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Lead-free halide perovskites have recently garnered significant attention due to their rich structural diversity and exceptionally ultralow lattice thermal conductivity (κL). Here, we employ first-principles calculations in conjunction with self-consistent phonon theory and Boltzmann transport equations to investigate the crystal structure, electronic structure, mechanical properties, and κLs of two typical vacancy-ordered halide perovskites, denoted with the general formula Cs3Bi2X9 (X = Br, I). Ultralow κLs of 0.401 and 0.262 W mK-1 at 300 K are predicted for Cs3Bi2Br9 and Cs3Bi2I9, respectively. Our findings reveal that the ultralow κLs are mainly associated with the Cs rattling-like motion, vibrations of halide polyhedral frameworks, and strong scattering in the acoustic and low-frequency optical phonon branches. The structural analysis indicates that these phonon dynamic properties are closely relevant to the bonding hierarchy. The presence of the extended Bi-X antibonding states at the valence band maximum contributes to the soft elastic lattice and low phonon group velocities. Compared to Cs3Bi2Br9, the face-sharing feature and weaker bond strength in Cs3Bi2I9 lead to a softer elasticity modulus and stronger anharmonicity. Additionally, we demonstrate the presence of wave-like κC in Cs3Bi2X9 by evaluating the coherent contribution. Our work provides the physical microscopic mechanisms of the wave-like κC in two typical lead-free halide perovskites, which are beneficial to designing intrinsic materials with the feature of ultralow κL.
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OBJECTIVE: To investigate the relationship between the expression of PD-L1 in OSCC and the clinicopathological features and prognosis of patients. METHODS: We retrospectively analyzed the clinicopathological data and prognosis of 381 OSCC patients. Immunohistochemical staining was performed on OSCC tumor specimens, and the expression level of PD-L1 was evaluated according to the combined positive score (CPS). Kaplan-Meier analysis was used to identify the effect of PD-L1 expression and clinicopathological features on the prognosis of patients. Univariate and multivariate Cox regression analyses were conducted to determine the hazard factors affecting the prognosis of patients. RESULTS: PD-L1 overexpression was significantly associated with cervical lymph node metastasis (p = 0.018), worse clinical stage (p = 0.022), worse tumor differentiation (p = 0.046), and worse depth of invasion (DOI) (p = 0.003). Poorer clinical stage and degree of tumor differentiation were significantly associated with poorer OS and DSS in patients. PD-L1 expression was not associated with prognosis in patients with OSCC. CONCLUSIONS: High PD-L1 expression was significantly associated with higher tumor malignancy in OSCC patients. Poorer clinical stage and degree of tumor differentiation were associated with poor prognosis in OSCC patients. Our results may help clinicians develop more appropriate individualized treatment strategies for their patients, thus improving their outcomes.
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Background: Ryanodine receptor 2 (RyR2) is one of the first substrates undergoing phosphorylation upon catecholaminergic stimulation. Yet, the role of RyR2 phosphorylation in the adrenergic response remains debated. To date, three residues in RyR2 are known to undergo phosphorylation upon adrenergic stimulation. We generated a model of RyR2 phospho-ablation of all three canonical phospho-sites (RyR2-S2031A/S2808A/S2814A, triple phospho-mutant, TPM) to elucidate the role of phosphorylation at these residues in the adrenergic response. Methods: Cardiac structure and function, cellular Ca 2+ dynamics and electrophysiology, and RyR2 channel activity both under basal conditions and under isoproterenol (Iso) stimulation were systematically evaluated. We used echocardiography and electrocardiography in anesthetized mice, single-cell Ca 2+ imaging and whole-cell patch clamp in isolated adult cardiomyocytes, and biochemical assays. Results: Iso stimulation produced normal chronotropic and inotropic responses in TPM mice as well as an increase in the global Ca 2+ transients in isolated cardiomyocytes. Functional studies revealed fewer Ca 2+ sparks in permeabilized TPM myocytes, and reduced RyR2-mediated Ca 2+ leak in intact myocytes under Iso stimulation, suggesting that the canonical sites may regulate RyR2-mediated Ca 2+ leak. TPM mice also displayed increased propensity for arrhythmia. TPM myocytes were prone to develop early afterdepolarizations (EADs), which were abolished by chelating intracellular Ca 2+ with EGTA, indicating that EADs require SR Ca 2+ release. EADs were also blocked by a low concentration of tetrodotoxin, further suggesting reactivation of the sodium current ( I Na ) as the underlying cause. Conclusion: Phosphorylation of the three canonical residues on RyR2 may not be essential for the global adrenergic responses. However, these sites play a vital role in maintaining electrical stability during catecholamine stimulation by fine-tuning RyR2-mediated Ca 2+ leak. These findings underscore the importance of RyR2 phosphorylation and a finite diastolic Ca 2+ leak in maintaining electrical stability during catecholamine stimulation.
