Coumarin-Quinazolinone based photosensitizers: Mitochondria and endoplasmic reticulum targeting for enhanced phototherapy via different cell death pathways.

Organelle-targeted photosensitizers (PSs) offer valuable tools for improving photodynamic therapy (PDT), yet systematic studies on how different organelles influence phototherapeutic outcomes are limited. In particular, the connection between organelle targeting and various modes of programmed cell death remains unclear. In this study, we developed a series of PSs using the Coumarin-Quinazolinone (CQ) scaffold, each designed to target different organelles, including the mitochondria, endoplasmic reticulum (ER), lysosome, and nucleolus. Our results show that their PDT performance is highly dependent on their localization, with phototoxic index (PI) ranging from 2 to 245. Notably, the mitochondria-targeted CQ-Mito and ER-targeted CQ-ER exhibited profound phototherapeutic performances, with PI of 167 and 245 respectively. Our further study reveals that CQ-Mito causes cell death by both apoptosis and ferroptosis, while CQ-ER primarily triggers ferroptosis. This study not only provides new agents for PDT but also offers insights into how organelle targeting influences cell death mechanisms, which can shed light on the design of PSs for controlled cell death.

Ag-Catalyzed cross-dehydrogenative-coupling for the synthesis of 1,4-dioxan-2-yl substituted quinazoline hybrids in an aqueous medium.

We herein developed an effective approach for the construction of 2- or 4-(1,4-dioxan-2-yl) substituted quinazolines under mild conditions. A silver-K2S2O8 catalyzed direct CDC reaction between quinazolines and 1,4-dioxane for the synthesis of a series of 2- or 4-(1,4-dioxan-2-yl) substituted quinazoline hybrids is reported. The reaction proceeded well in water under mild conditions and showed a broad substrate scope and good functional group compatibility.

Efficacy and safety of different doses of vamorolone in boys with Duchenne muscular dystrophy: a systematic review and network meta-analysis.

Background and objectives: Several recent clinical studies have indicated that vamorolone is comparable in effectiveness to glucocorticosteroids for treating Duchenne muscular dystrophy (DMD). However, there is a lack of extensive data regarding the efficacy and safety of various doses of vamorolone. We conducted a study to evaluate the efficacy of different doses of vamorolone in boys with DMD, and compare the safety of vamorolone vs. glucocorticosteroids, prednisone or deflazacort in boys with DMD. Methods: We performed systematic searches of the PubMed, Embase, and Cochrane Library databases for vamorolone, glucocorticosteroids, prednisone or deflazacort in boys with DMD. We assessed statistical heterogeneity across trials based on the Newcastle Ottawa scale (NOS) tool test and I2 values, and mean differences were pooled using the random-effects model. We used traditional meta-analysis to evaluate efficacy and safety of vamorolone 6.0 mg/kg/d vs. vamorolone 2.0 mg/kg/d and vamorolone vs. prednisone. A network meta-analysis was applied to estimated the safety of vamorolone in comparison to glucocorticosteroids, prednisone and deflazacort. Our meta-analysis were performed using Revman 5.4 software, and our network meta-analysis were performed using Stata/MP 18.0. Results: In the meta-analysis, a total of 193 patients were analyzed across four clinical trials (97 patients receiving vamorolone 2 mg/kg per day; 96 patients receiving vamorolone 2 mg/kg per day). We observed that there were statistically significant differences in boys with DMD between vamorolone 6.0 mg/kg/d and vamorolone 2.0 mg/kg/d in TTSTANDV (MD = 0.03, 95%CI = 0.00-0.06, p = 0.04), TTRWV (MD = 0.13, 95%CI = 0.08-0.19, p < 0.01), 6MWT (MD = 24.54, 95%CI = 4.46-44.82, p = 0.02), TTCLIMBV (MD = 0.04, 95%CI = 0.01-0.06, p = 0.009), no significant difference in BMI z score (MD = 0.09, 95%CI = -0.03-0.20, p = 0.13). Indirect comparisons derived from network meta-analysis did not show significant differences among vamorolone, glucocorticosteroids, prednisone and deflazacort in BMI z score. Conclusion: Our findings implied that boys with DMD who took vamorolone 6 mg/kg daily instead of 2 mg/kg daily may be safer and have superior motor function. However, more large sample randomized controlled trials are needed to confirm our results. Systematic Review Registration: This systematic review and meta-analysis has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (registration number: CRD42024562916).

