Astragalus polysaccharide promotes the regeneration of intestinal stem cells through HIF-1 signalling pathway.

Ionizing radiation (IR)-induced intestinal injury is usually accompanied by high lethality. Intestinal stem cells (ISCs) are critical and responsible for the regeneration of the damaged intestine. Astragalus polysaccharide (APS), one of the main active ingredients of Astragalus membranaceus (AM), has a variety of biological functions. This study was aimed to investigate the potential effects of APS on IR-induced intestine injury via promoting the regeneration of ISCs. We have established models of IR-induced intestinal injury and our results showed that APS played great radioprotective effects on the intestine. APS improved the survival rate of irradiated mice, reversed the radiation damage of intestinal tissue, increased the survival rate of intestinal crypts, the number of ISCs and the expression of intestinal tight junction-related proteins after IR. Moreover, APS promoted the cell viability while inhibited the apoptosis of MODE-K. Through organoid experiments, we found that APS promoted the regeneration of ISCs. Remarkably, the results of network pharmacology, RNA sequencing and RT-PCR assays showed that APS significantly upregulated the HIF-1 signalling pathway, and HIF-1 inhibitor destroyed the radioprotection of APS. Our findings suggested that APS promotes the regeneration of ISCs through HIF-1 signalling pathway, and it may be an effective radioprotective agent for IR-induced intestinal injury.

Acetone Serving as a Solvent and Interaction Partner Promotes the Direct Olefination of N-Tosylhydrazones under Visible Light.

The photochemistry of noncovalent interactions to promote organic transformations is an emerging approach to providing fresh opportunities in synthetic chemistry. Generally, the external substance is necessary to add as an interaction partner, thereby sacrificing the atom economy of the reaction. Herein, we describe a catalyst-free and noncovalent interaction-mediated strategy to access the olefination of N-tosylhydrazones using acetone as a solvent and an interaction partner. This protocol also features broad substrate scope, excellent functional group compatibility, and mild reaction conditions without transition metals. Moreover, the gram-scale synthesis of olefins and the generation of pharmaceutical intermediates highlighted its practical applicability. Lastly, mechanistic studies indicate that the reaction was initiated via noncovalent interactions between acetone and N-tosylhydrazone anion, which is also supported by density functional theory calculations.

Photo-Deactivation Strategy for Switchable ATRP with the Assistance of Molecular Switches.

Light irradiation is an external stimulus, rapidly developed in switchable atom transfer radical polymerization (ATRP) via photo-activation methods in recent years. Herein, a photo-deactivation strategy is introduced to regulate ATRP with the assistance of photoswitchable hexaarylbiimidozole (HABI). Under visible light irradiation and in the presence of HABI, ATRP is greatly decelerated or quenched depending on the concentration of HABI. Interestingly, with visible light off, ATRP can proceed smoothly and follow a first-order kinetics. Moreover, photo-switchable ATRP alternatively with light off and on is demonstrated. Besides, the mechanism of photo-deactivation ATRP involving radical quenching is proposed in the presence of HABI.

A Minimalist Method for Fully Oxygen-Tolerant RAFT Polymerization through Sulfur-Centered Trithiocarbonate Radical Initiation.

In recent years, the fully oxygen-tolerant reversible deactivation radical polymerization (RDRP) has become a highly researched area. In this contribution, a new and minimalist method is successfully employed to accomplish fully oxygen-tolerant reversible addition-fragmentation chain transfer (RAFT) polymerization using bis(trithiocarbonate) disulfides (BisTTC) as an iniferter agent, where the released sulfur-centered trithiocarbonate (TTC) radical can initiate monomer. Furthermore, polymerization kinetics revealed the typical "living" features of this polymerization system. More importantly, by high-throughput screening, it is found that dodecyl-substituted TTC is responsible for the fully oxygen-tolerant RAFT polymerization though trithiocarbonate radical initiation and R radical deoxygenation. It is believed that trithiocarbonate radical initiation strategy provides a powerful and minimalist tool for fully oxygen-tolerant RDRPs.