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Retinoblastoma (RB) is the most common intraocular malignancy in childhood. The causal variants in RB are mostly characterized by previously used short-read sequencing (SRS) analysis, which has technical limitations in identifying structural variants (SVs) and phasing information. Long-read sequencing (LRS) technology has advantages over SRS in detecting SVs, phased genetic variants, and methylation. In this study, we comprehensively characterized the genetic landscape of RB using combinatorial LRS and SRS of 16 RB tumors and 16 matched blood samples. We detected a total of 232 somatic SVs, with an average of 14.5 SVs per sample across the whole genome in our cohort. We identified 20 distinct pathogenic variants disrupting RB1 gene, including three novel small variants and five somatic SVs. We found more somatic SVs were detected from LRS than SRS (140 vs. 122) in RB samples with WGS data, particularly the insertions (18 vs. 1). Furthermore, our analysis shows that, with the exception of one sample who lacked the methylation data, all samples presented biallelic inactivation of RB1 in various forms, including two cases with the biallelic hypermethylated promoter and four cases with compound heterozygous mutations which were missing in SRS analysis. By inferring relative timing of somatic events, we reveal the genetic progression that RB1 disruption early and followed by copy number changes, including amplifications of Chr2p and deletions of Chr16q, during RB tumorigenesis. Altogether, we characterize the comprehensive genetic landscape of RB, providing novel insights into the genetic alterations and mechanisms contributing to RB initiation and development. Our work also establishes a framework to analyze genomic landscape of cancers based on LRS data.
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The PhI(OAc)2-promoted 1,2-transfer reaction between allylic alcohols and thiophenols, conducted in an argon atmosphere, has proven to be effective in producing ß-carbonyl sulfides from 1,1-disubstituted allylic alcohols in high yields. This method offers a fast and efficient way to synthesize ß-carbonyl sulfides, which are valuable intermediates in organic synthesis. This discussion focuses on the effects of the oxidizer, temperature, and solvent on the reaction. A proposed tentative mechanism for this reaction is also discussed.
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O-linked N-acetylglucosamine protein modification (O-GlcNAcylation) is a dynamic post-translational modification (PTM) involving the covalent binding of serine and/or threonine residues, which regulates bone cell homeostasis. Reactive oxygen species (ROS) are increased due to oxidative stress in various pathological contexts related to bone remodeling, such as osteoporosis, arthritis, and bone fracture. Autophagy serves as a scavenger for ROS within bone marrow-derived mesenchymal stem cells, osteoclasts, and osteoblasts. However, oxidative stress-induced autophagy is affected by the metabolic status, leading to unfavorable clinical outcomes. O-GlcNAcylation can regulate the autophagy process both directly and indirectly through oxidative stress-related signaling pathways, ultimately improving bone remodeling. The present interventions for the bone remodeling process often focus on promoting osteogenesis or inhibiting osteoclast absorption, ignoring the effect of PTM on the overall process of bone remodeling. This review explores how O-GlcNAcylation synergizes with autophagy to exert multiple regulatory effects on bone remodeling under oxidative stress stimulation, indicating the application of O-GlcNAcylation as a new molecular target in the field of bone remodeling.
