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ObjectiveAn adaptive neural control (ANC) scheme with specified performance is proposed for the tracking control of marine autonomous surface ships (MASS) subject to uncertain model parameters and unknown external environmental disturbances in cross-water scenarios. MethodsUnder the back-stepping design framework, a neural network is utilized to approximate the uncertain model parameters and unknown external environmental disturbances. A novel specified performance function is constructed and combined with the barrier Lyapunov function (BLF) to transform the cross-water design, while the dynamic surface control technique is employed to reduce the system's computational complexity. Stability analysis is then performed by means of Lyapunov theory to demonstrate that all signals within the control system are bounded.ResultsThe simulation results show that the designed control scheme is not only capable of solving the cross-water tracking control of MASS, but that the tracking error can satisfy the convergence to a given bounded range within a predefined time offline. ConclusionThe results of this study can solve the cross-water tracking control problems of MASS and provide valuable references for the tracking control of ships in restricted waters, giving them practical engineering significance.

Abstract Background Adolescent females have a high prevalence of temporomandibular joint (TMJ) anterior disc displacement (ADD), which can lead to condylar resorption and dentofacial deformity. Polycystic ovarian syndrome (PCOS) is a common endocrine disorder that disrupts bone metabolism. However, the effects of PCOS on bone remodeling especially after disc repositioning (DR) surgery are not well understood. Materials and methods This was a retrospective study. Patients aged 12 to 20 years diagnosed with ADD were reviewed and matched into 3 groups: A (ADD without PCOS), B (ADD with untreated PCOS), and C (ADD with treated PCOS). Each group was divided into 2 subgroups according to ADD observation (A1, B1, C1) and DR (A2, B2, C2). Condylar height (CH) was measured by MRI at the start (T0) and after more than 6 months follow-up (T1). ∆CH (T1-T0) were compared within and between groups. Results 93 patients (157 joints) with an average age of 15.17 ± 2.35 years and follow-up period of 14.04 ± 9.11 months were selected in the study. ∆CH in Group B1 was significantly larger than that in Groups A1 and C1 (p = 0.048, p = 0.018). While in Group B2, it was significant smaller than Groups A2 and C2 (p

Background: Transcatheter arterial chemoembolization combined with lenvatinib plus PD-1 inhibitors (triple therapy) is a promising treatment modality for uHCC. Identifying variables influencing prognosis can facilitate more personalized treatment. This study aimed to determine predictors of short-term survival (STS) and long-term survival (LTS) in patients with uHCC treated with triple therapy. Methods: This multicenter retrospective study reviewed patients with uHCC who underwent triple therapy at seven tertiary hospitals in China between June 2018 and May 2023. STS was defined as survival

Abstract Background With the advent of the smart phone era, managing blood glucose at home through apps will become more common for older individuals with diabetes. Adult children play important roles in glucose management of older parents. Few studies have explored how adult children really feel about engaging in the glucose management of their older parents with type 2 diabetes mellitus (T2DM) through mobile apps. This study provides insights into the role perceptions and experiences of adult children of older parents with T2DM participating in glucose management through mobile apps. Methods In this qualitative study, 16 adult children of older parents with T2DM, who had used mobile apps to manage blood glucose for 6 months, were recruited through purposive sampling. Semi-structured, in-depth, face-to-face interviews to explore their role perceptions and experiences in remotely managing their older parents’ blood glucose were conducted. The Consolidated Criteria for Reporting Qualitative Research (COREQ) were followed to ensure rigor in the study. The data collected were analyzed by applying Colaizzi’s seven-step qualitative analysis method. Results Six themes and eight sub-themes were identified in this study. Adult children’s perceived roles in glucose management of older parents with T2DM through mobile apps could be categorized into four themes: health decision-maker, remote supervisor, health educator and emotional supporter. The experiences of participation could be categorized into two themes: facilitators to participation and barriers to participation. Conclusion Some barriers existed for adult children of older parents with T2DM participating in glucose management through mobile apps; however, the findings of this study were generally positive. It was beneficial and feasible for adult children to co-manage the blood glucose of older parents. Co-managing blood glucose levels in older parents with T2DM can enhance both adherence rates and confidence in managing blood glucose effectively.