Association between fibrinogen levels and stroke-associated pneumonia in acute ischemic stroke patients.

PURPOSE: Prior research had indicated a relationship between fibrinogen and stroke-associated pneumonia (SAP), yet the nature of this relationship had not been thoroughly investigated. Therefore, this study was designed to elucidate the prognostic value of fibrinogen levels in forecasting the occurrence of SAP among patients with acute ischemic stroke (AIS). PATIENTS AND METHODS: In this retrospective cross-sectional analysis, we included 1092 patients who had experienced AIS and were admitted to our facility within 72 h of the onset of their symptoms. Based on the SAP diagnostic criteria, patients were classified into two groups: SAP and non-SAP. The correlation between serum fibrinogen concentration and SAP was examined using univariate analysis. Curve fitting and multivariable logistic regression model were utilized for statistical evaluation. RESULTS: Out of the ischemic stroke patients included in the study, SAP was identified in 112 (10.26%) patients. A direct correlation was observed between fibrinogen levels and the incidence of SAP. An increase in fibrinogen levels corresponded with a heightened incidence of SAP. Multivariable logistic regression revealed a significant positive association between fibrinogen levels and SAP incidence (OR = 1.53, 95% confidence interval [CI]: 1.18, 1.99)). CONCLUSION: A linear relationship between serum fibrinogen levels and the incidence of SAP in ischemic stroke patients was shown. The serum fibrinogen levels were positively and linearly correlated to SAP risk.

Design of a bipedal robot for water running based on a six-linkage mechanism inspired by basilisk lizards.

Legged robots have received widespread attention in academia and engineering owing to their excellent terrain adaptability. However, most legged robots can only adapt to high-hardness environments instead of flexible environments. Expanding the motion range of legged robots to water is a promising but challenging work. Inspired by basilisk lizards which can run on water surfaces by feet, this paper proposes a bipedal robot for water running by hydrodynamics instead of buoyancy. According to the motion parameters of the basilisk lizard during water running, a single-degree of freedom bipedal mechanism is proposed to reproduce the motion trajectory of the feet of the basilisk lizard. Scale optimization is conducted by a particle swarm optimization algorithm to determine the geometrical parameters of the mechanism. The effects of motion frequency and foot area on mechanism performance are studied and the optimal solutions are determined by the maximum single-cycle lift impulse through numerical calculations. A bipedal water running robot prototype was fabricated, and the experimental results show that the prototype can generate enough support for the robot running on the water by providing a maximum lift of 2.4 times its weight (160 g) and reaching a horizontal forward speed range of 0.3-0.8 m s-1, compared with the basilisk lizard weighs 2-200 g, generates a lift impulse that is 111%-225% of its body weight, and moves at a speed of 1.3 ± 0.1 m s-1.

Bioinformatics analysis of the prognostic role of alternative splicing data in lung adenocarcinoma.

Background: As a post-transcriptional regulatory mechanism, alternative splicing (AS) is engaged in a variety of pathophysiological processes, and it has been widely reported in connection with the occurrence, progression, metastasis, and drug resistance of cancer. However, the research on AS in lung adenocarcinoma (LUAD) is very limited. In addition, the prognostic effect of AS event (ASE) on LUAD and its related mechanism are not clear. This study aimed to explore the role and potential prognostic value of ASE in LUAD. Methods: Relevant data and ASE datasets of the sample were acquired from The Cancer Genome Atlas (TCGA) and TCGASpliceSeq databases. We constructed a new prognostic criterion based on ASEs. Then, Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis were used to construct the model. Based on this model, the risk score of each ASE was calculated, and the reliability of this model was evaluated by Kaplan-Meier survival and receiver operating characteristic (ROC) curve analyses. Finally, these results were verified on different network platforms. Results: We identified seven types of ASEs related to survival. The prognostic risk model for ASEs was established. The Kaplan-Meier curve showed that compared to the low-risk group, the overall survival (OS) rate of LUAD patients in the high-risk group was lower. ROC curve analysis showed that the prognostic risk model of LUAD patients was well predicted, and the area under the curve (AUC) also confirmed this. Conclusions: This study screened the ASE related to the prognosis of LUAD patients, and provided a theoretical basis for further study of the correlation between ASE and the prognosis of LUAD patients. It has provided new ideas for developing new biomarkers and therapeutic targets for LUAD patients.

