luminescent mechanism of a series of tripod-type Cu(I) complexes in solution and solids were comprehensively investigated through theoretical simulations. From a microscopic perspective, the experimental phenomenon is explained: (1) The intrinsic reason for the quenching of complex 1 in solution was attributed to the significant nonradiative transition caused by structural deformation; (2) In the solid, the reduced ΔEST for complex 2 effectively facilitate reverse intersystem crossing (RISC) and improves its luminescence efficiency; (3) The enhanced performance of complex 3 in solution is attributed to that its stronger steric hindrance is advantageous to decrease not only the ΔEST but also the reorganization energy through intramolecular weak interactions. Based on complex 3, the tert-butyl substituted isomeric complex 4 was designed. Complex 4 further amplifies the advantages of 3 to further promote the RISC to make full use of excitons. Meanwhile, it has an emission wavelength of 462.6 nm, which makes it an excellent candidate for high-efficiency deep-blue TADF materials. This study provides valuable information for obtaining efficient blue phosphorescence and TADF dual-channel luminescent materials.

A simple and sensitive LC-MS/MS method for the determination of loganic acid in rat plasma and its pharmacokinetic analysis.

Loganic acid is an iridoid compound extracted from Gentianaceae plant Gentiana macrophylla Pall. It can effectively inhibit inflammation and tumor migration and has antioxidant activity. In this paper, we establish a simple, fast, sensitive and validated LC-MS method with the purpose of quantification of loganic acid in rat plasma with gliclazide as an internal standard (IS). Methanol was used to precipitate the protein in the plasma sample, and a C18 column (2.1 × 50 mm, 1.7 µm) was used for the separation of the target compound. Meanwhile, 0.1% formic acid water-methanol was employed as the mobile phase. Multiple reaction monitoring detection mode was adopted in detection with m/z 375.1 > 213.2 for loganic acid and m/z 322.1 > 169.9 for the IS, respectively, in negative ion scan mode. The linear range of calibration curve was 5.77-11,540.00 ng/ml, and the lower limit of detedtion was 2.89 ng/ml. The inter-day and intra-day precision and accuracy were <15% for lower limit of quantitation, low, middle and high quality control samples. This method was successfully used for the pharmacokinetic study of loganic acid in rat plasma at a dose range of 50-150 mg/kg for oral administration and 2 mg/kg for intravenous administration. The pharmacokinetic results showed that the oral bioavailability of loganic acid was low (2.71-5.58%).

Integrating artificial intelligence (S-Detect software) and contrast-enhanced ultrasound for enhanced diagnosis of thyroid nodules: A comprehensive evaluation study.

PURPOSE: This study aims to assess the diagnostic efficacy of Korean Thyroid imaging reporting and data system (K-TIRADS), S-Detect software and contrast-enhanced ultrasound (CEUS) when employed individually, as well as their combined application, for the evaluation of thyroid nodules, with the objective of identifying the optimal method for diagnosing thyroid nodules. METHODS: Two hundred and sixty eight cases pathologically proven of thyroid nodules were retrospectively enrolled. Each nodule was classified according to K-TIRADS. S-Detect software was utilized for intelligent analysis. CEUS was employed to acquire contrast-enhanced features. RESULTS: The area under curve (AUC) values for diagnosing benign and malignant thyroid nodules using K-TIRADS alone, S-Detect software alone, CEUS alone, the combined application of K-TIRADS and CEUS, the combined application of S-Detect software and CEUS were 0.668, 0.668, 0.719, 0.741, and 0.759, respectively (p < 0.001). The sensitivity rate of S-Detect software was 89.9% (p < 0.001). It was the highest of the five diagnostic methods above. CONCLUSION: The utilization of S-Detect software can be served as a powerful tool for early screening. Notably, the combined utilization of S-Detect software with CEUS demonstrates superior diagnostic performance compared to employing K-TIRADS, S-Detect software, CEUS used individually, as well as the combined application of K-TIRADS with CEUS.

[Main nutritional components of food herbs in mountainous areas of Guizhou Province].

