Dynamic Structural Fluxionality in a Planar Tetracoordinate Carbon Cluster Stabilized by Boron Ligands.

The design of boron-based molecular rotors stems from boron-carbon binary clusters containing multiple planar hypercoordinate carbons (phCs, such as C2B8). However, the design of boron-coordinated phCs is challenging due to boron's tendency to occupy hypercoordinate centers more than carbon. Although this challenge has been addressed, the designed clusters of interest have not exhibited dynamic fluxionality similar to that of the initial C2B8. To address this issue, we report a σ/π doubly aromatic CB2H5+ cluster, the first global minimum containing a boron-coordinated planar tetracoordinate carbon atom with dynamic fluxionality. Dynamics simulations show that two ligand H atoms exhibit alternate rotation, resulting in an intriguing dynamic fluxionality in this cluster. Electronic structure analysis reveals the flexible bonding positions of the ligand H atoms because they do not participate in π delocalized bonding nor bond to any other non-carbon atom, highlighting this rotational fluxionality. Unprecedentedly, the fluxional process involves not only the usual conversion of the number of bonding atoms, but also the type of bonding (3c π bonds ↔ 4c σ bonds), which is an uncommon fluxional mechanism. The cluster represents an effort to apply phC species to molecular machines.

Prognostic heterogeneity of Ki67 in non-small cell lung cancer: A comprehensive reappraisal on immunohistochemistry and transcriptional data.

In the present study, the debatable prognostic value of Ki67 in patients with non-small cell lung cancer (NSCLC) was attributed to the heterogeneity between lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC). Based on meta-analyses of 29 studies, a retrospective immunohistochemical cohort of 1479 patients from our center, eight transcriptional datasets and a single-cell datasets with 40 patients, we found that high Ki67 expression suggests a poor outcome in LUAD, but conversely, low Ki67 expression indicates worse prognosis in LUSC. Furthermore, low proliferation in LUSC is associated with higher metastatic capacity, which is related to the stronger epithelial-mesenchymal transition potential, immunosuppressive microenvironment and angiogenesis. Finally, nomogram model incorporating clinical risk factors and Ki67 expression outperformed the basic clinical model for the accurate prognostic prediction of LUSC. With the largest prognostic assessment of Ki67 from protein to mRNA level, our study highlights that Ki67 also has an important prognostic value in NSCLC, but separate evaluation of LUAD and LUSC is necessary to provide more valuable information for clinical decision-making in NSCLC.

Strategies that regulate Hippo signaling pathway for novel anticancer therapeutics.

As a highly conserved signaling network across different species, the Hippo pathway is involved in various biological processes. Dysregulation of the Hippo pathway could lead to a wide range of diseases, particularly cancers. Extensive researches have demonstrated the close association between dysregulated Hippo signaling and tumorigenesis as well as tumor progression. Consequently, targeting the Hippo pathway has emerged as a promising strategy for cancer treatment. In fact, there has been an increasing number of reports on small molecules that target the Hippo pathway, exhibiting therapeutic potential as anticancer agents. Importantly, some of Hippo signaling pathway inhibitors have been approved for the clinical trials. In this work, we try to provide an overview of the core components and signal transduction mechanisms of the Hippo signaling pathway. Furthermore, we also analyze the relationship between Hippo signaling pathway and cancers, as well as summarize the small molecules with proven anti-tumor effects in clinical trials or reported in literatures. Additionally, we discuss the anti-tumor potency and structure-activity relationship of the small molecule compounds, providing a valuable insight for further development of anticancer agents against this pathway.

An Improved Football Team Training Algorithm for Global Optimization.