Achieving deep intratumoral penetration and multimodal combined therapy for tumor through algal photosynthesis.

BACKGROUND: Elevated interstitial fluid pressure within tumors, resulting from impaired lymphatic drainage, constitutes a critical barrier to effective drug penetration and therapeutic outcomes. RESULTS: In this study, based on the photosynthetic characteristics of algae, an active drug carrier (CP@ICG) derived from Chlorella pyrenoidosa (CP) was designed and constructed. Leveraging the hypoxia tropism and phototropism exhibited by CP, we achieved targeted transport of the carrier to tumor sites. Additionally, dual near-infrared (NIR) irradiation at the tumor site facilitated photosynthesis in CP, enabling the breakdown of excessive intratumoral interstitial fluid by generating oxygen from water decomposition. This process effectively reduced the interstitial pressure, thereby promoting enhanced perfusion of blood into the tumor, significantly improving deep-seated penetration of chemotherapeutic agents, and alleviating tumor hypoxia. CONCLUSIONS: CP@ICG demonstrated a combined effect of photothermal/photodynamic/starvation therapy, exhibiting excellent in vitro/in vivo anti-tumor efficacy and favorable biocompatibility. This work provides a scientific foundation for the application of microbial-enhanced intratumoral drug delivery and tumor therapy.

A non-antibiotic erythromycin derivative improves muscle endurance by regulating endogenous anti-fatigue protein orosomucoid in mice.

At present, there are no official approved drugs for improving muscle endurance. Our previous research found acute phase protein orosomucoid (ORM) is an endogenous anti-fatigue protein, and macrolides antibiotics erythromycin can elevate ORM level to increase muscle bioenergetics and endurance parameters. Here, we further designed, synthesized and screened a new erythromycin derivative named HMS-01, which lost its antibacterial activity in vitro and in vivo. Data showed that HMS-01 could time- and dose-dependently prolong mice forced-swimming time and running time, and improve fatigue index in isolated soleus muscle. Moreover, HMS-01 treatment could increase the glycogen content, mitochondria number and function in liver and skeletal muscle, as well as ORM level in these tissues and sera. In Orm-deficient mice, the anti-fatigue and glycogen-elevation activity of HMS-01 disappeared. Therefore, HMS-01 might act as a promising small molecule drug targeting ORM to enhance muscle endurance.

A systematic approach to adaptive sequential design for clinical trials: using simulations to select a design with desired operating characteristics.

The failure rates of phase 3 trials are high. Incorrect sample size due to uncertainty of effect size could be a critical contributing factor. Adaptive sequential design (ASD), which may include one or more sample size re-estimations (SSR), has been a popular approach for dealing with such uncertainties. The operating characteristics (OCs) of ASD, including the unconditional power and mean sample size, can be substantially affected by many factors, including the planned sample size, the interim analysis schedule and choice of critical boundaries and rules for interim analysis. We propose a systematic, comprehensive strategy which uses iterative simulations to investigate the operating characteristics of adaptive designs and help achieve adequate unconditional power and cost-effective mean sample size if the effect size is in a pre-identified range.

Adaptive sequential design for phase II single-arm oncology trials: an expansion of Simon's design.

Single-arm phase II trials are very common in oncology. A fixed sample trial may lack sufficient power if the true efficacy is less than the assumed one. Adaptive designs have been proposed in the literature. We propose a Simon's design based, adaptive sequential design. Simon's design is the most used fixed sample design for single-arm phase II oncology trials. A prominent feature of Simon's design is that it minimizes the sample size when there is no clinically meaningful efficacy. We identify Simon's trial as a special group sequential design. Established methods for sample size re-estimation (SSR) can be readily applied to Simon's design. Simulations show that simply adding SSR to Simon's design may still not provide desirable power. We propose some expansions to Simon's design. The expanded design with SSR can provide even more power.

Disparity of serum uric acid threshold for CKD among hypertensive and non-hypertensive individuals.