Synthesis of Selenium-Containing N-Quinazolinyl Acroleins via a 3,3-Radical Rearrangement Cascade Reaction.

An effective approach for the construction of 2-aryl-3-(3-oxo-1-aryl-2-(organoselanyl)prop-1-en-1-yl)quinazolin-4(3H)-ones was developed. Excellent to almost quantitative yields were obtained by the cascade reaction of propargyl quinazoline-4-yl ethers, diselenides, and 70% tert-butyl hydrogen peroxide aqueous solution under metal-free and mild conditions. The synthesized hybrids, with conglomeration of quinazolinone, organoselenium, aldehyde, and fully substituted alkene moieties in one molecule, will have the potential for applications in development of new drugs or drug candidates.

Endoplasmic Reticulum-Targeting Quinazolinone-Based Lipophilic Probe for Specific Photoinduced Ferroptosis and Its Induced Lipid Dynamic Regulation.

Lethal lipid peroxidation caused by reactive oxygen species occurs in different types of programmed cell death, especially in ferroptosis. Ferroptosis inducers, which serve as small-molecule probes, can provide insight into the mechanism of ferroptosis and facilitate drug discovery. The classical ferroptosis inducers indirectly lead to lipid peroxidation; thus, it is difficult to explore lipid regulation during the ferroptotic process. In this study, we designed two quinazolinone-based lipophilic probes BODIQPy-TPA and QPy-TPA, which proved to directly induce lipid peroxidation by light irradiation in vitro. The probe BODIQPy-TPA, which was mainly distributed in the endoplasmic reticulum (ER), specifically triggered ferroptosis in B16 and HepG2 cells upon light irradiation. As a comparison, the probe QPy-TPA, which was mainly distributed in lipid droplets (LDs), induced cell death by a nonferroptotic pathway. Further lipidomic analysis revealed that these two probes caused different patterns of lipid regulation and lipid peroxidation, suggesting that ferroptosis might activate distinct lipid regulation.

Transition metal-free regioselective direct acylation of quinazolines for the synthesis of acylquinazoline derivatives.

An efficient, mild method for direct regioselective acylation of quinazolines under metal-free conditions was developed with bis(trifluoroacetoxy)iodobenzene and trimethylsilyl azide at ambient temperature. The acylation reaction of quinazolines with aldehydes gave the corresponding acyl quinazolines in ethyl acetate with good to excellent yields and excellent functional group tolerance and site selectivity. In addition, the mechanism of the direct acylation of quinazolinone was investigated through HPLC-HRMS (high pressure liquid chromatography-high resolution mass spectrometry) and EPR (electron paramagnetic resonance) strategies.

Thionation toward High-Contrast ACQ-DIE Probes by Reprogramming the Aqueous Segregation Behavior: Enlightenment from a Sulfur-Substituted G-Quadruplex Ligand.

Small-molecule-based fluorescent chemosensors provide powerful tools for analytical chemistry. However, their organic essence often "cursed" them for aggregation-caused quenching (ACQ) in an aqueous context. Albeit the praxis of the disaggregation-induced emission (DIE) strategy as a potential solution, it still awaited improvement due to the uncontrollability of the aggregation/segregation process. To address this issue, herein, we supposed that sulfur substitution on a molecule could serve as a promising strategy to achieve an evolved ACQ-DIE probe. To prove this concept, a precursor G-quadruplex (G4) ligand CQ was modified to get its thionation version CTQ. Strikingly, CTQ exhibited more arranged aqueous segregation behavior, as compared with CQ, and therefore enhanced fluorescence performance. Our research, in the meantime, manifested that CTQ remained to possess favorable G4 selectivity, whereby it could function as an evolved probe for more accurate in vitro G4-related assays, specifically, a classification assay for distinguishing virus variants.

A Trajectory Tracking Control Based on a Terminal Sliding Mode for a Compliant Robot with Nonlinear Stiffness Joints.