The football team training algorithm (FTTA) is a new metaheuristic algorithm that was proposed in 2024. The FTTA has better performance but faces challenges such as poor convergence accuracy and ease of falling into local optimality due to limitations such as referring too much to the optimal individual for updating and insufficient perturbation of the optimal agent. To address these concerns, this paper presents an improved football team training algorithm called IFTTA. To enhance the exploration ability in the collective training phase, this paper proposes the fitness distance-balanced collective training strategy. This enables the players to train more rationally in the collective training phase and balances the exploration and exploitation capabilities of the algorithm. To further perturb the optimal agent in FTTA, a non-monopoly extra training strategy is designed to enhance the ability to get rid of the local optimum. In addition, a population restart strategy is then designed to boost the convergence accuracy and population diversity of the algorithm. In this paper, we validate the performance of IFTTA and FTTA as well as six comparison algorithms in CEC2017 test suites. The experimental results show that IFTTA has strong optimization performance. Moreover, several engineering-constrained optimization problems confirm the potential of IFTTA to solve real-world optimization problems.

GC-STCL: A Granger Causality-Based Spatial-Temporal Contrastive Learning Framework for EEG Emotion Recognition.

EEG signals capture information through multi-channel electrodes and hold promising prospects for human emotion recognition. However, the presence of high levels of noise and the diverse nature of EEG signals pose significant challenges, leading to potential overfitting issues that further complicate the extraction of meaningful information. To address this issue, we propose a Granger causal-based spatial-temporal contrastive learning framework, which significantly enhances the ability to capture EEG signal information by modeling rich spatial-temporal relationships. Specifically, in the spatial dimension, we employ a sampling strategy to select positive sample pairs from individuals watching the same video. Subsequently, a Granger causality test is utilized to enhance graph data and construct potential causality for each channel. Finally, a residual graph convolutional neural network is employed to extract features from EEG signals and compute spatial contrast loss. In the temporal dimension, we first apply a frequency domain noise reduction module for data enhancement on each time series. Then, we introduce the Granger-Former model to capture time domain representation and calculate the time contrast loss. We conduct extensive experiments on two publicly available sentiment recognition datasets (DEAP and SEED), achieving 1.65% improvement of the DEAP dataset and 1.55% improvement of the SEED dataset compared to state-of-the-art unsupervised models. Our method outperforms benchmark methods in terms of prediction accuracy as well as interpretability.

The volatile oil of Hyssopus cuspidatus Boriss. (HVO) ameliorates OVA-induced allergic asthma via inhibiting PI3K/Akt/JNK/P38 signaling pathway and maintaining airway barrier integrity.

ETHNOPHARMACOLOGICAL RELEVANCE: Hyssopus cuspidatus Boriss., a classic Uyghur medicine, is used to treat inflammatory lung diseases such as asthma. But the therapeutic effect and mechanism of the volatile oil of Hyssopus cuspidatus Boriss.(HVO) in asthma therapy remain unclear. AIM OF THE STUDY: We aim to characterize the constituents of HVO, investigate the therapeutic effect in OVA-induced allergic asthmatic mice and further explore the molecular mechanism. MATERIALS AND METHODS: In this study, we applied two-dimensional gas chromatography quadrupole time-of-flight mass spectrometry (GC × GC-QTOF MS) to identify the ingredients of HVO. We established OVA-induced asthmatic model to investigate the therapeutic effect of HVO. To further explore the potential molecular pathways, we used network pharmacology approach to perform GO and KEGG pathways enrichment, and then built an ingredient-target-pathway network to identify key molecular pathways. Finally, LPS-induced RAW 264.7 macrophages and OVA-induced asthmatic model were used to validate the potential signaling pathways. RESULTS: GC × GC-QTOF MS analysis revealed the presence of 123 compounds of HVO. The sesquiterpenes and monoterpenes are the main constituents. The in vivo study indicated that HVO suppressed OVA-induced eosinophilic infiltration in lung tissues, inhibited the elevation of IgE, IL-4, IL-5, and IL-13 levels, downregulated the expressions of phosphorylated PI3K, Akt, JNK and P38, and maintained epithelial barrier integrity via reducing the degradation of occludin, Zo-1, Zo-2, and E-cadherin. The in vitro study also revealed an inhibition of NO release and downregulation of phosphorylated PI3K, Akt, JNK and P38 levels. CONCLUSION: HVO alleviates airway inflammation in OVA-induced asthmatic mice by inhibiting PI3K/Akt/JNK/P38 signaling pathway and maintaining airway barrier integrity via reducing the degradation of occludin, Zo-1, Zo-2, and E-cadherin.

