GSH-activable heterotrimeric nano-prodrug for precise synergistic therapy of TNBC.

Combination chemotherapy is an effective approach for triple-negative breast cancer (TNBC) therapy, especially when drugs are administered at specific optimal ratios. However, at present, strategies involving precise and controllable ratios based on effective loading and release of drugs are unavailable. Herein, we designed and synthesized a glutathione (GSH)--responsive heterotrimeric prodrug and formulated it with an amphiphilic polymer to obtain nanoparticles (DSSC2 NPs) for precise synergistic chemotherapy of TNBC. The heterotrimeric prodrug was prepared using docetaxel (DTX) and curcumin (CUR) at the optimal synergistic ratio of 1: 2. DTX and CUR were covalently conjugated by disulfide linkers. Compared with control NPs, DSSC2 NPs had quantitative/ratiometric drug loading, high drug co-loading capacity, better colloidal stability, and less premature drug leakage. After systemic administration, DSSC2 NPs selectively accumulated in tumor tissues and released the encapsulated drugs triggered by high levels of GSH in cancer cells. In vitro and in vivo experiments validated that DSSC2 NPs released DTX and CUR at the predefined ratio and had a highly synergistic therapeutic effect on tumor suppression in TNBC, which can be attributed to ratiometric drug delivery and synchronous drug activation. Altogether, the heterotrimeric prodrug delivery system developed in this study represents an effective and novel approach for combination chemotherapy.

Clinical analysis of a new multifunctional instrument set for gasless endoscopic thyroidectomy with two different approaches.

BACKGROUND: Following the rapid development of endoscopic thyroidectomy techniques, various surgical procedures have been developed (e.g., transoral, submandibular, areolar, axillary, retroauricular, and combined procedures), and each of these procedures has its own advantages. In recent years, gasless endoscopic thyroidectomy has emerged as a feasible procedure, and it has replaced traditional CO2 insufflation approaches because of advantages such as stable cavity construction, pollution reduction, resource saving, and risk reduction. However, each gasless procedure requires special instruments for cavity construction, and this results in enormous wastage of medical resources. In the present study, we introduced a set of instruments developed by our team. This set of instruments is designed to be compatible with the current gasless endoscopic thyroidectomy approaches, including transoral, submandibular, transareolar, transaxillary, retroauricular, combined, and lateral cervical lymph node dissection. Here, we introduced this set of instruments for two gasless endoscopic thyroidectomy procedures (transaxillary and transareolar). Following the incorporation of this set of instruments in regular clinical practice, it could be used for more gasless endoscopic thyroidectomy procedures in the future. OBJECTIVE: To investigate the feasibility, safety, and efficacy of the self-developed instruments for gasless endoscopic thyroidectomy in two different approaches. METHODS: A total of 180 patients diagnosed to have papillary thyroid carcinoma (PTC) between January 2020 and April 2022 were retrospectively investigated. The patients were assigned to a gasless transaxillary group (group A) and a gasless transareolar group (group B). The same gasless endoscopic-assisted instruments were used for both groups. The clinical characteristics, treatment results, and complications were compared between the two groups. RESULTS: All 180 patients were successfully operated. The extent of surgical resection in all patients was the same: "unilateral glandular lobectomy + isthmus combined with ipsilateral central zone lymph node dissection." There were 130 and 50 patients in group A and group B, respectively; one patient in the former group was converted to open surgery due to intraoperative bleeding. No significant difference was observed between the two groups in terms of gender, age, body mass index (BMI), education level, and proportion of concomitant Hashimoto's thyroiditis (P > 0.05). The establishment of cavity time was significantly longer in group A than in group B (35.62 ± 5.07 min vs. 17.46 ± 2.55 min, P < 0.01). The number of lymph nodes cleared was slightly less in group A than in group B (4.06 ± 2.93 vs. 4.52 ± 2.38, P = 0.07). Moreover, the two groups showed no significant differences (P > 0.05) in the total operative time (145.54 ± 45.11 min vs. 143.06 ± 46.70 min), tumor size (0.68 ± 0.46 cm vs. 0.71 ± 0.49 cm), postoperative hospital stay (4.08 ± 1.48 days vs. 3.72 ± 1.07 days), vocal cord paralysis [4 (3.1%) vs. 2 (4%)], postoperative swallowing discomfort [24 (18.5%) vs. 5 (10%)], and postoperative recurrence and satisfaction scores (3.27 ± 1.52 vs. 3.28 ± 1.53). CONCLUSION: Although the two approaches of gasless endoscopic surgery have different operative paths and different time periods for cavity construction, both approaches are similar in terms of the principle of cavity construction, safe and reliable postoperative efficacy, and good cosmetic effect. Therefore, the same set of instruments can be used to complete the surgery in both approaches, thus saving medical resources and facilitating the popularization of this technology.