A nonlinear stiffness actuator (NSA) can achieve high torque/force resolution in the low stiffness range and high bandwidth in the high stiffness range. However, for the NSA, due to the imperfect performance of the elastic mechanical component such as friction, hysteresis, and unmeasurable energy consumption caused by former factors, it is more difficult to achieve accurate position control compared to the rigid actuator. Moreover, for a compliant robot with multiple degree of freedoms (DOFs) driven by NSAs, the influence of every NSA on the trajectory of the end effector is different and even coupled. Therefore, it is a challenge to implement precise trajectory control on a robot driven by such NSAs. In this paper, a control algorithm based on the Terminal Sliding Mode (TSM) approach is proposed to control the end effector trajectory of the compliant robot with multiple DOFs driven by NSAs. This control algorithm reduces the coupling of the driving torque, and mitigates the influence of parametric variation. The closed-loop system's finite time convergence and stability are mathematically established via the Lyapunov stability theory. Moreover, under the same experimental conditions, by the comparison between the Proportion Differentiation (PD) controller and the controller using TSM method, the algorithm's efficacy is experimentally verified on the developed compliant robot. The results show that the trajectory tracking is more accurate for the controller using the TSM method compared to the PD controller.

Polymicrobial Anaerobic Meningitis Detected by Next-Generation Sequencing: Case Report and Review of the Literature.

Background: Anaerobic meningitis is a severe central nervous system infection associated with significant neurological sequelae and high mortality. However, the precise detection of causative pathogen(s) remains difficult because anaerobic bacteria are difficult to culture. Next-generation sequencing is a technology that was developed recently and has been applied in many fields. To the best of our knowledge, the use of next-generation sequencing for cerebrospinal fluid analysis in the diagnosis of anaerobic meningitis has been rarely reported. Case presentation: Here, we report a case of polymicrobial anaerobic meningitis diagnosed using next-generation sequencing of cerebrospinal fluid in a 16-year-old girl. Five species of anaerobic bacteria (Porphyromonas gingivalis, Prevotella enoeca, Campylobacter rectus, Fusobacterium uncleatum, and Actinomyces israelii) were detected by next-generation sequencing and treated with antibacterial agents (ceftriaxone, vancomycin, and metronidazole). The patient responded well to antibacterial treatment. Further inspection revealed bone destruction at the base of the skull, which further confirmed that these bacteria had originated from the oral cavity. One month later, the patient's condition improved significantly. At the same time, we performed a literature review on anaerobic meningitis using studies published in the last 20 years. Conclusions: This case emphasizes the importance of applying metagenomic next-generation sequencing to clinch the clinical diagnosis for patients with central nervous system infection. Metagenomic next-generation sequencing has been reported to be an important diagnostic modality for identifying uncommon pathogens.

A Novel Biomimetic Compliant Structural Skin Based on Composite Materials for Biorobotics Applications.

Biorobotics is increasingly attracting engineers worldwide, due to the high impact this field can have on the society. Biorobotics aims at imitating or taking inspiration from mechanisms and strategies evolved by animals, including their locomotion abilities in real scenarios, such as swimming, running, crawling, and flying. However, the development of skin-mimicking structures, allowing protection without hindering artifacts' movements, has been rarely addressed. Skin-mimicking structures play a key role for biomimetic robots that have to move in unstructured environments. Currently most of the skin used for robots in engineering adopts soft materials or bellow structures to enable both structural deformation and protection. However, the elastic nature of the former can produce support failure and increasing strain with deformation, while the humpy surface of the latter reduces the interactive performance with the environment. Herein, we designed a novel compliant structure for biorobots' skin, fabricated through a special configuration of both soft and rigid materials to reproduce attributes provided by natural epithelial structures. The presented skin has a simple fabrication process, as well as it is cost effective. The structure of this skin includes a thin conical shape where rigid iron rings are wrapped by soft polyester fabrics, allowing a theoretically zero elastic modulus when bended and stretched. The dimension of fabrics was specified to allow rigid rings having a certain range of free rotation and translation. The possibility of free bending and stretching of the structure was implemented by overcoming low sliding friction of adjacent rings. To empirically test the effectiveness of the proposed structure, a model, including 20 segments, was also fabricated. Experimental results from the bending tests, both in aerial and underwater environments, as well as from the folding tests, demonstrated the successful performance of the skin prototype in terms of low resistance and energy consumption. Finally, the proposed highly compliant structural skin was mounted and tested on a fish robot previously developed by authors, to further show its effectiveness.

