Tetrahydrofolate attenuates cognitive impairment after hemorrhagic stroke by promoting hippocampal neurogenesis via PTEN signaling.

Intracerebral hemorrhage (ICH), the most common subtype of hemorrhagic stroke, leads to cognitive impairment and imposes significant psychological burdens on patients. Hippocampal neurogenesis has been shown to play an essential role in cognitive function. Our previous study has shown that tetrahydrofolate (THF) promotes the proliferation of neural stem cells (NSCs). However, the effect of THF on cognition after ICH and the underlying mechanisms remain unclear. Here, we demonstrated that administration of THF could restore cognition after ICH. Using Nestin-GFP mice, we further revealed that THF enhanced the proliferation of hippocampal NSCs and neurogenesis after ICH. Mechanistically, we found that THF could prevent ICH-induced elevated level of PTEN and decreased expressions of phosphorylated AKT and mTOR. Furthermore, conditional deletion of PTEN in NSCs of hippocampus attenuated the inhibitory effect of ICH on the proliferation of NSCs and abnormal neurogenesis. Taken together, these results provide molecular insights into ICH-induced cognitive impairment and suggest translational clinical therapeutic strategy for hemorrhagic stroke.Significance Statement Intracerebral hemorrhage (ICH) has been associated with cognitive dysfunction, yet its underlying mechanism remains elusive. Tetrahydrofolate (THF) has shown potential in promoting the proliferation of neural stem cells (NSCs), but its specific impact on cognitive recovery following ICH is still to be confirmed. Through the utilization of the Nestin-GFP genetic marker to track endogenous NSCs in mice, our study revealed that THF could regulate PTEN pathway to ameliorate cognitive impairment post-ICH by enhancing the proliferation of NSCs and sustaining neurogenesis. These findings contribute to valuable insights into the molecular mechanisms involved and suggest potential clinical applications for enhancing cognitive function recovery after ICH.

WNT3 promotes chemoresistance to 5-Fluorouracil in oral squamous cell carcinoma via activating the canonical ß-catenin pathway.

BACKGROUND: 5-Fluorouracil (5FU) is a primary chemotherapeutic agent used to treat oral squamous cell carcinoma (OSCC). However, the development of drug resistance has significantly limited its clinical application. Therefore, there is an urgent need to determine the mechanisms underlying drug resistance and identify effective targets. In recent years, the Wingless and Int-1 (WNT) signaling pathway has been increasingly studied in cancer drug resistance; however, the role of WNT3, a ligand of the canonical WNT signaling pathway, in OSCC 5FU-resistance is not clear. This study delved into this potential connection. METHODS: 5FU-resistant cell lines were established by gradually elevating the drug concentration in the culture medium. Differential gene expressions between parental and resistant cells underwent RNA sequencing analysis, which was then substantiated via Real-time quantitative PCR (RT-qPCR) and western blot tests. The influence of the WNT signaling on OSCC chemoresistance was ascertained through WNT3 knockdown or overexpression. The WNT inhibitor methyl 3-benzoate (MSAB) was probed for its capacity to boost 5FU efficacy. RESULTS: In this study, the WNT/ß-catenin signaling pathway was notably activated in 5FU-resistant OSCC cell lines, which was confirmed through transcriptome sequencing analysis, RT-qPCR, and western blot verification. Additionally, the key ligand responsible for pathway activation, WNT3, was identified. By knocking down WNT3 in resistant cells or overexpressing WNT3 in parental cells, we found that WNT3 promoted 5FU-resistance in OSCC. In addition, the WNT inhibitor MSAB reversed 5FU-resistance in OSCC cells. CONCLUSIONS: These data underscored the activation of the WNT/ß-catenin signaling pathway in resistant cells and identified the promoting effect of WNT3 upregulation on 5FU-resistance in oral squamous carcinoma. This may provide a new therapeutic strategy for reversing 5FU-resistance in OSCC cells.

Orexin Neurons to Sublaterodorsal Tegmental Nucleus Pathway Prevents Sleep Onset REM Sleep-Like Behavior by Relieving the REM Sleep Pressure.