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Acetylglucosamine , Autophagy , Bone Remodeling , Oxidative Stress , Humans , Animals , Acetylglucosamine/metabolism , Protein Processing, Post-TranslationalABSTRACT
The orbital angular momentum (OAM) of vortex beams has great potential in optical communications due to its communication confidentiality and low crosstalk. It is necessary to design a plausible OAM pattern recognition mechanism. Abandoning AI models that require large datasets, a single passive all-dielectric metasurface consisting of TiO2 nanopillars on a SiO2 substrate is used to recognize high-order optical vortexes. In this configuration, the proposed device is capable of simultaneously encoding the wavefront and the transmission paths in different incident OAM beams. Due to the presence of spin angular momentum (SAM), the vortex beam to be identified is spatially separated after passing through the metasurface. As a proof of concept, 14 signal channels are considered in the constructed metasurface, 12 of them can be encoded at will for the detection of any vortex beam with a predefined topological charge. These results make use of metasurfaces to enable OAM pattern recognition in an effective way, which may open avenues for the ultimate miniaturization of optical vortex communication and advanced OAM detection technologies.
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Finding suitable fiber amplifiers is one of the key strategies to increase the transmission capacity of fiber links. Recently, bismuth-doped fiber amplifiers (BDFAs) have attracted much attention due to their distinctive ultra-wideband luminescence properties. In this paper, we propose a linear cavity double pass structure for BDFA operating in the O and E bands. The design creates a linear cavity within the amplifier by combining a fiber Bragg grating (FBG) and a fiber mirror to achieve dual-wavelength pump at 1240â nm and 1310â nm. Meanwhile, the configuration of a circulator and mirror facilitates bidirectional signal propagation through the BDFA, resulting in a double-pass amplification structure. We have tested and analyzed the performance of the linear cavity double pass structure BDFA under different pump schemes and compared it with the conventional structure BDFA. The results show that the gain spectrum of the new structure is shifted toward longer wavelengths, and the gain band is extended from the O band to the O and E bands compared with the conventional structure. In particular, the linear cavity double pass structure BDFA has more relaxed requirements on the stability of the pump and signal power. This work provides a positive reference for the design, application, and development of BDFAs.
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The identification of genome-wide selection signatures can reveal the potential genetic mechanisms involved in the generation of new breeds through natural or artificial selection. In this study, we screened the genome-wide selection signatures of prolific Suffolk sheep, a new strain of multiparous mutton sheep, to identify candidate genes for reproduction traits and unravel the germplasm characteristics and population genetic evolution of this new strain of Suffolk sheep. Whole-genome resequencing was performed at an effective sequencing depth of 20× for genomic diversity and population structure analysis. Additionally, selection signatures were investigated in prolific Suffolk sheep, Suffolk sheep, and Hu sheep using fixation index (F ST) and heterozygosity H) analysis. A total of 5,236.338 Gb of high-quality genomic data and 28,767,952 SNPs were obtained for prolific Suffolk sheep. Moreover, 99 selection signals spanning candidate genes were identified. Twenty-three genes were significantly associated with KEGG pathway and Gene Ontology terms related to reproduction, growth, immunity, and metabolism. Through selective signal analysis, genes such as ARHGEF4, CATIP, and CCDC115 were found to be significantly correlated with reproductive traits in prolific Suffolk sheep and were highly associated with the mTOR signaling pathway, the melanogenic pathway, and the Hippo signaling pathways, among others. These results contribute to the understanding of the evolution of artificial selection in prolific Suffolk sheep and provide candidate reproduction-related genes that may be beneficial for the establishment of new sheep breeds.