INTRODUCTION: Hypertension and rising serum uric acid (sUA) played a pivotal role in the development of Chronic Kidney Disease (CKD). This study investigates the interactive effect of sUA and hypertension on CKD and identifies the optimal threshold of sUA among individuals with and without hypertension in the Chinese community population. MATERIALS AND METHODS: The study included 4180 individuals aged 45-85 years, derived from the China Health and Retirement Longitudinal Study (CHARLS) between 2011 and 2015. Additionally, a hospital-based study enrolled subjects in the Department of Nephrology at Zhongshan Hospital, China from January 1, 2019, to December 31, 2021. The interaction effect analysis were used to assess the impact of sUA and hypertension on CKD. We also compared the distribution of sUA and the CKD risk in community populations, distinguishing between those with and without hypertension. For the hospital-based population, kidney injury was marked by a KIM-1 positive area. RESULTS: Our results indicate a higher prevalence of CKD in the community population with hypertension (10.2% vs. 3.9%, p < .001). A significant additive synergistic effects of the sUA and hypertension on the CKD risk were found. When the sUA level was < 4.55 mg/dL in the hypertensive population and < 5.58 mg/dL in the non-hypertensive population, the risk of CKD was comparable (p = .809). In the propensity score matched (PSM) population, the result remained roughly constant. CONCLUSION: Therefore, even moderate levels of sUA was associated with a higher risk of CKD in middle-aged hypertensive patients, who warrant stricter sUA control.

Resveratrol-loaded pH-responsive Mesona chinensis polysaccharides-zein nanoparticles for effective treatment of ulcerative colitis.

BACKGROUND: Resveratrol (Res) is promising food functional factor with favorable antioxidant and anti-inflammatory properties, although its poor water solubility and low bioavailability limit extensive application. Therefore, in combination with another promising polysaccharide (Mesona chinensis polysaccharides, MCP), Res-loaded food nanocarriers (ResNPs) were developed to increase its water solubility, bioactivity and targeting properties. ResNPs were then applied to alleviate dextran sulfate sodium (DSS)-induced ulcerative colitis. RESULTS: Resveratrol can be well encapsulated in MCP-based nanoparticles in an amorphous state, improving its water solubility. ResNPs showed pH-response controlled release behavior in the gastrointestinal tract and increased the enrichment of Res in the colon. In vivo experiments of ResNPs against DSS-induced ulcerative colitis (UC) revealed that ResNPs significantly improved UC symptoms, modulated intestinal inflammation and down-regulated oxidative stress levels compared to free Res. ResNPs also play an positive role with respect to inhibiting the mitogen-activated protein kinase pathway and promoting the expression of tight junction proteins. In addition, ResNPs improved the species composition and relative abundance of intestinal flora in UC mice, which effectively regulated the balance of intestinal flora and promoted the production of short-chain fatty acids. CONCLUSION: These results suggest that MCP-based nanoparticles can effectively improve the solubility of resveratrol and enhance its in vivo bioactivity. Moreover, the present study also provides a new strategy for the prevention and treatment of UC with food polyphenol. © 2024 Society of Chemical Industry.

Efficient Offline Reinforcement Learning With Relaxed Conservatism.

Offline reinforcement learning (RL) aims at learning an optimal policy from a static offline data set, without interacting with the environment. However, the theoretical understanding of the existing offline RL methods needs further studies, among which the conservatism of the learned Q-function and the learned policy is a major issue. In this article, we propose a simple and efficient offline RL with relaxed conservatism (ORL-RC) framework for addressing this concern by learning a Q-function that is close to the true Q-function under the learned policy. The conservatism of learned Q-functions and policies of offline RL methods is analyzed. The analysis results support that the conservatism can lead to policy performance degradation. We establish the convergence results of the proposed ORL-RC, and the bounds of learned Q-functions with and without sampling errors, respectively, suggesting that the gap between the learned Q-function and the true Q-function can be reduced by executing the conservative policy improvement. A practical implementation of ORL-RC is presented and the experimental results on the D4RL benchmark suggest that ORL-RC exhibits superior performance and substantially outperforms existing state-of-the-art offline RL methods.