Proper timing of vigilance states serves fundamental brain functions. Although disturbance of sleep onset rapid eye movement (SOREM) sleep is frequently reported after orexin deficiency, their causal relationship still remains elusive. Here, we further study a specific subgroup of orexin neurons with convergent projection to the REM sleep promoting sublaterodorsal tegmental nucleus (OXSLD neurons). Intriguingly, although OXSLD and other projection-labeled orexin neurons exhibit similar activity dynamics during REM sleep, only the activation level of OXSLD neurons exhibits a significant positive correlation with the post-inter-REM sleep interval duration, revealing an essential role for the orexin-sublaterodorsal tegmental nucleus (SLD) neural pathway in relieving REM sleep pressure. Monosynaptic tracing reveals that multiple inputs may help shape this REM sleep-related dynamics of OXSLD neurons. Genetic ablation further shows that the homeostatic architecture of sleep/wakefulness cycles, especially avoidance of SOREM sleep-like transition, is dependent on this activity. A positive correlation between the SOREM sleep occurrence probability and depression states of narcoleptic patients further demonstrates the possible significance of the orexin-SLD pathway on REM sleep homeostasis.

Effect of Emergency Plan and First Aid Procedure on Injury Control and Precise Treatment of Patients with Acute Traumatic Cervical Spinal Cord Injury.

Objective: To investigate the effect of emergency plans and first aid procedures on injury control and precise treatment in patients with acute traumatic cervical spinal cord injury. Given the challenges in managing acute traumatic cervical spinal cord injuries and the need for efficient emergency plans and first aid procedures, the importance of this study is self-evident. Methods: A total of 103 patients with acute traumatic cervical spinal cord injury were enrolled in our study from January 2017 to December 2022, and these patients were divided into two groups according to the time of admission: 51 cases from January 2017 to December 2019 were in the control group, and 52 cases from January 2020 to December 2022 were in the study group. The control group was given routine emergency care. The study group received emergency plans and first aid procedures that included rapid assessment, optimized patient handling and transport, and immediate medical intervention. We compared the International Classification of Functioning, Disability and Health (ICF) scores, the Short Form Health Survey (SF-36) scores, the Activities of Daily Living (ADL) scores, and the occurrence of adverse events 3 months after rescue between the two groups. Results: The study group demonstrated significantly shorter times for prehospital emergency rescue, waiting time upon admission, time from admission to treatment, mechanical ventilation duration, and ICU stay when compared to the control group (P < .05). The intubation rate and mortality rate in the research group were 28.85% and 11.54%, respectively, compared to 31.37% and 13.73% in the control group, with no statistically significant differences (P > .05). Three months after the rescue, the study group showed significantly lower scores in environmental factors, activities and participation, body structure, and body function compared to the control group (P < .05). Three months after the rescue, the research group had significantly higher SF-36 scores (P < .05), and their ADL scores were significantly lower than those of the control group (P < .05). The research group had an adverse event rate of 3.85%, significantly lower than the control group's rate of 19.61% (P < .05). The study group experienced improvements in emergency response and hospital procedure times, higher SF-36 and ADL scores, and lower rates of adverse events, suggesting significant potential for improving patient outcomes in cases of acute traumatic cervical spinal cord injury. This demonstrates the effectiveness of the emergency plans that have been implemented and may influence the approach to emergency medical care in similar situations in the future. Conclusions: Emergency plans and first aid procedures can effectively shorten the first aid time, promote rehabilitation, reduce adverse events, and improve the quality of daily life in patients with acute traumatic cervical spinal cord injury. Based on these findings, future practice or policy may need to be adjusted to further enhance patient care quality.

Metal tolerance protein CsMTP4 has dual functions in maintaining zinc homeostasis in tea plant.

Plants have evolved a series of zinc (Zn) homeostasis mechanisms to cope with the fluctuating Zn in the environment. How Zn is taken up, translocated and tolerate by tea plant remains unknown. In this study, on the basis of RNA-Sequencing, we isolated a plasma membrane-localized Metal Tolerance Protein (MTP) family member CsMTP4 from Zn-deficient tea plant roots and investigated its role in regulation of Zn homeostasis in tea plant. Heterologous expression of CsMTP4 specifically enhanced the tolerance of transgenic yeast to Zn excess. Moreover, overexpression of CsMTP4 in tea plant hairy roots stimulated Zn uptake under Zn deficiency. In addition, CsMTP4 promoted the growth of transgenic Arabidopsis plants by translocating Zn from roots to shoots under Zn deficiency and conferred the tolerance to Zn excess by enhancing the efflux of Zn from root cells. Transcriptome analysis of the CsMTP4 transgenic Arabidopsis found that the expression of Zn metabolism-related genes were differentially regulated compared with wild-type plants when exposed to Zn deficiency and excess conditions. This study provides a mechanistic understanding of Zn uptake and translocation in plants and a new strategy to improve phytoremediation efficiency.