Abstract Natural killer (NK) cells play essential roles in the tumor development, diagnosis, and prognosis of tumors. In this study, we aimed to establish a reliable signature based on marker genes in NK cells, thus providing a new perspective for assessing immunotherapy and the prognosis of patients with gastric cancer (GC). We analyzed a total of 1560 samples retrieved from the public database. We performed a comprehensive analysis of single-cell RNA-sequencing (scRNA-seq) data of gastric cancer and identified 377 marker genes for NK cells. By performing Cox regression analysis, we established a 12-gene NK cell-associated signature (NKCAS) for the Cancer Genome Atlas (TCGA) cohort, that assigned GC patients into a low-risk group (LRG) or a high-risk group (HRG). In the TCGA cohort, the areas under curve (AUC) value were 0.73, 0.81, and 0.80 at 1, 3, and 5 years. External validation of the predictive ability for the signature was then validated in the Gene Expression Omnibus (GEO) cohorts (GSE84437). The expression levels of signature genes were measured and validated in GC cell lines by real-time PCR. Moreover, NKCAS was identified as an independent prognostic factor by multivariate analysis. We combined this with a variety of clinicopathological characteristics (age, M stage, and tumor grade) to construct a nomogram to predict the survival outcomes of patients. Moreover, the LRG showed higher immune cell infiltration, especially CD8+ T cells and NK cells. The risk score was negatively associated with inflammatory activities. Importantly, analysis of the independent immunotherapy cohort showed that the LRG had a better prognosis and immunotherapy response when compared with the HRG. The identification of NK cell marker genes in this study suggests potential therapeutic targets. Additionally, the developed predictive signatures and nomograms may aid in the clinical management of GC.

BackgroundChemicals may lead to acute liver injuries, posing a serious threat to human health. Achieving the precise safety profile of a compound is challenging due to the complex and expensive testing procedures. In silico approaches will aid in identifying the potential risk of drug candidates in the initial stage of drug development and thus mitigating the developmental cost.MethodsIn current studies, QSAR models were developed for hepatotoxicity predictions using the ensemble strategy to integrate machine learning (ML) and deep learning (DL) algorithms using various molecular features. A large dataset of 2588 chemicals and drugs was randomly divided into training (80%) and test (20%) sets, followed by the training of individual base models using diverse machine learning or deep learning based on three different kinds of descriptors and fingerprints. Feature selection approaches were employed to proceed with model optimizations based on the model performance. Hybrid ensemble approaches were further utilized to determine the method with the best performance.ResultsThe voting ensemble classifier emerged as the optimal model, achieving an excellent prediction accuracy of 80.26%, AUC of 82.84%, and recall of over 93% followed by bagging and stacking ensemble classifiers method. The model was further verified by an external test set, internal 10-fold cross-validation, and rigorous benchmark training, exhibiting much better reliability than the published models.ConclusionThe proposed ensemble model offers a dependable assessment with a good performance for the prediction regarding the risk of chemicals and drugs to induce liver damage.

Abstract Background Anthocyanins are a group of natural products widely found in plants. They have been found to alleviate the disorders of glucose metabolism in type 2 diabetes mellitus (T2DM), while the underlying mechanisms remain unclear. Methods HepG2 and L02 cells were incubated with 0.2 mM PA and 30 mM glucose for 24 h to induce IR, and cells treated with 5 mM glucose were used as the control. C57BL/6 J male mice and db/db male mice were fed with a chow diet and gavaged with pure water or cyanidin-3-O-glucoside (C3G) solution (150 mg/kg/day) for 6 weeks. Results In this study, the anthocyanin C3G, extracted from red bayberry, was found to alleviate disorders of glucose metabolism, which resulted in increased insulin sensitivity in hepatocytes, and achieved by enhancing the glucose consumption as well as glycogen synthesis in insulin resistance (IR) hepatpcytes. Subsequently, the expression of key proteins involved in IR was detected by western blotting analysis. Protein tyrosine phosphatase-1B (PTP1B), a negative regulator of insulin signaling, could reduce cellular sensitivity to insulin by inhibiting the phosphorylation of insulin receptor substrate-2 (IRS-2). Results of this study showed that C3G inhibited the increase in PTP1B after high glucose and palmitic acid treatment. And this inhibition was accompanied by increased phosphorylation of IRS proteins. Furthermore, the effect of C3G on improving IR in vivo was validated by using a diabetic db/db mouse model. Conclusion These findings demonstrated that C3G could alleviate IR in vitro and in vivo to increase insulin sensitivity, which may offer a new insight for regulating glucose metabolism during T2DM by using the natural dietary bioactive components. C3G promotes the phosphorylation of IRS-2 proteins by suppressing the expression of PTP1B, and then enhances the sensitivity of hepatocyte to insulin.