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BACKGROUND: Acupuncture is a method for treating tic disorder. However, there is a lack of sufficient clinical objective basis in regards of its treatment efficacy. Indeed, there are structural abnormalities present in energy metabolism and infrared thermography in children with tic disorder. Therefore, this study proposes a clinical trial scheme to explore the possible mechanism of acupuncture in treating tic disorder. METHODS: This randomized controlled trial will recruit a total of 90 children, in which they will be divided into non-intervention group and intervention group. The non-intervention group consists of 30 healthy children while the intervention group consists of 60 children with tic disorder. The intervention group will be randomly allocated into either the treatment group or the control group, with 30 children randomly assigned in each group. Children either received acupuncture treatment and behavioral therapy (treatment group) or sham acupuncture treatment and behavioral therapy (control group), 3 treatment sessions per week for a period of 12 weeks, with a total of 36 treatment sessions. Outcome measures include YGTSS, urinary and fecal metabolomics, infrared thermography of body surface including governor vessel. For the intervention group, these outcome measures will be collected at the baseline and 90th day prior to intervention. Whereas for the non-intervention group, outcome measures (excluding YGTSS) will be collected at the baseline. DISCUSSION: The main outcome will be to observe the changes of the severity of tic condition, the secondary outcome will be to observe the changes of structural characteristic of infrared thermography of body surface/acupoints along the governor vessel and to evaluate the changes of urinary and fecal metabolomics at the end of the treatment, so as to analyze the relationship between them and to provide further knowledge in understanding the possible mechanism of acupuncture in improving the clinical symptoms via regulating and restoring the body metabolomics network, which in future it can develop as a set of clinical guideline (diagnosis, treatment, assessment, prognosis) in treating tic disorder. ChiCTR2300075188(Chinese Clinical Trial Registry, http://www.chictr.org.cn , registered on 29 August 2023).
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Acupuncture Therapy , Metabolomics , Thermography , Tic Disorders , Humans , Thermography/methods , Acupuncture Therapy/methods , Child , Tic Disorders/therapy , Female , Male , Child, Preschool , Adolescent , Infrared Rays , Randomized Controlled Trials as TopicABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese herbal remedy Atractylodes macrocephala Koidz is renowned for its purported gastrointestinal regulatory properties and immune-enhancing capabilities. Atractylenolide III (ATL III), a prominent bioactive compound in Atractylodes macrocephala Koidz, has demonstrated significant pharmacological activities. However, its impact on neuroinflammation, oxidative stress, and therapeutic potential concerning Alzheimer's disease (AD) remain inadequately investigated. AIM OF THE STUDY: This study aims to assess the plasma pharmacokinetics of ATL III in Sprague-Dawley (SD) rats and elucidate its neuropharmacological effects on AD via the PI3K/AKT/GSK3ß pathway. Through this research, we endeavor to furnish experimental substantiation for the advancement of novel therapeutics centered on ATL III. MATERIALS AND METHODS: The pharmacokinetic profile of ATL III in SD rat plasma was analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). AD models were induced in SD rats through bilateral intracerebroventricular (ICV) administration of streptozotocin (STZ). ATL III was administered at doses of 0.6 mg/kg, 1.2 mg/kg, and 2.4 mg/kg, while donepezil (1 mg/kg) served as control. Cognitive function assessments were conducted employing behavioral tests including the Morris Water Maze and Novel Object Recognition. Neuronal pathology and histological changes were evaluated through Nissl staining and Hematoxylin-Eosin (HE) staining, respectively. Oxidative stress levels were determined by quantifying malondialdehyde (MDA) content and total superoxide dismutase (T-SOD) activity. Molecular docking analysis was employed to explore the direct binding between ATL III and its relevant targets, followed by validation using Western blot (WB) experiments to assess the expression of p-Tau, PI3K, AKT, GSK3ß, and their phosphorylated forms. RESULTS: Within the concentration range of 5-500 ng/mL, ATL III demonstrated exceptional linearity (R2 = 0.9991), with a quantification limit of 5 ng/mL. In male SD rats, ATL III exhibited a Tmax of 45 min, a t1/2 of 172.1 min, a Cmax of 1211 ng/L, and an AUC(0-t) of 156031 ng/L*min. Treatment with ATL III significantly attenuated Tau hyperphosphorylation in intracerebroventricular-streptozotocin (ICV-STZ) rats. Furthermore, ATL III administration mitigated neuroinflammation and oxidative stress, as evidenced by reduced Nissl body loss, alleviated histological alterations, decreased MDA content, and enhanced T-SOD activity. Molecular docking analyses revealed strong binding affinity between ATL III and the target genes PI3K, AKT, and GSK3ß. Experimental validation corroborated that ATL III stimulated the phosphorylation of PI3K and AKT while reducing the phosphorylation of GSK3ß. CONCLUSIONS: Our results indicate that ATL III can mitigate Tau protein phosphorylation through modulation of the PI3K/AKT/GSK3ß pathway. This attenuation consequently ameliorates neuroinflammation and oxidative stress, leading to enhanced learning and memory abilities in ICV-STZ rats.