Recognition of 3D Images by Fusing Fractional-Order Chebyshev Moments and Deep Neural Networks.

In order to achieve efficient recognition of 3D images and reduce the complexity of network parameters, we proposed a novel 3D image recognition method combining deep neural networks with fractional-order Chebyshev moments. Firstly, the fractional-order Chebyshev moment (FrCM) unit, consisting of Chebyshev moments and the three-term recurrence relation method, is calculated separately using successive integrals. Next, moment invariants based on fractional order and Chebyshev moments are utilized to achieve invariants for image scaling, rotation, and translation. This design aims to enhance computational efficiency. Finally, the fused network embedding the FrCM unit (FrCMs-DNNs) extracts depth features to analyze the effectiveness from the aspects of parameter quantity, computing resources, and identification capability. Meanwhile, the Princeton Shape Benchmark dataset and medical images dataset are used for experimental validation. Compared with other deep neural networks, FrCMs-DNNs has the highest accuracy in image recognition and classification. We used two evaluation indices, mean square error (MSE) and peak signal-to-noise ratio (PSNR), to measure the reconstruction quality of FrCMs after 3D image reconstruction. The accuracy of the FrCMs-DNNs model in 3D object recognition was assessed through an ablation experiment, considering the four evaluation indices of accuracy, precision, recall rate, and F1-score.

Neutrophil extracellular trap-mediated impairment of meningeal lymphatic drainage exacerbates secondary hydrocephalus after intraventricular hemorrhage.

Rationale: Hydrocephalus is a substantial complication after intracerebral hemorrhage (ICH) or intraventricular hemorrhage (IVH) that leads to impaired cerebrospinal fluid (CSF) circulation. Recently, brain meningeal lymphatic vessels (mLVs) were shown to serve as critical drainage pathways for CSF. Our previous studies indicated that the degradation of neutrophil extracellular traps (NETs) after ICH/IVH alleviates hydrocephalus. However, the mechanisms by which NET degradation exerts beneficial effects in hydrocephalus remain unclear. Methods: A mouse model of hydrocephalus following IVH was established by infusing autologous blood into both wildtype and Cx3cr1-/- mice. By studying the features and processes of the model, we investigated the contribution of mLVs and NETs to the development and progression of hydrocephalus following secondary IVH. Results: This study observed the widespread presence of neutrophils, fibrin and NETs in mLVs following IVH, and the degradation of NETs alleviated hydrocephalus and brain injury. Importantly, the degradation of NETs improved CSF drainage by enhancing the recovery of lymphatic endothelial cells (LECs). Furthermore, our study showed that NETs activated the membrane protein CX3CR1 on LECs after IVH. In contrast, the repair of mLVs was promoted and the effects of hydrocephalus were ameliorated after CX3CR1 knockdown and in Cx3cr1-/- mice. Conclusion: Our findings indicated that mLVs participate in the development of brain injury and secondary hydrocephalus after IVH and that NETs contribute to acute LEC injury and lymphatic thrombosis. CX3CR1 is a key molecule in NET-induced LEC damage and meningeal lymphatic thrombosis, which leads to mLV dysfunction and exacerbates hydrocephalus and brain injury. NETs may be a critical target for preventing the obstruction of meningeal lymphatic drainage after IVH.

Validation of biomechanical assessment of coronary plaque vulnerability based on intravascular optical coherence tomography and digital subtraction angiography.