In human body, the endocrine system, nervous system and immune system jointly shoulder the important responsibility of life support. Hormones are the material basis for coordination of endocrine system. Steroid hormones, also known as steride hormone, belong to a large category of hormones. The synthesis process of steroid hormones takes cholesterol as the precursor. Through the participation of various metabolic enzymes, steroid hormones are synthesized in the human adrenal cortex, mitochondria of placental cells, smooth Endoplasmic reticulum and gonads, producing 21C, 19C or 18C-backbones with different chemical structures. According to pharmacological effects, steroid hormones are mainly divided into progestogens, corticosteroids and sex hormones, which play an important role in regulating human growth, development, reproduction and maintaining the stability of human body environment. In clinical practice, the level of steroid hormones is used as diagnostic indicator for adrenal and psychiatric diseases. Therefore, accurate determination of steroid hormone content is very important. Steroid hormones in the human body can be detected using various methods, such as radioimmunoassay, chemiluminescence immunoassay, enzyme-linked immunosorbent assay, gas chromatography-tandem mass spectrometry (GC-MS/MS), and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Mass spectrometry has obvious advantages in terms of detection sensitivity and accuracy compared with immunoassay. GC-MS has been the main technique for steroid analysis due to its high specificity, wide analyte coverage, and sufficient sensitivity. However, the samples need to be derivatized, and the experimental processes are tedious. LC-MS/MS has the inherent advantages of high sensitivity and specificity, and has a high-throughput characteristic, thus it is an ideal tool for routine diagnosis. At present, common pretreatment techniques for serum samples include protein precipitation, liquid-liquid extraction, and solid phase extraction. Some new pretreatment methods have emerged in recent years, such as dispersed liquid-liquid extraction, ultrasonic-assisted extraction, and supramolecular extraction. Each pretreatment technique has its own advantages and disadvantages. For example, solid phase extraction (SPE) can achieve good recovery but requires more time and economic factors. In selection of pretreatment methods, the physical and chemical properties of analytes, the characteristics of matrices, the simplicity and durability of method establishment, and time, reliability, and cost required should be comprehensively considered. This article reviewed the application of LC-MS/MS in the determination of endogenous steroid hormones, especially in sample pretreatment, chromatographic and mass spectrometric conditions, so as to provide more accurate basis for clinical diagnosis and treatment based on steroid hormones.

Mutations in the parkin gene product Parkin give rise to autosomal recessive juvenile parkinsonism. Parkin is an E3 ubiquitin ligase that is a critical participant in the process of mitophagy. Parkin has a complex structure that integrates several allosteric signals to maintain precise control of its catalytic activity. Though its allosterically controlled structural reorganization has been extensively characterized by crystallography, the energetics and mechanisms of allosteric regulation of Parkin are much less well understood. Allostery is fundamentally linked to the energetics of the cooperative (sub)structure of the protein. Herein, we examine the mechanism of allosteric activation by phosphorylated ubiquitin binding to the enzymatic core of Parkin, which lacks the antagonistic Ubl domain. In this way, the allosteric effects of the agonist phosphorylated ubiquitin can be isolated. Using native-state hydrogen exchange monitored by mass spectrometry, we find that the five structural domains of the core of Parkin are energetically distinct. Nevertheless, association of phosphorylated ubiquitin destabilizes structural elements that bind the ubiquitin-like domain antagonist while promoting the dissociation of the catalytic domain and energetically poises the protein for transition to the fully activated structure.