LncRNA MIR31HG promotes cell proliferation and invasive properties of the MCF-7 cell line by regulation of receptor-interacting serine-threonine kinase 4.

LncRNA MIR31HG is involved in many types of cancers, while its roles in breast cancer are still unknown. The current study aimed to explore the function of lncRNA MIR31HG in breast cancer and the underlying mechanisms. Stable expression cell lines were constructed by using lentivirus particles. MTT assay was used to determine cell viability. Wound healing and Transwell assay were used to determine cell migration and invasion, respectively. The changes in biomarkers were determined by using qPR-PCT and Western blotting, respectively. BALB/c nude mice were used to generate a xenograft mouse model. MIR31HG regulated cell proliferation, migration and invasion in MCF7 cells. Besides, MIR31HG regulated N-Cadherin, Vimentin, and E-Cadherin. MIR31HG positively regulated receptor-interacting serine-threonine kinase 4 (RIPK4), as supported by the fact that knockdown of MIR31HG suppressed RIPK4, and the knockdown of RIPK4 did not affect MIR31HG. Additionally, we found that RIPK4 regulated cell proliferation, migration and invasion in MCF7 cells. The changes in RIPK4 regulated N-Cadherin, Vimentin, and E-Cadherin. Consistently, in vivo studies showed that the knockdown of MIR31HG or RIPK4 reduced tumor size in xenograft animal models. The roles of lncRNA MIR31HG in breast cancer were associated with its regulatory effects against RIPK4.

Aberrant Hippocampal Development in Early-onset Mental Disorders and Promising Interventions: Evidence from a Translational Study.

Early-onset mental disorders are associated with disrupted neurodevelopmental processes during adolescence. The methylazoxymethanol acetate (MAM) animal model, in which disruption in neurodevelopmental processes is induced, mimics the abnormal neurodevelopment associated with early-onset mental disorders from an etiological perspective. We conducted longitudinal structural magnetic resonance imaging (MRI) scans during childhood, adolescence, and adulthood in MAM rats to identify specific brain regions and critical windows for intervention. Then, the effect of repetitive transcranial magnetic stimulation (rTMS) intervention on the target brain region during the critical window was investigated. In addition, the efficacy of this intervention paradigm was tested in a group of adolescent patients with early-onset mental disorders (diagnosed with major depressive disorder or bipolar disorder) to evaluate its clinical translational potential. The results demonstrated that, compared to the control group, the MAM rats exhibited significantly lower striatal volume from childhood to adulthood (all P <0.001). In contrast, the volume of the hippocampus did not show significant differences during childhood (P >0.05) but was significantly lower than the control group from adolescence to adulthood (both P <0.001). Subsequently, rTMS was applied to the occipital cortex, which is anatomically connected to the hippocampus, in the MAM models during adolescence. The MAM-rTMS group showed a significant increase in hippocampal volume compared to the MAM-sham group (P <0.01), while the volume of the striatum remained unchanged (P >0.05). In the clinical trial, adolescents with early-onset mental disorders showed a significant increase in hippocampal volume after rTMS treatment compared to baseline (P <0.01), and these volumetric changes were associated with improvement in depressive symptoms (r = - 0.524, P = 0.018). These findings highlight the potential of targeting aberrant hippocampal development during adolescence as a viable intervention for early-onset mental disorders with neurodevelopmental etiology as well as the promise of rTMS as a therapeutic approach for mitigating aberrant neurodevelopmental processes and alleviating clinical symptoms.