Background: It has been suggested that biomechanical factors may influence plaque development. However, key determinants for assessing plaque vulnerability remain speculative. Methods: In this study, a two-dimensional (2D) structural mechanical analysis and a three-dimensional (3D) fluid-structure interaction (FSI) analysis were conducted based on intravascular optical coherence tomography (IV-OCT) and digital subtraction angiography (DSA) data sets. In the 2D study, 103 IV-OCT slices were analyzed. An in-depth morpho-mechanic analysis and a weighted least absolute shrinkage and selection operator (LASSO) regression analysis were conducted to identify the crucial features related to plaque vulnerability via the tuning parameter (λ). In the 3D study, the coronary model was reconstructed by fusing the IV-OCT and DSA data, and a FSI analysis was subsequently performed. The relationship between vulnerable plaque and wall shear stress (WSS) was investigated. Results: The influential factors were selected using the minimum criteria (λ-min) and one-standard error criteria (λ-1se). In addition to the common vulnerable factor of the minimum fibrous cap thickness (FCTmin), four biomechanical factors were selected by λ-min, including the average/maximal displacements and average/maximal stress, and two biomechanical factors were selected by λ-1se, including the average/maximal displacements. Additionally, the positions of the vulnerable plaques were consistent with the sites of high WSS. Conclusions: Functional indices are crucial for plaque status assessment. An evaluation based on biomechanical simulations might provide insights into risk identification and guide therapeutic decisions.

Iron/ROS/Itga3 mediated accelerated depletion of hippocampal neural stem cell pool contributes to cognitive impairment after hemorrhagic stroke.

Hemorrhagic stroke, specifically intracerebral hemorrhage (ICH), has been implicated in the development of persistent cognitive impairment, significantly compromising the quality of life for affected individuals. Nevertheless, the precise underlying mechanism remains elusive. Here, we report for the first time that the accumulation of iron within the hippocampus, distal to the site of ICH in the striatum, is causally linked to the observed cognitive impairment with both clinical patient data and animal model. Both susceptibility-weighted imaging (SWI) and quantitative susceptibility mapping (QSM) demonstrated significant iron accumulation in the hippocampus of ICH patients, which is far from the actual hematoma. Logistical regression analysis and multiple linear regression analysis identified iron level as an independent risk factor with a negative correlation with post-ICH cognitive impairment. Using a mouse model of ICH, we demonstrated that iron accumulation triggers an excessive activation of neural stem cells (NSCs). This overactivation subsequently leads to the depletion of the NSC pool, diminished neurogenesis, and the onset of progressive cognitive dysfunction. Mechanistically, iron accumulation elevated the levels of reactive oxygen species (ROS), which downregulated the expression of Itga3. Notably, pharmacological chelation of iron accumulation or scavenger of aberrant ROS levels, as well as conditionally overexpressed Itga3 in NSCs, remarkably attenuated the exhaustion of NSC pool, abnormal neurogenesis and cognitive decline in the mouse model of ICH. Together, these results provide molecular insights into ICH-induced cognitive impairment, shedding light on the value of maintaining NSC pool in preventing cognitive dysfunction in patients with hemorrhagic stroke or related conditions.

Establishing the role of BRCA1 in the diagnosis, prognosis and immune infiltrates of breast invasive cancer by bioinformatics analysis and experimental validation.

BACKGROUND: Breast cancer susceptibility gene 1 (BRCA1) is a well-known gene that acts a vital role in suppressing the growth of tumors. Previous studies have primarily focused on the genetic mutations of BRCA1 and its association with hereditary breast invasive carcinoma (BRCA). However, little research has been done to investigate the relationship between BRCA1 and immune infiltrates and prognosis in BRCA. METHODS: We obtained the expression profiles and clinical information of patients with BRCA from the Cancer Genome Atlas (TCGA) database. The levels of the BRCA1 gene between BRCA tissues and normal breast tissues were compared through the Wilcoxon rank-sum test. Additionally, we performed WB and RT-qPCR techniques to detect the expression of BRCA1. We conducted functional enrichment analyses. Furthermore, we assessed immune cell infiltration using a single-sample gene set enrichment analysis. The methylation status of the BRCA1 gene was analyzed using the UALCAN and MethSurv databases. The Cox regression analysis and (KM) Kaplan-Meier method were employed to determine the prognostic value of BRCA1. In order to provide a practical tool for predicting the overall survival rates at different time points, we also constructed a nomogram. RESULTS: Our analysis revealed that the expression of BRCA1 was significantly higher in BRCA tissues compared to normal tissues. Furthermore, this increased level of BRCA1 was found to be associated with specific BRCA subtypes, including T2, stage II, ER positive, ect. Importantly, the overexpression of BRCA1 was shown to be a negative prognostic marker for the overall survival rates of BRCA patients. Moreover, low methylation status of the BRCA1 gene was related to a poorer prognosis. Furthermore, our results indicated that high levels of BRCA1 are related to a decrease in level of killer immune cells, such as natural killer (NK) cells, macrophages, CD8+ T cells, and plasma-like dendritic cells (pDCs) within the tumor microenvironment. CONCLUSIONS: Our study is the first to provide evidence indicating that the presence of BRCA1 can serve as a reliable marker for both diagnosing and determining the prognosis of BRCA. Moreover, BRCA1 acts as a crucial indicator of the cancer's potential to infiltrate and invade the immune system, which has important implications for developing targeted therapies in BRCA.