As new variants of SARS-CoV-2 continue to emerge, it is important to assess the cross-neutralizing capabilities of antibodies naturally elicited during wild type SARS-CoV-2 infection. In the present study, we evaluate the activity of nine anti-SARS-CoV-2 monoclonal antibodies (mAbs), previously isolated from convalescent donors infected with the Wuhan-Hu-1 strain, against the SARS-CoV-2 variants of concern (VOC) Alpha, Beta, Gamma, Delta and Omicron. By testing an array of mutated spike receptor binding domain (RBD) proteins, cell-expressed spike proteins from VOCs, and neutralization of SARS-CoV-2 VOCs as pseudoviruses, or as the authentic viruses in culture, we show that mAbs directed against the ACE2 binding site (ACE2bs) are more sensitive to viral evolution compared to anti-RBD non-ACE2bs mAbs, two of which retain their potency against all VOCs tested. At the second part of our study, we reveal the neutralization mechanisms at high molecular resolution of two anti-SARS-CoV-2 neutralizing mAbs by structural characterization. We solve the structures of the Delta-neutralizing ACE2bs mAb TAU-2303 with the SARS-CoV-2 spike trimer and RBD at 4.5 Å and 2.42 Å resolutions, respectively, revealing a similar mode of binding to that between the RBD and ACE2. Furthermore, we provide five additional structures (at resolutions of 4.7 Å, 7.3 Å, 6.4 Å, 3.3 Å, and 6.1 Å) of a second antibody, TAU-2212, complexed with the SARS-CoV-2 spike trimer. TAU-2212 binds an exclusively quaternary epitope, and exhibits a unique, flexible mode of neutralization that involves transitioning between five different conformations, with both arms of the antibody recruited for cross linking intra- and inter-spike RBD subunits. Our study provides additional mechanistic understanding about how antibodies neutralize SARS-CoV-2 and its emerging variants and provides insights on the likelihood of reinfections.

Abstract Background This study aimed to develop a computed tomography (CT) model to predict Ki-67 expression in hepatocellular carcinoma (HCC) and to examine the added value of radiomics to clinico-radiological features. Methods A total of 208 patients (training set, n = 120; internal test set, n = 51; external validation set, n = 37) with pathologically confirmed HCC who underwent contrast-enhanced CT (CE-CT) within 1 month before surgery were retrospectively included from January 2014 to September 2021. Radiomics features were extracted and selected from three phases of CE-CT images, least absolute shrinkage and selection operator regression (LASSO) was used to select features, and the rad-score was calculated. CE-CT imaging and clinical features were selected using univariate and multivariate analyses, respectively. Three prediction models, including clinic-radiologic (CR) model, rad-score (R) model, and clinic-radiologic-radiomic (CRR) model, were developed and validated using logistic regression analysis. The performance of different models for predicting Ki-67 expression was evaluated using the area under the receiver operating characteristic curve (AUROC) and decision curve analysis (DCA). Results HCCs with high Ki-67 expression were more likely to have high serum α-fetoprotein levels (P = 0.041, odds ratio [OR] 2.54, 95% confidence interval [CI]: 1.04–6.21), non-rim arterial phase hyperenhancement (P = 0.001, OR 15.13, 95% CI 2.87–79.76), portal vein tumor thrombus (P = 0.035, OR 3.19, 95% CI: 1.08–9.37), and two-trait predictor of venous invasion (P = 0.026, OR 14.04, 95% CI: 1.39–144.32). The CR model achieved relatively good and stable performance compared with the R model (AUC, 0.805 [95% CI: 0.683–0.926] vs. 0.678 [95% CI: 0.536–0.839], P = 0.211; and 0.805 [95% CI: 0.657–0.953] vs. 0.667 [95% CI: 0.495–0.839], P = 0.135) in the internal and external validation sets. After combining the CR model with the R model, the AUC of the CRR model increased to 0.903 (95% CI: 0.849–0.956) in the training set, which was significantly higher than that of the CR model (P = 0.0148). However, no significant differences were found between the CRR and CR models in the internal and external validation sets (P = 0.264 and P = 0.084, respectively). Conclusions Preoperative models based on clinical and CE-CT imaging features can be used to predict HCC with high Ki-67 expression accurately. However, radiomics cannot provide added value.