A Nanobody/Monoclonal Antibody "hybrid" sandwich technology offers an improved immunoassay strategy for detection of African trypanosome infections.

The scarcity of reliable devices for diagnosis of Animal African trypanosomiasis (AAT) presents a limitation to control of the disease. Existing high-sensitivity technologies such as PCR are costly, laborious, time-consuming, complex, and require skilled personnel. Hence, utilisation of most diagnostics for AAT is impracticable in rural areas, where the disease occurs. A more accessible point-of-care test (POCT) capable of detecting cryptic active infection, without relying on expensive equipment, would facilitate AAT detection. In turn, early management, would reduce disease incidence and severity. Today, several ongoing research projects aim at modifying complex immunoassays into POCTs. In this context, we report the development of an antigen (Ag) detection sandwich ELISA prototype for diagnosis of T. congolense infections, which is comprised of nanobody (Nb) and monoclonal antibody (mAb) reagents. The Nb474H used here, originated from a past study. Briefly, the Nb was engineered starting from mRNA of peripheral blood lymphocytes of an alpaca immunized with soluble lysate of Trypanosoma congolense (TC13). T. congolense glycosomal fructose-1,6-bisphosphate aldolase (TcoALD) was discovered as the cognate Ag of Nb474H. In this study, splenocytes were harvested from a mouse immunized with recombinant TcoALD and fused with NS01 cells to generate a hybridoma library. Random screening of the library on TcoALD retrieved a lone binder, designated IgM8A2. Using Nb474H as Ag-capture reagent in combination with the IgM8A2 monoclonal antibody Ag-detection reagent resulted in a tool that effectively detects native TcoALD released during infection by T. congolense parasites. Hitherto, development of POCT for detection of active trypanosome infection is elusive. The Nanobody/Monoclonal Antibody (Nb/mAb) "hybrid" sandwich technology offers prospects for exploration, using the unique specificity of Nb as a key determinant in Ag capturing, while using the versatility of monoclonal Ab to adapt to various detection conditions.

Comprehensive molecular characterization of TFE3-rearranged renal cell carcinoma.

TFE3-rearranged renal cell cancer (tRCC) is a rare form of RCC that involves chromosomal translocation of the Xp11.2 TFE3 gene. Despite its early onset and poor prognosis, the molecular mechanisms of the pathogenesis of tRCC remain elusive. This study aimed to identify novel therapeutic targets for patients with primary and recurrent tRCC. We collected 19 TFE3-positive RCC tissues that were diagnosed by immunohistochemistry and subjected them to genetic characterization to examine their genomic and transcriptomic features. Tumor-specific signatures were extracted using whole exome sequencing (WES) and RNA sequencing (RNA-seq) data, and the functional consequences were analyzed in a cell line with TFE3 translocation. Both a low burden of somatic single nucleotide variants (SNVs) and a positive correlation between the number of somatic variants and age of onset were observed. Transcriptome analysis revealed that four samples (21.1%) lacked the expected fusion event and clustered with the genomic profiles of clear cell RCC (ccRCC) tissues. The fusion event also demonstrated an enrichment of upregulated genes associated with mitochondrial respiration compared with ccRCC expression profiles. Comparison of the RNA expression profile with the TFE3 ChIP-seq pattern data indicated that PPARGC1A is a metabolic regulator of the oncogenic process. Cell proliferation was reduced when PPARGC1A and its related metabolic pathways were repressed by its inhibitor SR-18292. In conclusion, we demonstrate that PPARGC1A-mediated mitochondrial respiration can be considered a potential therapeutic target in tRCC. This study identifies an uncharacterized genetic profile of an RCC subtype with unique clinical features and provides therapeutic options specific to tRCC.

Targeting focal adhesion kinase (FAK) in cancer therapy: A recent update on inhibitors and PROTAC degraders.