The Nrf2 Pathway Alleviates Overloading Force-Induced TMJ Degeneration by Downregulating Oxidative Stress Reactions.

Objective: Oxidative stress is involved in the mechanisms associated with temporomandibular joint (TMJ) diseases. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial oxidative stress marker, but the specific mechanisms of its regulation in the early stages of mandibular condylar cartilage (MCC) degeneration remain unclear. This study aimed to explore the regulatory role of Nrf2 and its related oxidative stress signaling pathway in the early stage of MCC degeneration. Materials and Methods: Overloading force-induced MCC degeneration was performed in wild-type and Nrf2 knockout mice, as well as in mice after treatment with the Nrf2 activator cardamonin. Changes in MCC degeneration and the expression of oxidative stress markers in the corresponding situations were observed. Results: Nrf2 and NADPH oxidase 2 (NOX2) expression were elevated during early MCC degeneration induced by an overloading force. MCC degeneration was aggravated when Nrf2 was knocked out, accompanied by increased NOX2 and superoxide dismutase 2 (SOD2) expression. The MCC degeneration process was alleviated after cardamonin treatment, with activation of the Nrf2 pathway and decreased NOX2 and SOD2 expression. Conclusion: Early MCC degeneration is accompanied by mild oxidative stress progression. Activated Nrf2 and related pathways could alleviate the degeneration of MCC.

Large Microsphere Structure of a Co/C Composite Derived from Co-MOF with Excellent Wideband Electromagnetic Microwave Absorption Performance.

In the field of electromagnetic wave (EMW) absorption, carbon matrix materials based on metal-organic frameworks (MOFs) have drawn more interest as a result of their outstanding advantages, such as porous structure, lightweight, controlled morphology, etc. However, how to broaden the effective absorption bandwidth [EAB; reflection loss (RL) ≤ -10 dB] is still a challenge. In this paper, large microsphere structures of a Co/C composite composed of small particle clusters were successfully prepared by the solvothermal method and annealing treatment. At a filling ratio of 40 wt %, the Co/C composite shows attractive microwave absorption (MA) performance after being annealed at 600 °C in an atmosphere of argon. With an EAB of 6.32 GHz (9.92-16.24 GHz) and a thickness of just 2.57 mm, the minimum RL can be attained at -54.55 dB. Most importantly, the EAB can attain 7.12 GHz (10.88-18.0 GHz) when the thickness is 2.38 mm, which is larger than that of the majority of MOF-derived composites. The superior MA performance is strongly related to excellent impedance matching and a higher attenuation constant. This study provides a simple strategy for synthesizing a MOF-derived Co/C composite with a wide EAB.

Ankle biomechanics of the three-step layup in a basketball player with chronic ankle instability.