The effect of delay time after injecting gadobutrol on the diagnosis of endolymphatic hydrops.

OBJECTIVES: The aim of this study was to reduce the time delay between gadolinium injection and 3D-FLAIR (three-dimensional fluid-attenuated inversion recovery) MRI by using a single dose of intravenous gadobutrol in Menière's disease patients. METHODS: 17 patients diagnosed with definite unilateral Meniere's disease underwent 3D-FLAIR MRI scans at 2, 4, and 6 h post-intravenous administration of a single-dose of gadobutrol. The signal intensity ratio of bilateral inner ear, cochlear and vestibular hydrops was measured at 2 h, 4 h and 6 h, while the differences in signal intensity ratio and endolymphatic hydrops were evaluated at three time points. RESULTS: The cochlea, vestibule, and semicircular canal exhibit clear structural features with distinct perilymph-endolymph boundaries at 2 h, 4 h, and 6 h. The signal intensity ratio of the affected ear was significantly higher than that of the unaffected ear at 2 h, 4 h, and 6 h. The signal intensity ratio at 4 h and 6 h in both the affected and unaffected ears was significantly higher than that at 2 h, but there was no significant difference between 4 h and 6 h. Cochlear hydrops and vestibular hydrops show no significant differences at these time points, demonstrating excellent consistency. CONCLUSIONS: We have demonstrated that 3D-FLAIR images acquired 2 h after intravenous administration of a single-dose gadobutrol are of high quality and equally effective as those obtained at the conventional 4-h time point for diagnosing endolymphatic hydrops in Menière's disease. In clinical practice, the delay time can be safely shortened to 2 h.

Safety-Preserving Lyapunov-Based Model Predictive Rendezvous Control for Heterogeneous Marine Vehicles Subject to External Disturbances.

This article investigates the cooperative rendezvous control problem for perturbed heterogeneous marine systems composed of an autonomous underwater vehicle (AUV) and an autonomous surface vehicle (ASV). A novel Lyapunov-based model predictive control (LMPC) framework is presented to accomplish safe and precise rendezvous under input limitations and external disturbances. First, by incorporating the prescribed performance control (PPC) technique into the LMPC framework, we transform the original ascending state of the AUV into a self-constrained state, which serves as the decision variable of the model predictive control (MPC) optimization problem. Then, PPC-aided auxiliary control laws based on disturbance observers (DOBs) are designed to establish a robust contractive constraint to provide stability margins. Combining the LMPC with the PPC technique makes the original state-constrained problem an equivalent state-constraint-free problem. By addressing the MPC problem for the equivalent unconstrained system, the proposed method preserves the rendezvous safety. With the robust contractive constraint, the proposed safety-preserving LMPC (SP-LMPC) controller can inherit robustness and stability from the robust auxiliary control laws. Furthermore, theoretical analyses are conducted to assess recursive feasibility and closed-loop stability. With comprehensive theoretical support, the proposed method provides a new framework to simultaneously address state constraints and disturbances for highly nonlinear marine systems. Finally, simulations and comparisons are conducted to demonstrate the effectiveness and advantages of the proposed algorithm.

Offline Reinforcement Learning With Behavior Value Regularization.

Offline reinforcement learning (offline RL) aims to find task-solving policies from prerecorded datasets without online environment interaction. It is unfortunate that extrapolation errors can cause over-optimistic Q-value estimates when learning with a fixed dataset, limiting the performance of the learned policy. To tackle this issue, this article proposes an offline actor-critic with behavior value regularization (OAC-BVR) method. In the policy evaluation stage, the difference between the Q-function and the value of the behavior policy is considered as the regularization term, driving the learned value function to approach the value of the behavior policy. The convergence of the proposed policy evaluation with behavior value regularization (PE-BVR) and the value function difference are analyzed, respectively. Compared with existing offline actor-critic methods, the proposed OAC-BVR method integrates the value of the behavior policy, thereby simultaneously alleviating over-optimistic Q-value estimates and reducing Q-function bias. Experimental results on the D4RL MuJoCo and Maze2d datasets demonstrate the validity of the proposed PE-BVR and the performance advantage of OAC-BVR over the state-of-the-art offline RL algorithms. The code of OAC-BVR is available at https://github.com/LongyangHuang/OAC-BVR.