Subject(s)
Cognitive Dysfunction , Glycogen Synthase Kinase 3 beta , Lactones , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Sesquiterpenes , Streptozocin , Animals , Male , Rats , Cognitive Dysfunction/drug therapy , Disease Models, Animal , Glycogen Synthase Kinase 3 beta/metabolism , Lactones/pharmacology , Lactones/pharmacokinetics , Lactones/administration & dosage , Maze Learning/drug effects , Molecular Docking Simulation , Neuroprotective Agents/pharmacology , Neuroprotective Agents/pharmacokinetics , Neuroprotective Agents/administration & dosage , Oxidative Stress/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Rats, Sprague-Dawley , Sesquiterpenes/pharmacology , Sesquiterpenes/pharmacokinetics , Sesquiterpenes/administration & dosage , Signal Transduction/drug effectsABSTRACT
This article puts forth a new training data-untethered model poisoning (MP) attack on federated learning (FL). The new MP attack extends an adversarial variational graph autoencoder (VGAE) to create malicious local models based solely on the benign local models overheard without any access to the training data of FL. Such an advancement leads to the VGAE-MP attack that is not only efficacious but also remains elusive to detection. VGAE-MP attack extracts graph structural correlations among the benign local models and the training data features, adversarially regenerates the graph structure, and generates malicious local models using the adversarial graph structure and benign models' features. Moreover, a new attacking algorithm is presented to train the malicious local models using VGAE and sub-gradient descent, while enabling an optimal selection of the benign local models for training the VGAE. Experiments demonstrate a gradual drop in FL accuracy under the proposed VGAE-MP attack and the ineffectiveness of existing defense mechanisms in detecting the attack, posing a severe threat to FL.
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O-linked N-acetylglucosamine (O-GlcNAc) protein modification (O-GlcNAcylation) is a critical post-translational modification (PTM) of cytoplasmic and nuclear proteins. O-GlcNAcylation levels are regulated by the activity of two enzymes, O-GlcNAc transferase (OGT) and OGlcNAcase (OGA). While OGT attaches O-GlcNAc to proteins, OGA removes O-GlcNAc from proteins. Since its discovery, researchers have demonstrated O-GlcNAcylation on thousands of proteins implicated in numerous different biological processes. Moreover, dysregulation of O-GlcNAcylation has been associated with several pathologies, including cancers, ischemia-reperfusion injury, and neurodegenerative diseases. In this review, we focus on progress in our understanding of the role of O-GlcNAcylation in bone pathophysiology, and we discuss the potential molecular mechanisms of O-GlcNAcylation modulation of bone-related diseases. In addition, we explore significant advances in the identification of O-GlcNAcylation-related regulators as potential therapeutic targets, providing novel therapeutic strategies for the treatment of bone-related disorders.
Subject(s)
Acetylglucosamine , N-Acetylglucosaminyltransferases , Humans , Animals , N-Acetylglucosaminyltransferases/metabolism , Acetylglucosamine/metabolism , Bone and Bones/metabolism , Protein Processing, Post-Translational , Bone Diseases/metabolismABSTRACT
High-resolution and dynamic bioimaging is essential in life sciences and biomedical applications. In recent years, microspheres combined with optical microscopes have offered a low cost but promising solution for super-resolution imaging, by breaking the diffraction barrier. However, challenges still exist in precisely and parallelly superlens controlling using a noncontact manner, to meet the demands of large-area scanning imaging for desired targets. This study proposes an acoustic wavefield-based strategy for assembling and manipulating micrometer-scale superlens arrays, in addition to achieving on-demand scanning imaging through phase modulation. In experiments, acoustic pressure nodes are designed to be comparable in size to microspheres, allowing spatially dispersed microspheres to be arranged into arrays with one unit per node. Droplet microlenses with various diameters can be adapted in the array, allowing for a wide range of spacing periods by applying different frequencies. In addition, through the continuous phase shifting in the x and y directions, this acoustic superlens array achieves on-demand moving for the parallel high-resolution virtual image capturing and scanning of nanostructures and biological cell samples. As a comparison, this noncontact and cost-effective acoustic manner can obtain more than â¼100 times the acquisition efficiency of a single lens, holding promise in advancing super-resolution microscopy and subcellular-level bioimaging.