At present, the effects of chronic ankle instability (CAI) on the biomechanics of the ankle joint in the three-step layup of basketball players are not clear. This work aims to thoroughly investigate the impact of CAI on the biomechanical characteristics of the ankle during the execution of a three-step layup in basketball players. Thirty male basketball players were stratified into distinct groups-namely, a CAI group and a non-CAI group-comprising 15 individuals each, based on the presence or absence of CAI. Demographic attributes, including age, weight, height, and the Cumberland Ankle Instability Tool (CAIT) score, were subjected to rigorous statistical examination within both athlete cohorts. The research employed four Whistler 9281CA 3D force measuring platforms (Switzerland), recording at 1000 Hz, in conjunction with eight camera motion analysis systems (USA), functioning at a frequency of 200 Hz. The study recorded maximal plantarflexion angle, inversion angle, dorsiflexion angle, and peak ankle dorsiflexion moment across the subjects during the distinct phases of push-off, landing, and the ensuing landing period. The findings notably exhibited that within the context of the one-foot push-off phase, the maximum ankle inversion angle was notably diminished in the CAI group as contrasted with the non-CAI group, demonstrating statistical significance (t = - 3.006, P < 0.01). The CAI group exhibited a lesser alteration in ankle inversion angle compared to the non-CAI group. Notably, during the one-foot landing period, the CAI group demonstrated a significantly greater maximum ankle inversion angle in contrast to the non-CAI group (t = 8.802, P < 0.001). Furthermore, the CAI group displayed a substantially larger maximum dorsiflexion angle at the ankle joint compared to the non-CAI group (t = 2.265, P < 0.05). Additionally, the CAI group exhibited a prolonged peak time for ankle dorsiflexion moment as compared to the non-CAI group (t = - 2.428, P < 0.05). Collectively, the findings elucidated a reduction in the maximum ankle joint inversion angle during the one-foot push-off phase in individuals with CAI. Furthermore, increased maximum inversion angle and maximum dorsiflexion angle of the ankle joint were observed during the one-foot landing period, alongside a lengthening of the peak time of ankle dorsiflexion moment. These results contribute valuable insights into the selection of training methodologies for basketball players afflicted by CAI.

Plant-derived nanovesicles: harnessing nature's power for tissue protection and repair.

Tissue damage and aging lead to dysfunction, disfigurement, and trauma, posing significant global challenges. Creating a regenerative microenvironment to resist external stimuli and induce stem cell differentiation is essential. Plant-derived nanovesicles (PDNVs) are naturally bioactive lipid bilayer nanovesicles that contain proteins, lipids, ribonucleic acid, and metabolites. They have shown potential in promoting cell growth, migration, and differentiation into various types of tissues. With immunomodulatory, microbiota regulatory, antioxidant, and anti-aging bioactivities, PDNVs are valuable in resisting external stimuli and facilitating tissue repair. The unique structure of PDNVs provides an optimal platform for drug encapsulation, and surface modifications enhance their stability and specificity. Moreover, by employing synergistic administration strategies, PDNVs can maximize their therapeutic potential. This review summarized the progress and prospects of PDNVs as regenerative tools, provided insights into their selection for repair activities based on existing studies, considered the key challenge for clinical application, and anticipated their continued prominent role in the field of biomedicine.

Deep learning-based multi-stage postoperative type-b aortic dissection segmentation using global-local fusion learning.

Objective.Type-b aortic dissection (AD) is a life-threatening cardiovascular disease and the primary treatment is thoracic endovascular aortic repair (TEVAR). Due to the lack of a rapid and accurate segmentation technique, the patient-specific postoperative AD model is unavailable in clinical practice, resulting in impracticable 3D morphological and hemodynamic analyses during TEVAR assessment. This work aims to construct a deep learning-based segmentation framework for postoperative type-b AD.Approach.The segmentation is performed in a two-stage manner. A multi-class segmentation of the contrast-enhanced aorta, thrombus (TH), and branch vessels (BV) is achieved in the first stage based on the cropped image patches. True lumen (TL) and false lumen (FL) are extracted from a straightened image containing the entire aorta in the second stage. A global-local fusion learning mechanism is designed to improve the segmentation of TH and BR by compensating for the missing contextual features of the cropped images in the first stage.Results.The experiments are conducted on a multi-center dataset comprising 133 patients with 306 follow-up images. Our framework achieves the state-of-the-art dice similarity coefficient (DSC) of 0.962, 0.921, 0.811, and 0.884 for TL, FL, TH, and BV, respectively. The global-local fusion learning mechanism increases the DSC of TH and BV by 2.3% (p< 0.05) and 1.4% (p< 0.05), respectively, based on the baseline. Segmenting TH in stage 1 can achieve significantly better DSC for FL (0.921 ± 0.055 versus 0.857 ± 0.220,p< 0.01) and TH (0.811 ± 0.137 versus 0.797 ± 0.146,p< 0.05) than in stage 2. Our framework supports more accurate vascular volume quantifications compared with previous segmentation model, especially for the patients with enlarged TH+FL after TEVAR, and shows good generalizability to different hospital settings.Significance.Our framework can quickly provide accurate patient-specific AD models, supporting the clinical practice of 3D morphological and hemodynamic analyses for quantitative and more comprehensive patient-specific TEVAR assessments.