Distributed estimation and control over mobile sensor networks with jointly connected topology: Event-triggered approach.

This article deals with the problem of distributed event-triggered tracking control in mobile sensor networks (MSNs) with a jointly connected topology (JCT). Two schemes are proposed for linear and Lipschitz nonlinear MSNs to estimate and track a mobile target. The proposed schemes are established using an event-triggered method to avoid continuous exchange of information between sensor nodes. In comparison with the other research under event-triggered communication strategies where states of the target are available, this paper considers that the states of the target are not available and two event-triggered algorithms are established for sensor nodes to estimate and follow the states of the continuous-time targets that can be seen in various real-world applications. Also, the proposed schemes are designed for the JCT with disconnected graphs which means the communication topology of the MSN is not required to be connected for all time instants. By employing the Cauchy convergence criterion and a common Lyapunov function, sufficient conditions are also established to ensure event-based tracking control subject to JCT. The effectiveness of the proposed work is verified by presenting simulation examples.

High expression of KIFC1 is a poor prognostic biomarker and correlates with TP53 mutation in lung cancer.

The Kinesin Family Member C1 (KIFC1) is highly expressed in a variety of tumors. Since it is linked with tumorigenesis and progression, KIFC1 has emerged as a promising candidate for targeted chemotherapies. Thus, this study aims to find out the association between KIFC1 and lung cancer. The original data were assessed from The Cancer Genome Atlas and Gene Expression Omnibus databases. Compared to normal lung tissues, both mRNA and protein levels of KIFC1 were significantly increased in lung cancer tissues. The upregulation of KIFC1 was significantly correlated with sex, pathological stage, and TMN stage. Survival analysis revealed that increased KIFC1 expression was associated with poor overall survival, first-progression survival and post-progression survival in lung cancer. Based on the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis, we observed that KIFC1 upregulation was linked to enrichment of the cell cycle and TP53 signaling pathway. Additionally, the overexpression of KIFC1 was positively correlated with TP53 mutations in lung cancer. Based on real-world cohort results, western blotting and RT-qPCR showed high-KIFC1 expression in lung cancer, which may be related to the malignancy of lung cancer. Finally, experiments in vitro showed that KIFC1 inhibitor could significantly inhibit the proliferation and invasion of lung cancer cells. In conclusion, KIFC1 is a poor prognostic biomarker, and patients with high-KIFC1 levels may benefit from targeted therapy.

Data Augmentation of a Corrosion Dataset for Defect Growth Prediction of Pipelines Using Conditional Tabular Generative Adversarial Networks.

Due to corrosion characteristics, there are data scarcity and uneven distribution in corrosion datasets, and collecting high-quality data is time-consuming and sometimes difficult. Therefore, this work introduces a novel data augmentation strategy using a conditional tabular generative adversarial network (CTGAN) for enhancing corrosion datasets of pipelines. Firstly, the corrosion dataset is subjected to data cleaning and variable correlation analysis. The CTGAN is then used to generate external environmental factors as input variables for corrosion growth prediction, and a hybrid model based on machine learning is employed to generate corrosion depth as an output variable. The fake data are merged with the original data to form the synthetic dataset. Finally, the proposed data augmentation strategy is verified by analyzing the synthetic dataset using different visualization methods and evaluation indicators. The results show that the synthetic and original datasets have similar distributions, and the data augmentation strategy can learn the distribution of real corrosion data and sample fake data that are highly similar to the real data. Predictive models trained on the synthetic dataset perform better than predictive models trained using only the original dataset. In comparative tests, the proposed strategy outperformed other data generation methods.