Focal adhesion kinase (FAK) is considered as a pivotal intracellular non-receptor tyrosine kinase, and has garnered significant attention as a promising target for anticancer drug development. As of early 2024, a total of 12 drugs targeting FAK have been approved for clinical or preclinical studies worldwide, including three PROTAC degraders. In recent three years (2021-2023), significant progress has been made in designing targeted FAK anticancer agents, including the development of a novel benzenesulfofurazan type NO-releasing FAK inhibitor and the first-in-class dual-target inhibitors simultaneously targeting FAK and HDACs. Given the pivotal role of FAK in the discovery of anticancer drugs, as well as the notable advancements achieved in FAK inhibitors and PROTAC degraders in recent years, this review is underbaked to present a comprehensive overview of the function and structure of FAK. Additionally, the latest findings on the inhibitors and PROTAC degraders of FAK from the past three years, along with their optimization strategies and anticancer activities, were summarized, which might help to provide novel insights for the development of novel targeted FAK agents with promising anticancer potential and favorable pharmacological profiles.

Multiview Spatial-Temporal Meta-Learning for Multivariate Time Series Forecasting.

Multivariate time series modeling has been essential in sensor-based data mining tasks. However, capturing complex dynamics caused by intra-variable (temporal) and inter-variable (spatial) relationships while simultaneously taking into account evolving data distributions is a non-trivial task, which faces accumulated computational overhead and multiple temporal patterns or distribution modes. Most existing methods focus on the former direction without adaptive task-specific learning ability. To this end, we developed a holistic spatial-temporal meta-learning probabilistic inference framework, entitled ST-MeLaPI, for the efficient and versatile learning of complex dynamics. Specifically, first, a multivariate relationship recognition module is utilized to learn task-specific inter-variable dependencies. Then, a multiview meta-learning and probabilistic inference strategy was designed to learn shared parameters while enabling the fast and flexible learning of task-specific parameters for different batches. At the core are spatial dependency-oriented and temporal pattern-oriented meta-learning approximate probabilistic inference modules, which can quickly adapt to changing environments via stochastic neurons at each timestamp. Finally, a gated aggregation scheme is leveraged to realize appropriate information selection for the generative style prediction. We benchmarked our approach against state-of-the-art methods with real-world data. The experimental results demonstrate the superiority of our approach over the baselines.

Updated roles of the gut microbiota in exploring shrimp etiology, polymicrobial pathogens, and disease incidence.

Litopenaeus vannamei is the most extensively cultured shrimp species globally, recognized for its scale, production, and economic value. However, its aquaculture is plagued by frequent disease outbreaks, resulting in rapid and massive mortality. etiological research often lags behind the emergence of new diseases, leaving the causal agents of some shrimp diseases unidentified and leading to nomenclature based on symptomatic presentations, especially in cases involving co- and polymicrobial pathogens. Comprehensive data on shrimp disease statuses remain limited. In this review, we summarize current knowledge on shrimp diseases and their effects on the gut microbiome. Furthermore, we also propose a workflow integrating primary colonizers, "driver" taxa in gut networks from healthy to diseased states, disease-discriminatory taxa, and virulence genes to identify potential polymicrobial pathogens. We examine both abiotic and biotic factors (e.g., external and internal sources and specific-disease effects) that influence shrimp gut microbiota, with an emphasis on the "holobiome" concept and common features of gut microbiota response to diverse diseases. After excluding the effects of confounding factors, we provide a diagnosis model for quantitatively predicting shrimp disease incidence using disease common-discriminatory taxa, irrespective of the causal agents. Due to the conservation of functional genes used in designing specific primers, we propose a practical strategy applying qPCR-assayed abundances of disease common-discriminatory functional genes. This review updates the roles of the gut microbiota in exploring shrimp etiology, polymicrobial pathogens, and disease incidence, offering a refined perspective for advancing shrimp aquaculture health management.

Preparation of Zn-Co Bimetallic Catalysts and Their Catalytic Properties for Thermal Decomposition of Ammonium Perchlorate.