A novel Bayesian ensembling model for wind power forecasting.

Precise and robust wind power prediction can effectively alleviate the problem caused by the randomness and volatility of wind power. Ensemble learning can successfully improve forecasting precision and robustness, and quantify the uncertainty of the prediction. This paper presents a new ensemble probabilistic forecasting framework, based on modified randomized maximum a posteriori (MAP) sampling technique, echo state network (ESN) and generalized mixture (GM) function to bring superior forecasting results. The proposed model first trains a set of independent ESN models for probabilistic forecasting using the modified randomized MAP sampling technique, and then dynamically weighs and ensembles the base model forecasting through the GM function. The proposed model and other benchmark models have been implemented on four wind power datasets from different places to illustrate the advantage of the proposed method. The compared result indicates that the suggested model outperforms some state-of-the-art models and can successfully achieve dynamic ensemble probabilistic prediction.

Research on Wind Power Short-Term Forecasting Method Based on Temporal Convolutional Neural Network and Variational Modal Decomposition.

Wind energy reserves are large worldwide, but their randomness and volatility hinder wind power development. To promote the utilization of wind energy and improve the accuracy of wind power prediction, we comprehensively consider the influence of wind farm environmental factors and historical power on wind power generation. This paper presents a short-term wind power prediction model based on time convolution neural network (TCN) and variational mode decomposition (VMD). First, due to the non-smooth characteristics of the wind farm environmental data, this paper uses VMD to decompose the data of each environmental variable to reduce the influence of the random noise of the data on the prediction model. Then, the modal components with rich feature information are extracted according to the Pearson correlation coefficient and Maximal information coefficient (MIC) between each modal component and the power. Thirdly, a prediction model based on TCN is trained according to the preferred modal components and historical power data to achieve accurate short-term wind power prediction. In this paper, the model is trained and tested with a public wind power dataset provided by the Spanish Power Company. The simulation results show that the model has higher prediction accuracy, with MAPE and R2 are 2.79% and 0.9985, respectively. Compared with the conventional long short-term neural network (LSTM) model, the model in this paper has good prediction accuracy and robustness.

Novel dry pericardiocentesis: Transvenous puncture of the right ventricle with the back end of a 0.014-inch PTCA guidewire and a 1.8 Fr microcatheter.

Background: Dry transthoracic pericardiocentesis is challenging and carries the risk of right ventricle (RV) or coronary artery injury. The RV can usually control bleeding automatically. For example, most perforations of the RV caused by pacemaker leads are treated without open surgery. Thus, we performed a transvenous puncture of the RV for dry pericardiocentesis with the back end of a 0.014-inch percutaneous transluminal coronary angioplasty (PTCA) guidewire and a 1.8 Fr microcatheter. Methods: The back end of a 0.014-inch PTCA guidewire within a 1.8 Fr microcatheter was used to transvenously punctured through the middle of the acute margin of the RV into the pericardial space in 12 Yorkshire swine and 5 beagles. PTCA balloons of different diameters were used to dilate the puncture holes for 15 min under anticoagulation in all the animals to assess the ability of the RV to control the bleeding. Then, for 3 days, the puncture hole was dilated by a 6 Fr catheter in 9 swine and 5 dogs. Results: The puncture was successful in all the animals. After withdrawal of the 2.5-mm balloon or the 6 Fr catheter, none of the animals exhibited pericardial effusion, as observed by echocardiography. There was no sustained ventricular arrhythmia or other complications. All the animals survived. Conclusion: Transvenous puncture of the right ventricle with the back end of a 0.014-inch PTCA guidewire and 1.8 Fr microcatheter may be feasible and have a good safety margin.

Artificial Intelligence System Detection in English Teaching Based on Heuristic Genetic Algorithm.