OBJECTIVE: To investigate the nutritional content of edible medicinal materials in mountainous areas of Guizhou Province and compare the comprehensive nutritional value of different varieties. METHODS: A total of 15 kinds of edible herbs were collected from Guizhou Province. According to the national standard, direct drying method, Kjeldahl nitrogen determination method, Soxhlet extraction method, high performance liquid chromatography, inductively coupled plasma mass spectrometry and other detection method were used to determine the content of general nutrients, fat soluble vitamins, minerals and ash. According to the weight ranking of nutritional indexes in principal component analysis and membership function analysis, the quality of 9 kinds of food and drug substances and 6 kinds of Chinese medicinal materials were evaluated and ranked. RESULTS: The eigenvalues of the first 4 principal components were greater than 1, and the cumulative contribution rate was 82.32%. Compared with membership function analysis, the top 5 in comprehensive evaluation were Eucommia, Epimedium and honeysuckle, all of which were food and drug substances. The contents of calcium(851.69 mg/100 g), phosphorus(270.22 mg/100 g) and potassium(1446.48 mg/100 g) were the highest. The contents of carotene(21 963.87 µg/100 g) and vitamin E(57.82 mg/100 g) were the highest in the fat-soluble vitamins of Herbimedium. The contents of various indexes of honeysuckle were relatively high. CONCLUSION: Food and pharmaceutical substances have both medicinal value and nutritional value, and the overall nutritional benefit is higher than that of Chinese medicinal materials.

Self-Consistent Quantum Mechanics/Embedded Charge Study on Aggregation-Enhanced Delayed Fluorescence of Cu(I) Complexes: Luminescence Mechanism and Molecular Design Strategy.

To elucidate the luminescence mechanism of highly efficient blue Cu(N^N)(POP)+-type thermally activated delayed fluorescence (TADF) materials, we have selected Cu(pytfmpz)(POP)+ (1) and Cu(pympz)(POP)+ (2) as targets to investigate the photophysical properties in both solution and solid phases. The self-consistent electrostatic potential (ESP) embedded charge within the quantum mechanics/molecular mechanics (QM/MM) method demonstrates a greater advantage over the charge equilibrium (QEQ) in accurately calculating atomic charges and reasonably describing the polarization effect, ultimately resulting in a favorable consistency between simulation and experimental measurements. After systematic and quantitative simulation, it has been found that complex 2, with an electron-donating group of -CH3, exhibits a much more blue-shifted spectrum and a significantly enhanced efficiency in comparison to complex 1 with -CF3. This is due to the widened HOMO-LUMO gap as well as the narrowed energy gap between the lowest singlet and triplet excited states (ΔEST), respectively. Then, the designed complex 3 is introduced with a stronger electron donor and larger tert-butyl group, which plays a key role in simultaneously suppressing the structural distortion and reducing the ΔEST. This leads to a faster reverse intersystem crossing process than that of the two experimental complexes in solution, turning out to be a new deep-blue-emitting material with excellent TADF performance.

Molecular Design of Highly Efficient Heavy-Atom-free NpImidazole Derivatives for Two-Photon Photodynamic Therapy and ClO- Detection.

Two-photon photodynamic therapy (TP-PDT), as a treatment technology with deep penetration and less damage, provides a broad prospect for cancer treatment. Nowadays, the development of TP-PDT suffers from the low two-photon absorption (TPA) intensity and short triplet state lifetime of photosensitizers (PSs) used in TP-PDT. Herein, we propose some novel modification strategies based on the thionated NpImidazole (the combination of naphthalimide and imidazole) derivatives to make efforts on those issues and obtain corresponding fluorescent probes for detecting ClO- and excellent PSs for TP-PDT. Density functional theory (DFT) and time-dependent DFT (TD-DFT) are used to help us characterize the photophysical properties and TP-PDT process of the newly designed compounds. Our results show that the introduction of different electron-donating groups at the position 4 of NpImidazole can effectively improve their TPA and emission properties. Specifically, 3s with a N,N-dimethylamino group has a large triplet state lifetime (τ = 699 µs) and TPA cross section value (δTPA = 314 GM), which can effectively achieve TP-PDT; additionally, 4s (with electron-donating group 2-oxa-6-azaspiro[3.3]heptane in NpImidazole) effectively realizes the dual-function of a PS for TP-PDT (τ = 25,122 µs, δTPA = 351 GM) and a fluorescent probe for detecting ClO- (Φf = 29% of the product 4o). Moreover, an important problem is clarified from a microscopic perspective, that is, why the transition property of 3s and 4s (1π-π*) from S1 to S0 is different from that of 1s and 2s (1n-π*). It is hoped that our work can provides valuable theoretical clues for the design and synthesis of heavy-atom-free NpImidazole-based PSs and fluorescent probes for the detection of hypochlorite.