This research delves into the preparation of heteronuclear bimetallic catalysts and explores their catalytic properties in the thermal decomposition of ammonium perchlorate (AP). The study's central focus is on enhancing the thermal decomposition characteristics of AP and, consequently, the combustion performance of composite solid propellants. The synthesized materials underwent structural characterization by XRD, XPS, SEM, and FTIR. Catalytic properties were examined using DTA tests. Notably, catalysts derived from calcination at 500 °C exhibited heightened catalytic activity. They advanced the pyrolysis temperature by 135.4 °C and reduced the activation energy by 82.38 kJ/mol compared with pure AP. To further elucidate the decomposition mechanism of AP, the investigation also employed a combined approach involving DSC-TG-FTIR-MS analysis.

Intrauterine Exposure to Long-Chain Perfluorocarboxylic Acids (PFCAs) Were Associated with Reduced Primary Bile Acids in Three-Year-Old Children: Findings from a Prospective Birth Cohort Study.

Bile acids (BAs) play a crucial role in lipid metabolism of children. However, the association between per- and polyfluoroalkyl substance (PFAS) exposure and BAs profiles in children is scarce. To address this need, we selected 252 children from the Maoming Birth Cohort and measured 32 PFAS, encompassing short- and long-chain perfluorocarboxylic acids (PFCAs) and perfluorosulfonic acids (PFSAs) in the cord blood. Additionally, we analyzed nine primary and eight secondary BAs in the serum of three-year-old children. Generalized linear models with FDR-adjusted and Bayesian kernel machine regression (BKMR) were used to explore the associations of individual and mixture effects of PFAS and BAs. We found negative associations between cord blood long-chain PFCAs and serum primary BAs in three-year-old children. For example, one ln-unit (ng/mL) increase of perfluoro-n-tridecanoic acid (PFTrDA), perfluoro-n-undecanoic acid (PFUnDA) and perfluoro-n-decanoic acid (PFDA) were associated with decreased taurochenodeoxycholic acid, with estimated percentage change of -24.28% [95% confidence interval (CI): -36.75%, -9.35%], -25.84% (95% CI: -39.67%, -8.83%), and -22.97% (95% CI: -34.45%, -9.47%) respectively. Notably, the observed association was more pronounced in children with lower vegetable intake. Additionally, the BKMR model also demonstrated a monotonical decline in primary BAs as the PFAS mixture increased. We provided the first evidence between intrauterine PFAS and its mixture exposure with BAs in children. Further large-sample-size studies are needed to verify this finding.

Vulnerability assessment for physical protection systems of cave temples: A fuzzy petri net approach.

Preservation of cultural relics is crucial for cultural sustainability, particularly in the case of cave temples, which are a unique and immovable part of our heritage, nested within mountains. These structures bear immense historical significance and possess considerable economic value, making them vulnerable to criminal activities, notably theft. Establishing a robust physical protection system (PPS) is imperative to safeguard these relics from potential damage. This paper proposes a novel approach for assessing the vulnerability of cave temples' PPS. Based on the fuzzy Petri net (FPN) principle, a comprehensive vulnerability assessment index system was developed within the PPS framework, considering the unique characteristics of cave temples. This study refines the formal definition of the FPN, enhancing its precision and effectiveness for vulnerability assessment. The practicality and effectiveness of the proposed method are verified through simulation experiments. An illustrative example is provided to demonstrate this approach.

Ischemia-Modified Albumin, Lactate, and Combination for Predicting Mortality in Patients with Septic Shock in the Emergency Department.

Ischemia-modified albumin (IMA) is produced during ischemia and reactive oxygen species production. This study aimed to evaluate the association between IMA and mortality in a larger population and the prognostic value of the combination of IMA and lactate for predicting mortality in septic shock patients in the emergency department. This retrospective observational study included adult septic shock patients between October 2019 and December 2021. A multivariable Cox proportional hazards model was performed. IMA was significantly higher in the non-surviving group than in the surviving group (89.1 ± 7.2 vs. 83.8 ± 6.2 U/mL, p < 0.001). IMA was independently associated with 28-day mortality after adjustments (adjusted hazard ratio [aHR]: 1.075, 95% confidence interval [CI]: 1.016-1.138, p = 0.012). The area under the ROC curve (AUROC) of IMA was 0.712 (95% CI: 0.648-0.775, p < 0.001) and was comparable to that of lactate. The AUROC of the combination of IMA and lactate was 0.838 (95% CI: 0.786-0.889, p < 0.001). The group with both high lactate and high IMA levels showed an extremely high risk of mortality than other groups (86.1%; aHR 8.956, 95% CI 4.071-19.70, p < 0.001). The elevation of IMA was associated with mortality in septic shock patients. The combination of IMA and lactate can be a helpful tool for early risk stratification of septic shock patients.