Subject(s)
Acoustics , Humans , Microspheres , Lenses , Particle SizeABSTRACT
Biofiltration systems harbored and disseminated antibiotic resistance genes (ARGs), when confronting antibiotic-contained wastewater. Biochar, a widely used environmental remediation material, can mitigate antibiotic stress on adjoining microbes by lowering the availability of sorbed antibiotics, and enhance the attachment of denitrifiers. Herein, bench-scale biofiltration systems, packed with commercial biochars, were established to explore the pivotal drivers affecting ARG emergence. Results showed that biofiltration columns, achieving higher TN removal and denitrification capacity, showed a significant decrease in ARG accumulation (p < 0.05). The relative abundance of ARGs (0.014 ± 0.0008) in the attached biofilms decreased to 1/5-folds of that in the control group (0.065 ± 0.004). Functional analysis indicated ARGs' accumulation was less attributed to ARG activation or horizontal gene transfer (HGT) driven by sorbed antibiotics. Most denitrifiers, like Bradyrhizobium, Geothrix, etc., were found to be enriched and host ARGs. Nitrosative stress from deficient denitrification was demonstrated to be the dominant driver for affecting ARG accumulation and dissemination. Metagenomic and metaproteomic analysis revealed that nitrosative stress promoted the conjugative HGT of ARGs mainly via increasing the transmembrane permeability and enhancing the amino acid transport and metabolism, such as cysteine, methionine, and valine metabolism. Overall, this study highlighted the risks of deficient denitrification in promoting ARG transfer and transmission in biofiltration systems and natural ecosystems.
Subject(s)
Charcoal , Denitrification , Drug Resistance, Microbial , Gene Transfer, Horizontal , Charcoal/chemistry , Drug Resistance, Microbial/genetics , Anti-Bacterial Agents , Filtration/methods , Waste Disposal, Fluid/methods , Wastewater/microbiology , BiofilmsABSTRACT
A new multiple-time scale integration method is presented that propagates ab initio path integral molecular dynamics (PIMD). This method uses a large time step to generate an approximate geometrical configuration whose energy and gradient are evaluated at the level of an ab initio method, and then, a more precise integration scheme, e.g., the Bulirsch-Stoer method or velocity Verlet integration with a smaller time step, is used to integrate from the previous step using the computationally efficient interpolated potential energy surface constructed from two consecutive points. This method makes the integration of PIMD more efficient and accurate compared with the velocity Verlet integration. A Nosé-Hoover chain thermostat combined with this new multiple-time scale method has good energy conservation even with a large time step, which is usually challenging in velocity Verlet integration for PIMD due to the very small chain mass when a large number of beads are used. The new method is used to calculate infrared spectra and free energy profiles to demonstrate its accuracy and capabilities.
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To achieve an autonomously controlled reconfigurable microwave waveform generator, this study proposes and demonstrates a self-adjusting synthesis method based on a photonic delay reservoir computer with ring resonator. The proposed design exploits the ring resonator to configure the reservoir, facilitating a nonlinear transformation and providing delay space. A theoretical analysis is conducted to explain how this configuration addresses the challenges of microwave waveform generation. Considering the generalization performance of waveform generation, the simulations demonstrate the system's capability to produce six distinct representative waveforms, all exhibiting a highly impressive root mean square error (RMSE) of less than 1%. To further optimize the system's flexibility and accuracy, we explore the application of various artificial intelligence algorithms at the reservoir computer's output layer. Furthermore, our investigation delves deeply into the complexities of system performance, specifically exploring the influence of reservoir neurons and micro-ring resonator parameters on calculation performance. We also delve into the scalability of reservoirs, considering both parallel and cascaded arrangements.