Operando imaging in electrocatalysis: insights into microstructural materials design.

Electrocatalysis plays a pivotal role in renewable energy conversion and associated chemical production, enabling a variety of emerging sustainability technologies with societal impacts. Achieving marked improvement in electrocatalytic performance relies on a deep understanding of catalyst microstructures and catalytic mechanisms, with a particular emphasis on the detailed, spatiotemporally resolved characterizations of the underlying fundamental electrocatalytic processes. This fundamental need drives the development of operando imaging techniques, which improve the ability to detect dynamic structural changes in electrocatalysts and establish clear structure-performance relationships for morphologically complex, hierarchically structured catalytic materials. This review aims to highlight significant advancements in the application of operando imaging techniques to develop a deeper understanding of important heterogeneous electrocatalytic reactions critical for emerging sustainability technologies. We summarize the up-to-date key mechanistic insights regarding these reactions achieved through a range of operando imaging techniques, including electron microscopies, X-ray imaging techniques, scanning probe microscopies, and optical microscopies. We conclude by pointing out emerging directions and future prospects within the field of operando imaging in electrocatalysis.

Output-Feedback Consensus Maneuvering of Uncertain MIMO Strict-Feedback Multiagent Systems Based on a High-Order Neural Observer.

In this article, a distributed output-feedback consensus maneuvering problem is investigated for a class of uncertain multiagent systems with multi-input and multi-output (MIMO) strict-feedback dynamics. The followers are subject to immeasurable states and external disturbances. A distributed neural observer-based adaptive control method is designed for consensus maneuvering of uncertain MIMO multiagent systems. The method is based on a modular structure, resulting in the separation of three modules: 1) a variable update law for the parameterized path; 2) a high-order neural observer; and 3) an output-feedback consensus maneuvering control law. The proposed distributed neural observer-based adaptive control method ensures that all followers agree on a common motion guided by a desired parameterized path, and the proposed method evades adopting the adaptive backstepping or dynamic surface control design by reformulating the dynamics of agents, thereby reducing the complexity of the control structure. Combined with the cascade system analysis and interconnection system analysis, the input-to-state stability of the consensus maneuvering closed loop is established in the Lyapunov sense. A simulation example is presented to demonstrate the performance of the proposed distributed neural observer-based adaptive control method for output-feedback consensus maneuvering.

Multiple pulmonary sclerosing pneumocytoma, based on a study of 36 cases worldwide.

To analyze the clinical characteristics and to improve clinicians' understanding of multiple pulmonary sclerosing pneumocytoma (PSP) patients. A total of 36 PSP patients with multiple tumor characteristics were identified from the literature search. They were compared with 43 solitary PSP patients diagnosed and treated in our hospital in the past 5 years. Thus, the pathogenesis, clinical symptoms, diagnosis methods, treatment strategies, and prognosis of pulmonary sclerosing pneumocytoma (PSP) patients with multiple tumors were explored. Patients with multiple PSP are mostly distributed in Asia (88.89%) and are females (83.33%). PSP can be located in any one lobe (19.44%), or grow across ipsilateral lobes (44.44%), or even, bilateral lobes (36.11%). It can be accompanied by metastasis (9.09%) and is prone to misdiagnosis (27.78%). Compared with solitary PSP, the occurrence age of multiple PSP was younger (mean ± standard deviation [SD]: 40.36 ± 18.12: 51.28 ± 12.74 years), but there was no significant difference in sex, tumor size (mean ± SD: 43.54 ± 46.18: 30.56 ± 17.62 mm), or symptoms. Individualized surgical resection is required for treatment, including pneumonectomy (17.65%), lobectomy (23.53%), subpulmonary lobectomy (38.24%), or combined lobectomy (5.88%). Multiple PSP is relatively rare. Surgical resection within a limited time should be the main treatment for such patients. The prognosis of patients with multiple PSP is generally good, but inappropriate diagnosis and treatment plans may lead to poor prognosis.