Discovery of YS-363 as a highly potent, selective, and orally efficacious EGFR inhibitor.

The Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard first-line therapy for EGFR-mutated NSCLC. However, long-term clinical treatment often leads to acquired drug resistance, making NSCLC refractory. Therefore, it is essential to design new EGFR inhibitors as potential drugs against NSCLC. This study reports on a novel quinazoline-based compound called YS-363 that acts as a new EGFR inhibitor. YS-363 demonstrated potent inhibition against both wild-type and L858R mutant forms of EGFR with IC50 values of 0.96 nM and 0.67 nM, respectively. Additionally, YS-363 had a reversible inhibitory effect on cellular EGFR signaling, had excellent inhibitory activity on cell proliferation and migration, and induced G0/G1 cell cycle arrest and apoptosis. In xenograft models dependent on EGFR signaling, oral administration of YS-363 substantially suppressed tumor growth by inhibiting this pathway. In summary, YS-363 is a promising selective reversible inhibitor with a novel quinazoline scaffold that can potentially develop more effective anti-lung cancer agents targeting EGFR in patients who have developed resistance to current therapies such as TKIs like gefitinib or erlotinib.

Insights into Electrochemical Dehalogenation by Non-Noble Metal Single-Atom Cobalt with High Efficiency and Low Energy Consumption.

It is critical to discover a non-noble metal catalyst with high catalytic activity capable of replacing palladium in electrochemical reduction. In this work, a highly efficient single-atom Co-N/C catalyst was synthesized with metal-organic frameworks (MOFs) as a precursor for electrochemical dehalogenation. X-ray absorption spectroscopy (XAS) revealed that Co-N/C exhibited a Co-N4 configuration, which had more active sites and a faster charge-transfer rate and thus enabled the efficient removal of florfenicol (FLO) at a wide pH, achieving a rate constant 3.5 and 2.1 times that of N/C and commercial Pd/C, respectively. The defluorination and dechlorination efficiencies were 67.6 and 95.6%, respectively, with extremely low Co leaching (6 µg L-1), low energy consumption (22.7 kWh kg-1), and high turnover frequency (TOF) (0.0350 min-1), demonstrating excellent dehalogenation performance. Spiking experiments and density functional theory (DFT) verified that Co-N4 was the active site and had the lowest energy barrier for forming atomic hydrogen (H*) (ΔGH*). Capture experiments, electron paramagnetic resonance (EPR), electrochemical tests, and in situ Fourier transform infrared (FTIR) proved that H* and direct electron transfer were responsible for dehalogenation. Toxicity assessment indicated that FLO toxicity decreased significantly after dehalogenation. This work develops a non-noble metal catalyst with broad application prospects in electrocatalytic dehalogenation.

A Dual-Targeted Metal-Organic Framework Based Nanoplatform for the Treatment of Rheumatoid Arthritis by Restoring the Macrophage Niche.

Inflammatory infiltration and bone destruction are important pathological features of rheumatoid arthritis (RA), which originate from the disturbed niche of macrophages. Here, we identified a niche-disrupting process in RA: due to overactivation of complement, the barrier function of VSIg4+ lining macrophages is disrupted and mediates inflammatory infiltration within the joint, thereby activating excessive osteoclastogenesis and bone resorption. However, complement antagonists have poor biological applications due to superphysiologic dose requirements and inadequate effects on bone resorption. Therefore, we developed a dual-targeted therapeutic nanoplatform based on the MOF framework to achieve bone-targeted delivery of the complement inhibitor CRIg-CD59 and pH-responsive sustained release. The surface-mineralized zoledronic acid (ZA) of ZIF8@CRIg-CD59@HA@ZA targets the skeletal acidic microenvironment in RA, and the sustained release of CRIg-CD59 can recognize and prevent the complement membrane attack complex (MAC) from forming on the surface of healthy cells. Importantly, ZA can inhibit osteoclast-mediated bone resorption, and CRIg-CD59 can promote the repair of the VSIg4+ lining macrophage barrier to achieve sequential niche remodeling. This combination therapy is expected to treat RA by reversing the core pathological process, circumventing the pitfalls of traditional therapy.