Using the traditional English teaching mode is difficult to help correct students, and it is difficult to achieve human-computer interaction in oral English communication. In order to improve the effect of English detection and improve teaching efficiency, this article builds an artificial intelligence-assisted teaching system suitable for English teaching based on heuristic genetic algorithms. Furthermore, this article extends the multioffspring genetic algorithm, improves the offspring generation method, and proposes GMOGA, which makes the choice of the number of offspring more flexible. At the same time, it also enables the value of the number of children of the algorithm to be a value that cannot be obtained by the previous algorithm, which further improves the efficiency of the algorithm. In addition, this article combines the actual needs to construct the functional structure of the artificial intelligence system and designs two sets of comparative experiments to verify and analyze the model's performance. The research results show that the model constructed in this article meets the multifunctional requirements of the system and can be applied to practice.

Local Destruction of Tumors for Systemic Immunoresponse: Engineering Antigen-Capturing Nanoparticles as Stimulus-Responsive Immunoadjuvants.

Immunotherapy has established a new paradigm for cancer treatment and made many breakthroughs in clinical practice. However, the rarity of immune response suggests that additional intervention is necessary. In recent years, it has been reported that local tumor destruction (LTD) can cause cancer cell death and induce an immunologic response. Thus, the combination of immunotherapy and LTD methods will be a promising approach to improve immune efficiency for cancer treatment. Herein, a nanobiotechnology platform to achieve high-precision LTD for systemic cancer immunotherapy has been successfully constructed. Possessing radio-sensitizing and photothermal properties, the engineered immunoadjuvant-loaded nanoplatform, which could precisely induce radiotherapy (RT)/photothermal therapy (PTT) to eliminate local tumor and meanwhile lead to the release of tumor-derived protein antigens (TDPAs), has been facilely fabricated by commercialized SPG membrane emulsification technology. Further on, the TDPAs could be captured and form personal nanovaccines in situ to serve as both reservoirs of antigen and carriers of immunoadjuvant, which can effectively improve the immune response. The investigations suggest that the combination of RT/PTT and improved immunotherapy using adjuvant-encapsulated antigen-capturing nanoparticles holds tremendous promise in cancer treatments.

Frontal-posterior functional imbalance and aberrant function developmental patterns in schizophrenia.

Schizophrenia (SZ) is a neurodevelopmental disorder. There remain significant gaps in understanding the neural trajectory across development in SZ. A major research focus is to clarify the developmental functional changes of SZ and to identify the specific timing, the specific brain regions, and the underlying mechanisms of brain alterations during SZ development. Regional homogeneity (ReHo) characterizing brain function was collected and analyzed on humans with SZ (hSZ) and healthy controls (HC) cross-sectionally, and methylazoxymethanol acetate (MAM) rats, a neurodevelopmental model of SZ, and vehicle rats longitudinally from adolescence to adulthood. Metabolomic and proteomic profiling in adult MAM rats and vehicle rats was examined and bioanalyzed. Compared to HC or adult vehicle rats, similar ReHo alterations were observed in hSZ and adult MAM rats, characterized by increased frontal (medial prefrontal and orbitofrontal cortices) and decreased posterior (visual and associated cortices) ReHo. Longitudinal analysis of MAM rats showed aberrant ReHo patterns as decreased posterior ReHo in adolescence and increased frontal and decreased posterior ReHo in adulthood. Accordingly, it was suggested that the visual cortex was a critical locus and adolescence was a sensitive window in SZ development. In addition, metabolic and proteomic alterations in adult MAM rats suggested that central carbon metabolism disturbance and mitochondrial dysfunction were the potential mechanisms underlying the ReHo alterations. This study proposed frontal-posterior functional imbalance and aberrant function developmental patterns in SZ, suggesting that the adolescent visual cortex was a critical locus and a sensitive window in SZ development. These findings from linking data between hSZ and MAM rats may have a significant translational contribution to the development of effective therapies in SZ.

The knockdown of the sepiapterin reductase gene suppresses the proliferation of breast cancer by inducing ROS-mediated apoptosis.