Summary: Higher-order genome structure influences the transcriptional regulation of cellular genes through the juxtaposition of regulatory elements, such as enhancers, close to promoters of target genes. While enhancer activation has emerged as an important facet of Kaposi sarcoma-associated herpesvirus (KSHV) biology, the mechanisms controlling enhancer-target gene expression remain obscure. Here, we discover that the KSHV genome tethering protein latency-associated nuclear antigen (LANA) potentiates enhancer-target gene expression in primary effusion lymphoma (PEL), a highly aggressive B cell lymphoma causally associated with KSHV. Genome-wide analyses demonstrate increased levels of enhancer RNA transcription as well as activating chromatin marks at LANA-bound enhancers. 3D genome conformation analyses identified genes critical for latency and tumorigenesis as targets of LANA-occupied enhancers, and LANA depletion results in their downregulation. These findings reveal a mechanism in enhancer-gene coordination and describe a role through which the main KSHV tethering protein regulates essential gene expression in PEL.

The Karijolich laboratory describes an atlas of A-to-I RNA editing during the KSHV lifecycle in primary effusion lymphoma. These analyses identified conserved editing events within a viral-encoded microRNA, revealing a critical role for the microRNA and its modification in virus infection.

Abstract Background Endometrial cancer (EC) is one of the most common gynecological malignancies globally, and the development of innovative, effective drugs against EC remains a key issue. Phytoestrogen kaempferol exhibits anti-cancer effects, but the action mechanisms are still unclear. Method MTT assays, colony-forming assays, flow cytometry, scratch healing, and transwell assays were used to evaluate the proliferation, apoptosis, cell cycle, migration, and invasion of both ER-subtype EC cells. Xenograft experiments were used to assess the effects of kaempferol inhibition on tumor growth. Next-generation RNA sequencing was used to compare the gene expression levels in vehicle-treated versus kaempferol-treated Ishikawa and HEC-1-A cells. A network pharmacology and molecular docking technique were applied to identify the anti-cancer mechanism of kaempferol, including the building of target-pathway network. GO analysis and KEGG pathway enrichment analysis were used to identify cancer-related targets. Finally, the study validated the mRNA and protein expression using real-time quantitative PCR, western blotting, and immunohistochemical analysis. Results Kaempferol was found to suppress the proliferation, promote apoptosis, and limit the tumor-forming, scratch healing, invasion, and migration capacities of EC cells. Kaempferol inhibited tumor growth and promotes apoptosis in a human endometrial cancer xenograft mouse model. No significant toxicity of kaempferol was found in human monocytes and normal cell lines at non-cytotoxic concentrations. No adverse effects or significant changes in body weight or organ coefficients were observed in 3–7 weeks’ kaempferol-treated animals. The RNA sequencing, network pharmacology, and molecular docking approaches identified the overall survival-related differentially expressed gene HSD17B1. Interestingly, kaempferol upregulated HSD17B1 expression and sensitivity in ER-negative EC cells. Kaempferol differentially regulated PPARG expression in EC cells of different ER subtypes, independent of its effect on ESR1. HSD17B1 and HSD17B1-associated genes, such as ESR1, ESRRA, PPARG, AKT1, and AKR1C1\2\3, were involved in several estrogen metabolism pathways, such as steroid binding, 17-beta-hydroxysteroid dehydrogenase (NADP+) activity, steroid hormone biosynthesis, and regulation of hormone levels. The molecular basis of the effects of kaempferol treatment was evaluated. Conclusions Kaempferol is a novel therapeutic candidate for EC via HSD17B1-related estrogen metabolism pathways. These results provide new insights into the efficiency of the medical translation of phytoestrogens.