Effect of different hemodialysis modalities on hepcidin clearance in patients undergoing maintenance hemodialysis.

INTRODUCTION: Hepcidin is a master regulator of iron utilization and takes part in the pathophysiology of anemia in maintenance hemodialysis (MHD) patients. Hepcidin is a moderate-molecular-weight substance and partially binds to plasma proteins in the circulation, which theoretically might be removed efficiently by hemoperfusion (HP). This study aimed to compare the effect of different dialysis modalities on hepcidin removal and discuss its effect on the iron and anemia status in MHD patients. MATERIALS AND METHODS: In a longitudinal interventional study of 26 stable MHD patients, the serum hepcidin, ß2-microglobulin (ß2-MG), and intact parathyroid hormone (iPTH) were measured before and after one treatment session of hemodialysis (HD), hemodiafiltration (HDF), HD + HP, and HDF + HP, separately. One-way analysis of variance (ANOVA) was used to identify the effect of dialysis modalities on the intra-dialysis clearance ratios. RESULTS: The combined dialysis modalities (HD + HP and HDF + HP) achieved greater clearance ratios of serum hepcidin than HD and HDF alone, HD + HP vs. HD (16 ± 15% vs. 4 ± 13%, p < 0.001), HDF + HP vs. HDF (18 ± 5% vs. 10 ± 13%, p = 0.0036). Similarly, the combined dialysis modalities also performed better than HD and HDF alone in removing ß2-MG. There was no significant difference in iPTH clearance among these four modalities, except that HDF + HP achieved a greater clearance ratio than HD. Furthermore, the anemia was improved after the 6-month treatment with regular HD/HDF plus HP, which was indicated by increasing hemoglobin (p = 0.0004) and reduction of erythropoiesis-stimulating agents (ESAs) resistance index (ERI) (p = 0.0431). CONCLUSIONS: Our findings suggest that the combined dialysis modalities of HD/HDF plus HP could achieve better clearance ratios of hepcidin than HD/HDF alone, thereby, might improve iron utilization, and benefit anemia management in MHD patients. Further studies with larger sample-size patients and longer follow-up duration are still needed.

Nanoconfined Crystallization in Poly(lactic acid) (PLA) and Poly(ethylene terephthalate) (PET) Induced by Various Forms of Premelt-Deformation.

The processing-structure-property relationship using poly(lactic acid) (PLA) and poly(ethylene terephthalate) (PET) is explored. Specifically, both pre-extension and preshear of amorphous PLA and PET above their glass transition temperatures Tg , carried out in the affine deformation limit, can induce a specific type of cold crystallization during annealing, i.e., nanoconfined crystallization (NCC) where crystal sizes are limited to a nanoscopic scale in all dimensions so as to render the processed PLA and PET optically transparent. The new polymer structure after premelt deformation can show considerably enhanced mechanical properties. For example, premelt stretching produces geometric condensation of the chain network. This structural alternation can profoundly change the mechanical characteristics, e.g., turning brittle PLA ductile. In contrast, after preshear of amorphous PLA above Tg , the NCC containing PLA remains brittle, showing the importance to have geometric condensation from processing. Both AFM imaging and SAXS measurements are performed to verify that premelt deformation of PLA and PET indeed results in NCC from annealing that permits the strain-induced cold crystallization to take place on the length scale of the mesh size of the deformed chain network.