BACKGROUND: Sepiapterin reductase (SPR) is an important regulator of the biosynthesis of tetrahydrobiopterin (BH4), which has been shown to be a promoter of different kinds of tumors. This study aims to investigate the role of SPR in breast cancer and to explore its molecular mechanism. METHODS: SPR expressions in breast cancer tissues with different pathological stages were compared with the corresponding pericarcinomatous tissues and were analyzed using immunohistochemical staining and western blot. SPR knockdown was performed in MDA-MB-231 and MDA-MB-468 triple-negative breast cancer cells using specific siRNAs. Quantitative real-time PCR and western blot were used to determine the efficiency of the SPR knockdown. The intracellular BH4 levels were measured using HPLC, and the intracellular ROS levels were measured using an ROS detection kit. Clone formation and cell proliferation assays were used to study the effect of the SPR knockdown on cell proliferation. Annexin V/PI double staining, cell mitochondria isolation, and western blot were performed to study the effect of the SPR knockdown on cell apoptosis. ROS scavenger NAC was used to inhibit increased ROS caused by the SPR knockdown. RESULTS: SPR is highly expressed in breast cancer tissues compared with the pericarcinomatous tissues and positively correlated with the pathological stages. The knockdown of SPR causes decreased intracellular BH4 and increased intracellular ROS and inhibits the proliferation of MDA-MB-231 and MDA-MB-468 cells. The knockdown of SPR also induces mitochondrial pathway-mediated apoptosis. NAC suppresses the SPR knockdown-caused cell apoptosis and cell death. CONCLUSIONS: SPR promotes the proliferation of breast cancer cells. The knockdown of SPR suppresses the proliferation of breast cancer cells by inducing ROS-mediated apoptosis.

High-quality-draft genome sequence of the heavy metal resistant and exopolysaccharides producing bacterium Mucilaginibacter pedocola TBZ30T.

Mucilaginibacter pedocola TBZ30T (= CCTCC AB 2015301T = KCTC 42833T) is a Gram- negative, rod-shaped, non-motile and non-spore-forming bacterium isolated from a heavy metal contaminated paddy field. It shows resistance to multiple heavy metals and can adsorb/remove Zn2+ and Cd2+ during cultivation. In addition, strain TBZ30T produces exopolysaccharides (EPS). These features make it a great potential to bioremediate heavy metal contamination and biotechnical application. Here we describe the genome sequence and annotation of strain TBZ30T. The genome size is 7,035,113 bp, contains 3132 protein-coding genes (2736 with predicted functions), 50 tRNA encoding genes and 14 rRNA encoding genes. Putative heavy metal resistant genes and EPS associated genes are found in the genome.

Mucilaginibacter pedocola sp. nov., isolated from a heavy-metal-contaminated paddy field.

Strain TBZ30T was isolated from soil of a heavy-metal-contaminated paddy field. Cells of strain TBZ30T were Gram-staining-negative, rod-shaped, non-motile and non-spore-forming. The isolate was strictly aerobic, pink-pigmented, catalase- and oxidase-positive and produced exopolysaccharides. On the basis of 16S rRNA gene phylogeny, strain TBZ30T belonged to the genus Mucilaginibacter and appeared most closely related to Mucilaginibacter gynuensis YC7003T (95.8 %), Mucilaginibacter litoreus BR-18T (95.4 %) and Mucilaginibacter mallensis MP1X4T (95.4 %). Strain TBZ30T contained menaquinone-7 as the only ubiquinone. The main cellular fatty acids included summed feature 3 (C16 : 1ω7c and/or iso-C15 : 0 2-OH), iso-C15 : 0, C16 : 0, iso-C17 : 0 3-OH and C16 : 1ω5c. The polar lipids were phosphatidylethanolamine, an unidentified phospholipid, two unidentified aminophospholipids, four unidentified aminolipids, three unidentified lipids and two unidentified glycolipids. The genomic DNA G+C content was 49.0 mol%. On the basis of polyphasic taxonomy analyses, strain TBZ30T represents a novel species of the genus Mucilaginibacter, for which the name Mucilaginibacter pedocola sp. nov. is proposed. The type strain is TBZ30T (=KCTC 42833T=CCTCC AB 2015301T).