BackgroundNature therapy can significantly benefit the physiology and psychology of middle-aged and older people, but previous studies have focused on forest environments. The restoration potential of rural environments in urban fringe areas, which are more accessible to older people on a daily basis, has not been fully studied. This study assessed the effects of nature therapy on the physical and mental health of older women in a rural setting (locally known as Linpan) in the urban fringe area of Chengdu, China.MethodsWe recruited a total of 60 older women (65.3 ± 5.5 years old) living in cities for 3 days of nature therapy in the winter (30 subjects) and spring (30 subjects), including 20 hypertensive patients.ResultsThe results showed that the overall blood pressure, pulse and sleep dysfunction rating scores of the participants were significantly lower than the pretest levels, and the finger blood oxygen saturation, mid-day salivary alpha-amylase and cortisol were increased post-treatment. Increases in these biomarker indicates and increase in stress. There were significant differences in the changes in systolic blood pressure between the hypertension group (HTN) and the normal group (normal) (HTN decreased by 8.8%, normal decreased by 5.4%), salivary alpha-amylase content (HTN decreased by 0.3%, normal increased by 16.9%), and sleep dysfunction rating scores (HTN decreased by 59.6%, normal decreased by 54%). The decreases in systolic blood pressure and pulse in the winter group were higher than those in the spring group by 1.8 and 4.4%, respectively, while the increases in salivary alpha-amylase content and salivary cortisol content were lower than those in the spring group by 11.7 and 11.2%, respectively, and the decrease in sleep dysfunction rating scores was lower than that in the spring group by 7.1%.ConclusionOur study concluded that nature therapy based on various health activities in the Linpan has significant health effects on older women. It can regulate blood pressure and pulse in older women, relieve cardiovascular disease, improve sleep quality. Meanwhile, older women with high blood pressure experienced a more significant effect than the healthy group.

Tidal flats are accumulations of fine-grained sediment formed under the action of tides and play a very important role in coastal protection. The northern part of Jiangsu coast, as a typical example of muddy coasts found all over the world, has experienced serious erosion since the Yellow River shifted northward, and the range of erosion has been gradually extending southward, now reaching the south of the Sheyang River estuary (SYRE). In order to address coastal erosion near the SYRE through protective measures, there is an urgent need for research on the spatial and temporal variation of coastal erosion processes and their control mechanisms in the SYRE and adjacent coastal areas. For this study, the tidal flats on the south side of the SYRE were selected as the study area, and the sediment dynamics in the upper and lower intertidal flat were observed in different seasons to investigate the erosion processes and their dynamic mechanisms. The results show that the tidal current and wave action in the observed intertidal flats are stronger in winter than in summer, and these intertidal flats erode under the combined action of waves and currents. During winter, the net transport of the near-bottom suspended sediment and bedload is primarily towards the southeast, while in summer, the direction tends toward the north and northeast. The net transport fluxes are larger in the lower part of the intertidal flat than in the upper part in summer and also larger in winter than in summer within the lower intertidal flat. Furthermore, the tidal flat erosion in the study area manifests as shoreline retreat and flat surface erosion. The average shoreline retreat rate increased from 23.3 m/a during 2014–2019 to 43.5 m/a during 2019–2021, and the average erosion depth of the lower and upper parts of the intertidal flat over a tidal cycle is, respectively, 1.98 cm and 0.24 cm in winter and 1.65 cm and 0.26 cm in summer. The ratio of the wave-induced bottom shear stress to the tidal current-induced bottom shear stress is 0.40~0.46 in the lower intertidal flat and increases to 0.66~0.67 in the upper intertidal flat, indicating that the intertidal flat erosion in the study area is primarily driven by tidal currents, with significant contributions from wave action, especially in the upper intertidal flat.

Abstract Background Exercise plays a major role in helping patients with type 2 diabetes mellitus and sarcopenia to increase muscle mass and muscle strength. However, little is known about perceptions of exercise and exercise instruction in these patients. This study aimed to explore the perceptions of exercise and exercise instruction from the patient’s perspective. Methods In a descriptive qualitative study, semi-structured face-to-face in-depth interviews were conducted with 16 patients with type 2 diabetes mellitus and sarcopenia at a tertiary hospital. The Consolidated Criteria for Reporting Qualitative Research (COREQ) guidelines were followed to ensure rigor in the study. The interviews were analysed using a thematic analysis method. Results Four themes and 13 sub-themes were identified in this study. The four themes were knowledge-attitudes-practices surrounding exercise, motivators and barriers regarding exercise, and attitudes towards professional exercise instruction. Conclusion This study provides a detailed understanding of the knowledge-attitudes-practices, motivators and barriers regarding exercise among patients with type 2 diabetes mellitus and sarcopenia, as well as attitudes related to exercise instruction. The current findings can guide healthcare professionals, patients’ families, and policymakers to motivate patients to be physically active through policy initiatives and other types of incentives and programmes, such as providing more health education and holistic support, increasing family and friends’ companionship and care, and providing suitable exercise conditions.