Theoretical study of the tuning role of ß-methylthio or ß-methylselenyl on the charge-transport properties of acenedithiophenes derivatives.

To date, the manipulation of intermolecular nonconjugation interactions in organic crystals is still a great challenge due to the complexity of weak intermolecular interactions. Here we designed molecules substituted by ß-methylselenyl on naphtho[1,2-b:5,6-b']dithiophene and anthra[2,3-b:6,7-b']dithiophene, respectively (anti-ß-MS-NDT, anti-ß-MS-ADT), which together with anti-ß-MS-BDT synthesized experimentally all exhibited 2D brickwork π-stacking. Moreover, their maximum molecular carrier mobilities reached 3.30 and 16.46 cm2 V-1 s-1. These results indicated that the substitution of ß-methylselenyl could be a strategy to directionally adjust the parent herringbone stacking into 2D brickwork π-stacking. Hirshfeld surface analysis and symmetry-adapted perturbation theory (SAPT) were used to investigate the nonconjugated interactions in the pitched π-stacking formed by the ß-methylthio-substituted acenedithiophene derivatives and the 2D brickwork π-stacking of the ß-methylselenyl-substituted ones; wherein, the steric hindrance caused by the introduction of the substituents promoted Csp2-Csp2⋯π interactions to replace Csp2-H⋯π to stabilize the face-to-face stacking. Moreover, by calculating the decomposition energy of the intermediate state model of the molecular stacking mode that may exist in the replacement conversion process, it was found that the energy of this intermediate state was larger than that of the actual ones, finally confirming the inevitability of the actual existence in this stacking. In addition, because of the reduction in intensity of the special vibration modes, it could be found that the ß-methylselenyl substitution showed better phonon assistance than ß-methylthio substitution in terms of dynamic disorder. This study is a further step toward fully understanding the relationship between intermolecular interactions and regulation of the molecular stacking.

Nomograms for the prediction of decannulation in patients with neurological injury: a study based on clinical practice.

BACKGROUND: Rational prediction of the probability of decannulation in tracheotomy patients is of great importance to clinicians and patients' families. This study aimed to develop a prediction model for decannulation in tracheotomized patients with neurological injury using routine clinical data and blood tests. METHODS: We developed a prediction model based on 186 tracheotomized patients, and data were collected from January 2018 to March 2021. The least absolute shrinkage and selection operator (LASSO) regression model was used to optimize feature selection for the decannulation risk model. The performance of the prediction model was evaluated in terms of discrimination, calibration, and clinical utility using measures such as C-index, calibration plot, and decision curve analysis (DCA). Internal validation was performed through bootstrapping validation. RESULTS: A total of 66.13% (123/186) of patients were decannulated. Predictors included in the prediction nomogram were age, gender, subtype of neurological injury, Glasgow Coma Scale (GCS) score, swallowing function, duration of tracheotomy, procalcitonin (PCT) level, white blood cell (WBC) count, and serum albumin (ALB) level. The predictive model showed good discrimination, with a C-index of 0.755 (95% confidence interval: 0.68-0.83). Internal validation also confirmed a satisfactory C-index of 0.690. The DCA indicated that the nomogram added substantial value in predicting decannulation risk for patients with threshold probabilities falling between >21% and <98% compared to the existing scheme. CONCLUSIONS: This predictive model serves as a valuable instrument for clinicians to quantitatively assess the probability of decannulation in patients with neurological injury, aiding in informed decision-making and patient management.

JAC4 Inhibits EGFR-Driven Lung Adenocarcinoma Growth and Metastasis through CTBP1-Mediated JWA/AMPK/NEDD4L/EGFR Axis.