Alantolactone attenuates high-fat diet-induced inflammation and oxidative stress in non-alcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a chronic disease with an increasing incidence, which can further develop into liver fibrosis and hepatocellular carcinoma at the end stage. Alantolactone (Ala), a sesquiterpene lactone isolated from Asteraceae, has shown anti-inflammatory effects in different models. However, the therapeutic effect of Ala on NAFLD is not clear. METHODS: C57BL/6 mice were fed a high-fat diet (HFD) to induce NAFLD. After 16 weeks, Ala was administered by gavage to observe its effect on NAFLD. RNA sequencing of liver tissues was performed to investigate the mechanism. In vitro, mouse cell line AML-12 was pretreated with Ala to resist palmitic acid (PA)-induced inflammation, oxidative stress and fibrosis. RESULTS: Ala significantly inhibited inflammation, fibrosis and oxidative stress in HFD-induced mice, as well as PA-induced AML-12 cells. Mechanistic studies showed that the effect of Ala was related to the induction of Nrf2 and the inhibition of NF-κB. Taken together, these findings suggested that Ala exerted a liver protective effect on NAFLD by blocking inflammation and oxidative stress. CONCLUSIONS: The study found that Ala exerted a liver protective effect on NAFLD by blocking inflammation and oxidative stress, suggesting that Ala is an effective therapy for NAFLD.

Investigation of disinfection failure of flexible gastrointestinal endoscope due to Burkholderia cepacia contamination in irrigation tubing.

BACKGROUND AND AIMS: This study aims to identify the cause of disinfection failure of multiple flexible gastrointestinal endoscopes and to enhance the cleaning and disinfection procedures. METHODS: Samples from endoscopy devices, surrounding objects, cleaning water, automatic sterilizer, and integrated endoscopic washing workstation in a Digestive Endoscopy Center were collected and analyzed for microbial contamination and DNA/gene contents, between May and July 2021. RESULTS: The sample analysis revealed that the sink irrigation tubing of the washing workstation was contaminated with Burkholderia cepacia. After effective disinfection measures, the B. cepacia detection in the disinfected endoscope dropped from 13.23% to 0% (p=0.041). The presence of B. cepacia was confirmed through homology search and gene sequencing. CONCLUSIONS: The primary reason for endoscope disinfection failure is the contamination of the sink irrigation tubing by the B. cepacia bacteria. These findings emphasize the need for thorough cleaning of irrigation tubings in integrated endoscopic washing workstations, which is generally neglected in routine maintanance.

Thigh muscle mass evaluated by point-of-care ultrasound is associated with short-term mortality in patients with sepsis in the emergency department.

Muscle mass depletion is associated with mortality and morbidity in various conditions including sepsis. However, few studies have evaluated muscle mass using point-of-care ultrasound in patients with sepsis. This study aimed to evaluate the association between thigh muscle mass, evaluated using point-of-care ultrasound with panoramic view in patients with sepsis in the emergency department, and mortality. From March 2021 to October 2022, this prospective observational study used sepsis registry. Adult patients who were diagnosed with sepsis at the emergency department and who underwent point-of-care ultrasounds for lower extremities were included. The thigh muscle mass was evaluated by the cross-sectional area of the quadriceps femoris (CSA-QF) on point-of-care ultrasound using panoramic view. The primary outcome was 28 day mortality. Multivariable Cox proportional hazard model was performed. Of 112 included patients with sepsis, mean CSA-QF was significantly lower in the non-surviving group than surviving group (49.6 [34.3-56.5] vs. 63.2 [46.9-79.6] cm2, p = 0.002). Each cm2 increase of mean CSA-QF was independently associated with decreased 28 day mortality (adjusted hazard ratio 0.961, 95% CI 0.928-0.995, p = 0.026) after adjustment for potential confounders. The result of other measurements of CSA-QF were similar. The muscle mass of the quadriceps femoris evaluated using point-of-care ultrasound with panoramic view was associated with mortality in patients with sepsis. It might be a promising tool for determining risk factors for mortality in sepsis patients in the early stages of emergency department.