DMF-Assisted Radical Cyclization of o-Isocyanodiaryl Ethers via 1,5-Aryl Migration: Construction of 2-Arylbenzoxazoles.

A novel DMF-assisted radical cyclization of o-isocyanodiaryl ethers via 1,5-aryl migration has been developed for the synthesis of a series of 2-arylbenzoxazoles by the FeCl3/TBHP/Et3N catalytic system in DMF. However, N,N-dimethylbenzo[d]thiazole-2-carboxamide and N,N-dimethylbenzo[d]selenazole-2-carboxamide were obtained from the corresponding substrate 2-isocyanophenyl p-methoxyphenyl thioether and 2-isocyanodiphenyl selenoether under the same conditions. A possible mechanism may involve aryl 1,5-migration and DMF-assisted radical cyclization of o-isocyanodiaryl ethers.

A Novel Biopsy Capsule Robot Based on High-Speed Cutting Tissue.

The capsule robot (CR) is a promising endoscopic method in gastrointestinal diagnosis because of its low discomfort to users. Most CRs are used to acquire image information only and lack the ability to collect samples. Although some biopsy capsule robots (BCRs) have been developed, it remains challenging to acquire the intestinal tissue while avoiding tearing and adhesion due to the flexibility of colonic tissue. In this study, we develop a BCR with a novel sampling strategy in which soft tissue is scratched with sharp blades rotating at high speed to avoid tissue tearing. In the BCR design, a spiral spring with prestored energy is used to release high energy within a short period of time, which is difficult for a motor or magnet to perform within a small capacity installation space. The energy of the tightened spiral spring is transmitted to drive sharp blades to rotate quickly via a designed gear mechanism. To guarantee reliable sampling, a Bowden cable is used to transmit the user's manipulation to trigger the rotation of the blades, and the triggering force transmitted by the cable can be monitored in real time by a force sensor installed at the manipulating end. A prototype of the proposed BCR is designed and fabricated, and its performance is tested through in vitro experiments. The results show that the proposed BCR is effective and the size of its acquired samples satisfies clinical requirements.

Subtle Structural Changes of Dyes Lead to Distinctly Different Fluorescent Behaviors in Cellular Context: The Role of G-Quadruplex DNA Interaction Using Coumarin-Quinazolinone Conjugates as a Case Study.

Fluorogenic organic materials have gained tremendous attention due to their unique properties. However, only a few of them are suitable for bioimaging. Their different behaviors in organic and cellular environments hinder their application in bioimaging. Thus understanding the photoluminescent behaviors of organic materials in a cellular context is particularly important for their rational design. Herein, we describe two coumarin-quinazolinone conjugates: CQ and MeCQ. The high structure similarity makes them possess similar physical and photophysical properties, including bright fluorescence ascribed to the monomer forms in organic solvents and aggregation-caused quenching (ACQ) effect due to self-assembly aggregation in aqueous solution. However, they behave quite differently in cellular context: that is, CQ exhibits bright fluorescence in living cells, while the fluorescence of MeCQ is almost undetectable. The different performance between CQ and MeCQ in living cells is attributed to their different scenario in G-quadruplex (G4) DNA interaction. CQ selectively binds with G4 DNA to recover its fluorescence via aggregation-disaggregation switching in living cells, while MeCQ remained in the aggregate form due to its poor interplay with G4 DNA. Furthermore, CQ is applied as a two-photon fluorescent dye, and its photoswitchable fluorescence capability is exploited for super-resolution imaging of the specific mitochondrial structure in living cells via the STORM technique.

Rhodium-catalyzed oxidative annulation of 1H-indazoles with alkynes for the synthesis of indazolo[3,2-a]isoquinolines via C-H bond functionalization.

A Rh(iii)-catalyzed oxidative annulation of 1H-indazoles with internal alkynes via C-C and C-N coupling for the preparation of highly functionalized indazolo[3,2-a]isoquinolines is disclosed. This reaction features the use of easily accessible starting materials, is operationally simple, has a relatively wide substrate scope, and shows good functional group tolerance. Furthermore, some of the prepared compounds exhibit bright emission in both dilute solution and in the solid state, with a Stokes shift of up to 161 nm. The derivative 3ia, bearing the strong electron-withdrawing group -NO2, exhibits remarkable solvatochromic fluorescence.