Lung adenocarcinoma (LUAD) is the most common lung cancer, with high mortality. As a tumor-suppressor gene, JWA plays an important role in blocking pan-tumor progression. JAC4, a small molecular-compound agonist, transcriptionally activates JWA expression both in vivo and in vitro. However, the direct target and the anticancer mechanism of JAC4 in LUAD have not been elucidated. Public transcriptome and proteome data sets were used to analyze the relationship between JWA expression and patient survival in LUAD. The anticancer activities of JAC4 were determined through in vitro and in vivo assays. The molecular mechanism of JAC4 was assessed by Western blot, quantitative real-time PCR (qRT-PCR), immunofluorescence (IF), ubiquitination assay, co-immunoprecipitation, and mass spectrometry (MS). Cellular thermal shift and molecule-docking assays were used for confirmation of the interactions between JAC4/CTBP1 and AMPK/NEDD4L. JWA was downregulated in LUAD tissues. Higher expression of JWA was associated with a better prognosis of LUAD. JAC4 inhibited LUAD cell proliferation and migration in both in-vitro and in-vivo models. Mechanistically, JAC4 increased the stability of NEDD4L through AMPK-mediated phosphorylation at Thr367. The WW domain of NEDD4L, an E3 ubiquitin ligase, interacted with EGFR, thus promoting ubiquitination at K716 and the subsequent degradation of EGFR. Importantly, the combination of JAC4 and AZD9191 synergistically inhibited the growth and metastasis of EGFR-mutant lung cancer in both subcutaneous and orthotopic NSCLC xenografts. Furthermore, direct binding of JAC4 to CTBP1 blocked nuclear translocation of CTBP1 and then removed its transcriptional suppression on the JWA gene. The small-molecule JWA agonist JAC4 plays a therapeutic role in EGFR-driven LUAD growth and metastasis through the CTBP1-mediated JWA/AMPK/NEDD4L/EGFR axis.

Hierarchical Pt-In Nanowires for Efficient Methanol Oxidation Electrocatalysis.

Direct methanol fuel cells (DMFC) have attracted increasing research interest recently; however, their output performance is severely hindered by the sluggish kinetics of the methanol oxidation reaction (MOR) at the anode. Herein, unique hierarchical Pt-In NWs with uneven surface and abundant high-index facets are developed as efficient MOR electrocatalysts in acidic electrolytes. The developed hierarchical Pt89In11 NWs exhibit high MOR mass activity and specific activity of 1.42 A mgPt-1 and 6.2 mA cm-2, which are 5.2 and 14.4 times those of Pt/C, respectively, outperforming most of the reported MORs. In chronoamperometry tests, the hierarchical Pt89In11 NWs demonstrate a longer half-life time than Pt/C, suggesting the better CO tolerance of Pt89In11 NWs. After stability, the MOR activity can be recovered by cycling. XPS, CV measurement and CO stripping voltammetry measurements demonstrate that the outstanding catalytic activity may be attributed to the facile removal of CO due to the presence of In site-adsorbing hydroxyl species.

CNN-based neural network model for amplified laser pulse temporal shape prediction with dynamic requirement in high-power laser facility.

The temporal shape of laser pulses is one of the essential performances in the inertial confinement fusion (ICF) facility. Due to the complexity and instability of the laser propagation system, it is hard to predict the pulse shapes precisely by pure analytic methods based on the physical model [Frantz-Nodvik (F-N) equation]. Here, we present a data-driven model based on a convolutional neural network (CNN) for precise prediction. The neural network model introduces sixteen parameters neglected in the F-N equation based models to expand the representation dimension. The sensitivity analysis of the experimental results confirms that these parameters have different degrees of influence on the temporal output shapes and cannot be ignored. The network characterizes the whole physical process with commonality and specificity features to improve the description ability. The prediction accuracy evaluated by a root mean square of the proposed model is 7.93%, which is better compared to three optimized physical models. This study explores a nonanalytic methodology of combining prior physical knowledge with data-driven models to map the complex physical process by numerical models, which has strong representation capability and great potential to model other measurable processes in physical science.

OLA1 promotes colorectal cancer tumorigenesis by activation of HIF1α/CA9 axis.