A study on the physical aging characteristics of the older people over 70 years old in China.

Aim: In China, with the increase of life expectancy and the decrease of fertility rate, the aging problem has become increasingly prominent, and the physical problems of the older people over 70 years are the key and difficult problems. Method: Based on the interactive logic between the aging problem and the older people health, in the study, a questionnaire survey and a nationwide physical fitness test were carried out on the older people over 70, to divide into different age groups (70-74 years old, 75-79 years old, 80-84 years old, 85 years old and older) and different genders. There were 8,400 valid samples, and 1,050 persons in each group. One-way ANOVA was used to compare the differences among groups of different ages, and a broken line chart was drawn to discuss the aging characteristics of various physical indexes of the older people over 70 in China. Result: (1) Body morphology: male waist circumference, male waist-to-height ratio and female BMI showed a gradual downward trend with the increase of age; (2) Physiological function: male and female vital capacity showed a decreasing trend with the increase of age, while female pulse pressure showed a gradual upward trend. (3) Physical quality: the indicators of male and female muscle strength, flexibility quality, aerobic endurance and balance showed a downward trend with the increase of age. Conclusion: Vital capacity, flexibility quality, muscle strength, aerobic endurance, balance ability and so on, decreased significantly with the growth of age. 80 years old is the inflection point of the rapid decline of various indicators. Blood pressure, silent pulse, BMI, waist-to-hip ratio, waist-to-height ratio and other indicators did not change regularly with age. Indicators such as blood pressure, BMI, waist-to-hip ratio and waist-to-height ratio were in the high-risk range of metabolic diseases and cardiovascular and cerebrovascular diseases. The study conducted physical fitness test on the older people over 70 years old in 7 geographical regions of China, which is the first nationwide physical fitness test for the older people, which is an extension and expansion of the national physical fitness monitoring system, and also shows that the test indicators involved in the "Health fitness scale" are simple and feasible. And the study added a series of test data over 70 years old, which is the basis for scientific and reasonable formulation of physical fitness evaluation standards for the older people, and is of great significance for improving the national physical fitness database and grasping the dynamic changes of national physical health status, and providing data support for scientific guidance of physical exercise for the older people.

Synthesis and biological evaluation of 4-phenyl-5-quinolinyl substituted isoxazole analogues as potent cytotoxic and tubulin polymerization inhibitors against ESCC.

The identification of chemically different inhibitors that target the colchicine site of tubulin is still of great value for cancer treatment. Combretastatin A-4(CA-4), a naturally occurring colchicine-site binder characterized by its structural simplicity and biological activity, has served as a structural blueprint for the development of novel analogues with improved safety and therapeutic efficacy. In this study, a library of forty-eight 4-phenyl-5-quinolinyl substituted triazole, pyrazole or isoxazole analouges of CA-4, were synthesized and evaluated for their cytotoxicity against Esophageal Squamous Cell Carcinoma (ESCC) cell lines. Compound C11, which features a 2-methyl substitution at the quinoline and carries an isoxazole ring, emerged as the most promising, with 48 h IC50s of less than 20 nmol/L against two ESCC cell lines. The findings from EBI competitive assay, CETA, and in vitro tubulin polymerization assay of C11 are consistent with those of the positive control colchicine, demonstrating the clear affinity of compound C11 to the colchicine binding site. The subsequent cellular-based mechanism studies revealed that C11 significantly inhibited ESCC cell proliferation, arrested cell cycle at the M phase, induced apoptosis, and impeded migration. Experiments conducted in vivo further confirmed that C11 effectively suppressed the growth of ESCC without showing any toxicity towards the selected animal species. Overall, our research suggests that the tubulin polymerization inhibitor incorporating quinoline and the isoxazole ring may deserve consideration for cancer therapy.