Prediction of Passive Torque on Human Shoulder Joint Based on BPANN.

In upper limb rehabilitation training by exploiting robotic devices, the qualitative or quantitative assessment of human active effort is conducive to altering the robot control parameters to offer the patients appropriate assistance, which is considered an effective rehabilitation strategy termed as assist-as-needed. Since active effort of a patient is changeable for the conscious or unconscious behavior, it is considered to be more feasible to determine the distributions of the passive resistance of the patient's joints versus the joint angle in advance, which can be adopted to assess the active behavior of patients combined with the measurement of robotic sensors. However, the overintensive measurements can impose a burden on patients. Accordingly, a prediction method of shoulder joint passive torque based on a Backpropagation neural network (BPANN) was proposed in the present study to expand the passive torque distribution of the shoulder joint of a patient with less measurement data. The experiments recruiting three adult male subjects were conducted, and the results revealed that the BPANN exhibits high prediction accurate for each direction shoulder passive torque. The results revealed that the BPANN can learn the nonlinear relationship between the passive torque and the position of the shoulder joint and can make an accurate prediction without the need to build a force distribution function in advance, making it possible to draw up an assist-as-needed strategy with high accuracy while reducing the measurement burden of patients and physiotherapists.

Efficacy and safety of sonothrombolysis in patients with acute ischemic stroke: A systematic review and meta-analysis.

BACKGROUND: Accumulating clinical evidence has indicated that sonothrombolysis can aid in the treatment of ischemic stroke; however, these findings remain controversial. The purpose of the present meta-analysis was to assess randomized clinical studies concerning the effects of sonothrombolysis on ischemic stroke to evaluate its safety and efficacy. METHODS: We systematically searched the Cochrane Library, PubMed, and EMBASE databases for literature published between the inception of electronic data and May 2019 regarding sonothrombolysis for acute ischemic stroke. Only randomized controlled trials were included. Data extraction was based on patient characteristics, ultrasound variables (any duration or frequency, without microbubble), and outcome variables (safety and efficacy). RESULTS: Five trials were included in the present study. Clinical functional recovery was evaluated at different time points (several days or 3 months), and heterogeneity was low. Sonothrombolysis did not lead to an increase in symptomatic intracranial hemorrhagic complications or death. Our results demonstrated that patients treated with sonothrombolysis had significantly higher rates of recanalization and asymptomatic intracerebral hemorrhage than patients treated with intravenous thrombolysis alone. In the subgroup of middle cerebral artery (MCA) occlusion patients, sonothrombolysis was found to greatly increase the efficacy outcomes compared to intravenous thrombolysis. CONCLUSIONS: Evidence suggests that sonothrombolysis is a technically feasible and potentially effective treatment that has beneficial effects on recanalization and increases the rate of asymptomatic intracerebral hemorrhage in stroke patients. Additionally, short- and long-term clinical outcome analyses were improved in the MCA occlusion sonothrombolysis subgroup. Larger clinical trials of MCA occlusion patients are necessary to verify these findings.

Trajectory Tracking Control for Flexible-Joint Robot Based on Extended Kalman Filter and PD Control.

The robot arm with flexible joint has good environmental adaptability and human robot interaction ability. However, the controller for such robot mostly relies on data acquisition of multiple sensors, which is greatly disturbed by external factors, resulting in a decrease in control precision. Aiming at the control problem of the robot arm with flexible joint under the condition of incomplete state feedback, this paper proposes a control method based on closed-loop PD (Proportional-Derivative) controller and EKF (Extended Kalman Filter) state observer. Firstly, the state equation of the control system is established according to the non-linear dynamic model of the robot system. Then, a state prediction observer based on EKF is designed. The state of the motor is used to estimate the output state, and this method reduces the number of sensors and external interference. The Lyapunov method is used to analyze the stability of the system. Finally, the proposed control algorithm is applied to the trajectory control of the flexible robot according to the stability conditions, and compared with the PD control algorithm based on sensor data acquisition under the same experimental conditions, and the PD controller based on sensor data acquisition under the same test conditions. The experimental data of comparison experiments show that the proposed control algorithm is effective and has excellent trajectory tracking performance.