Targeting ASIC1a Promotes Neural Progenitor Cell Migration and Neurogenesis in Ischemic Stroke.

Cell replacement therapy using neural progenitor cells (NPCs) has been shown to be an effective treatment for ischemic stroke. However, the therapeutic effect is unsatisfactory due to the imbalanced homeostasis of the local microenvironment after ischemia. Microenvironmental acidosis is a common imbalanced homeostasis in the penumbra and could activate acid-sensing ion channels 1a (ASIC1a), a subunit of proton-gated cation channels following ischemic stroke. However, the role of ASIC1a in NPCs post-ischemia remains elusive. Here, our results indicated that ASIC1a was expressed in NPCs with channel functionality, which could be activated by extracellular acidification. Further evidence revealed that ASIC1a activation inhibited NPC migration and neurogenesis through RhoA signaling-mediated reorganization of filopodia formation, which could be primarily reversed by pharmacological or genetic disruption of ASIC1a. In vivo data showed that the knockout of the ASIC1a gene facilitated NPC migration and neurogenesis in the penumbra to improve behavioral recovery after stroke. Subsequently, ASIC1a gain of function partially abrogated this effect. Moreover, the administration of ASIC1a antagonists (amiloride or Psalmotoxin 1) promoted functional recovery by enhancing NPC migration and neurogenesis. Together, these results demonstrate targeting ASIC1a is a novel strategy potentiating NPC migration toward penumbra to repair lesions following ischemic stroke and even for other neurological diseases with the presence of niche acidosis.

A CT-based predictive model for stent-induced vessel damage: application to type B aortic dissection.

OBJECTIVES: The distal stent-induced new entry (distal SINE) is a life-threatening device-related complication after thoracic endovascular aortic repair (TEVAR). However, risk factors for distal SINE are not fully determined, and prediction models are lacking. This study aimed to establish a predictive model for distal SINE based on the preoperative dataset. METHODS: Two hundred and six patients with Stanford type B aortic dissection (TBAD) that experienced TEVAR were involved in this study. Among them, thirty patients developed distal SINE. Pre-TEVAR morphological parameters were measured based on the CT-reconstructed configurations. Virtual post-TEVAR morphological and mechanical parameters were computed via the virtual stenting algorithm (VSA). Two predictive models (PM-1 and PM-2) were developed and presented as nomograms to help risk evaluation of distal SINE. The performance of the proposed predictive models was evaluated and internal validation was conducted. RESULTS: Machine-selected variables for PM-1 included key pre-TEVAR parameters, and those for PM-2 included key virtual post-TEVAR parameters. Both models showed good calibration in both development and validation subsamples, while PM-2 outperformed PM-1. The discrimination of PM-2 was better than PM-1 in the development subsample, with an optimism-corrected area under the curve (AUC) of 0.95 and 0.77, respectively. Application of PM-2 in the validation subsample presented good discrimination with an AUC of 0.9727. The decision curve demonstrated that PM-2 was clinically useful. CONCLUSION: This study proposed a predictive model for distal SINE incorporating the CT-based VSA. This predictive model could efficiently predict the risk of distal SINE and thus might contribute to personalized intervention planning. CLINICAL RELEVANCE STATEMENT: This study established a predictive model to evaluate the risk of distal SINE based on the pre-stenting CT dataset and planned device information. With an accurate VSA tool, the predictive model could help to improve the safety of the endovascular repair procedure. KEY POINTS: • Clinically useful prediction models for distal stent-induced new entry are still lacking, and the safety of the stent implantation is hard to guarantee. • Our proposed predictive tool based on a virtual stenting algorithm supports different stenting planning rehearsals and real-time risk evaluation, guiding clinicians to optimize the presurgical plan when necessary. • The established prediction model provides accurate risk evaluation for vessel damage, improving the safety of the intervention procedure.