BACKGROUND: Obg-like ATPase 1 (OLA1) is a highly conserved GTPase, which was over expressed in a variety of malignant tumors, but its role in colorectal cancer (CRC) was poorly studied. PATIENTS AND METHODS: Three public CRC gene databases were applied for OLA1 mRNA expression detection. The clinical data of 111 CRC patients were retrospectively collected from the Second Affiliated Hospital of Zhejiang University (SAHZU) for OLA1 protein expression and Kaplan-Meier Survival analysis. OLA1 stably knocked out CRC cell lines were conducted by CRISPR-Cas9 for experiments in vitro and in vivo. RESULTS: OLA1 was highly expressed in 84% CRC compared to matched surrounding tissues. Patients with OLA1 high expression had a significantly lower 5-year survival rate (47%) than those with OLA1 low expression (75%). OLA1 high expression was an independent factor of poor prognosis in CRC patients. OLA1-KO CRC cell lines showed lower ability of growth and tumorigenesis in vitro and in vivo. By mRNA sequence analysis, we found 113 differential express genes in OLA1-KO cell lines, of which 63 were hypoxic related. HIF1α was a key molecule in hypoxic regulation. Further molecular mechanisms showed HIF1α /CA9 mRNA and/or protein levels were heavily downregulated in OLA1-KO cell lines, which could explain the impaired tumorigenesis. According to previous studies, HIF1α was a downstream gene of GSK3ß, we verified GSK3ß was over-activated in OLA1-KO cell lines. CONCLUSION: OLA1 was a new gene that was associated with carcinogenesis and poor outcomes in CRC by activation of HIF1α/CA9 axis, which may be interpreted by GSK3ß.

Photophysical Exploration of Zn(II) Polypyridine Photosensitizers in Two-Photon Photodynamic Therapy: Insights from Theory.

The high incidence and difficulties of treatment of cancer have always been a challenge for mankind. Two-photon photodynamic therapy (TP-PDT) as a less invasive technique provides a new perspective for tumor treatment due to its low-energy near-infrared excitation, high targeting, and minor damage. At present, the emerging metal complexes used as the photosensitizers (PSs) in TP-PDT have aroused great interest. However, most metal complexes as PSs in TP-PDT still face some problems, such as slow clearance, unsatisfactory two-photon absorption (TPA) characteristics, high price, low reactivity, and poor solubility. In this work, density functional theory and time-dependent density functional theory were used to characterize the one/two-photon response, solvation free energy, and lipophilicity of a series of novel PSs applied in TP-PDT. The results suggest that based on complex 1, replacing Ru(II) center with Zn(II) (complex 2) can effectively prolong the triplet excited state lifetime while reducing the cost and environmental pollution, and the azetidine heterospirocycles were introduced into the ligand scaffold (complex 3), which effectively reduced the vibration relaxation of the ligand group and improved the water solubility; further, the addition of acetylenyl groups subtly enhanced the light absorption and significantly improved the two-photon response (complex 4). In addition, all complexes met the requirement of a PS and could be used as potential candidates for TP-PDT. In particular, complex 4 has the advantages of high solvation free energy, a large TPA cross-section (1413 GM), a long triplet state lifetime (671 µs), good chemical reactivity, and low cost, and it is easy to be scavenged by organisms. Overall, this contribution may provide an important clue to formulate clear design principles for type I/II PSs and rational design of PSs with high intersystem crossing rates, a long lifetime, and therapeutic excitation wavelengths.

tRF-3013b inhibits gallbladder cancer proliferation by targeting TPRG1L.

BACKGROUND: tRNA-derived fragments (tRFs) are newly discovered noncoding RNAs and regulate tumor progression via diverse molecular mechanisms. However, the expression and biofunction of tRFs in gallbladder cancer (GBC) have not been reported yet. METHODS: The expression of tRFs in GBC was detected by tRF and tiRNA sequencing in GBC tissues and adjacent tissues. The biological function of tRFs was investigated by cell proliferation assay, clonal formation assay, cell cycle assay, and xenotransplantation model in GBC cell lines. The molecular mechanism was discovered and verified by transcriptome sequencing, fluorescence in situ hybridization (FISH), target gene site prediction, and RNA binding protein immunoprecipitation (RIP). RESULTS: tRF-3013b was significantly downregulated in GBC compared with para-cancer tissues. Decreased expression of tRF-3013b in GBC patients was correlated with poor overall survival. Dicer regulated the production of tRF-3013b, and its expression was positively correlated with tRF-3013b in GBC tissues. Functional experiments demonstrated that tRF-3013b inhibited GBC cell proliferation and induced cell-cycle arrest. Mechanically, tRF-3013b exerted RNA silencing effect on TPRG1L by binding to AGO3, and then inhibited NF-κB. TPRG1L overexpression could rescue the effects of tRF-3013b on GBC cell proliferation. CONCLUSIONS: This study indicated that Dicer-induced tRF-3013b inhibited GBC proliferation by targeting TPRG1L and repressed NF-κB, pointing to tRF-3013b as a novel potential therapeutic target of GBC.

Prediction models for risk of diabetic kidney disease in Chinese patients with type 2 diabetes mellitus.

BACKGROUND: Diabetic kidney disease (DKD) is a common and serious complication in patients with diabetic mellitus (DM), the risk of cardiovascular events and all-cause mortality also increases in DKD patients. This study aimed to detect the influencing factors of DKD in type 2 DM (T2DM) patients, and construct DKD prediction models and nomogram for clinical decision-making. METHODS: A total of 14,628 patients with T2DM were included. These patients were divided into pre-DKD and non-DKD groups, depending on the occurrence of DKD during a 3-year follow-up from first clinic attendance. The influencing indicators of DKD were analyzed, the prediction models were established by multivariable logistic regression, and a nomogram was drawn for DKD risk assessment. RESULTS: Two prediction models for DKD were built by multivariate logistic regression analysis. Model 1 was created based on 17 variables using the forward selection method, Model 2 was established by 19 variables using the backward elimination method. The Somers' D values of both models were 0.789. Four independent predictors were selected to build the nomogram, including age, UACR, eGFR, and neutrophil percentages. The C-index of the nomogram reached 0.864, suggesting a good predictive accuracy for DKD development. CONCLUSIONS: Our prediction models had strong predictive powers, and our nomogram provided visual aids to DKD risk calculation, which was simple and fast. These algorithms can provide early DKD risk prediction, which might help to improve the medical care for early detection and intervention in T2DM patients, and then consequently improve the prognosis of DM patients.

Transcriptome Analysis of Air Space-Type Variegation Formation in Trifolium pratense.

Air space-type variegation is the most diverse among the species of known variegated leaf plants and is caused by conspicuous intercellular spaces between the epidermal and palisade cells and among the palisade cells at non-green areas. Trifolium pratense, a species in Fabaceae with V-shaped air space-type variegation, was selected to explore the application potential of variegated leaf plants and accumulate basic data on the molecular regulatory mechanism and evolutionary history of leaf variegation. We performed comparative transcriptome analysis on young and adult leaflets of variegated and green plants and identified 43 candidate genes related to air space-type variegation formation. Most of the genes were related to cell-wall structure modification (CESA, CSL, EXP, FLA, PG, PGIP, PLL, PME, RGP, SKS, and XTH family genes), followed by photosynthesis (LHCB subfamily, RBCS, GOX, and AGT family genes), redox (2OG and GSH family genes), and nitrogen metabolism (NodGS family genes). Other genes were related to photooxidation, protein interaction, and protease degradation systems. The downregulated expression of light-responsive LHCB subfamily genes and the upregulated expression of the genes involved in cell-wall structure modification were important conditions for air space-type variegation formation in T. pratense. The upregulated expression of the ubiquitin-protein ligase enzyme (E3)-related genes in the protease degradation systems were conducive to air space-type variegation formation. Because these family genes are necessary for plant growth and development, the mechanism of the leaf variegation formation in T. pratense might be a widely existing regulation in air space-type variegation in nature.