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Purpose: To assess the efficacy and safety of intrastromal lenticule implantation for the treatment of hyperopia. Methods: A systematic search of PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Internet, and Wan Fang Database identified studies on small-incision intrastromal lenticule implantation for hyperopia correction until January 2023. The Joanna Briggs Institute (JBI) critical appraisal tool was used to assess the quality of the retrospective research, and the Methodological Index for Non-randomized Studies (MINORS) was used to assess the quality of the prospective research. This study included postoperative visual outcomes, corneal morphology, and biomechanical outcomes. Results: A total of 456 articles were identified, of which 10 were included in the meta-analysis. Ten single-arm studies involving 190 eyes were included. A meta-analysis demonstrated that corneal intrastromal lenticule implantation treatment significantly improved hyperopia. Uncorrected distance visual acuity (UDVA) significantly improved compared to the preoperative value (p = 0.027), corrected distance visual acuity showed no difference compared to the preoperative value (p = 0.27), and 87% eyes have no loss of one or more lines in the Snellen lines of CDVA (p < 0.00001). There was a significant difference between the spherical equivalent refractive (SE) and preoperative examination (p < 0.00001), 52% of eyes had ±0.5 diopters (D) postoperative SE (p < 0.00001), and 74% eyes had ±1.0 D postoperative SE (p < 0.00001). The central corneal thickness (CCT) increased by 72.68 µm compared to that preoperatively (p < 0.00001), and corneal curvature increased by 4.18D (p < 0.00001). The Q-value decreased by 0.82 (p < 0.00001), and higher-order aberration (HOA) decreased by 0.66 (p < 0.00001). Conclusion: Small-incision intrastromal lenticule implantation may be an effective solution for correcting hyperopia. The effect of improved vision is significant, but further exploration is needed for changes in corneal biomechanics and long-term safety.Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42023432343.
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Background/aims: The reciprocal promotion of cancer and stroke occurs due to changes in shared risk factors, such as metabolic pathways and molecular targets, creating a "vicious cycle." Cancer plays a direct or indirect role in the pathogenesis of ischemic stroke (IS), along with the reactive medical approach used in the treatment and clinical management of IS patients, resulting in clinical challenges associated with occult cancer in these patients. The lack of reliable and simple tools hinders the effectiveness of the predictive, preventive, and personalized medicine (PPPM/3PM) approach. Therefore, we conducted a multicenter study that focused on multiparametric analysis to facilitate early diagnosis of occult cancer and personalized treatment for stroke associated with cancer. Methods: Admission routine clinical examination indicators of IS patients were retrospectively collated from the electronic medical records. The training dataset comprised 136 IS patients with concurrent cancer, matched at a 1:1 ratio with a control group. The risk of occult cancer in IS patients was assessed through logistic regression and five alternative machine-learning models. Subsequently, select the model with the highest predictive efficacy to create a nomogram, which is a quantitative tool for predicting diagnosis in clinical practice. Internal validation employed a ten-fold cross-validation, while external validation involved 239 IS patients from six centers. Validation encompassed receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA), and comparison with models from prior research. Results: The ultimate prediction model was based on logistic regression and incorporated the following variables: regions of ischemic lesions, multiple vascular territories, hypertension, D-dimer, fibrinogen (FIB), and hemoglobin (Hb). The area under the ROC curve (AUC) for the nomogram was 0.871 in the training dataset and 0.834 in the external test dataset. Both calibration curves and DCA underscored the nomogram's strong performance. Conclusions: The nomogram enables early occult cancer diagnosis in hospitalized IS patients and helps to accurately identify the cause of IS, while the promotion of IS stratification makes personalized treatment feasible. The online nomogram based on routine clinical examination indicators of IS patients offered a cost-effective platform for secondary care in the framework of PPPM. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00354-8.
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NEK2 is a serine/threonine protein kinase that is involved in regulating the progression of various tumors. Our previous studies have found that NEK2 is highly expressed in gastric cancer and suggests that patients have a worse prognosis. However, its role and mechanism in gastric cancer are only poorly studied. In this study, we established a model of ferroptosis induced by RSL3 or Erastin in AGS cells in vitro, and konckdown NEK2, HOMX1, Nrf2 by siRNA. The assay kit was used to analyzed cell viability, MDA levels, GSH and GSSG content, and FeRhoNox™-1 fluorescent probe, BODIPY™ 581/591 C11 lipid oxidation probe, CM-H2DCFDA fluorescent probe were used to detected intracellular Fe2+, lipid peroxidation, and ROS levels, respectively. Calcein-AM/PI staining was used to detect the ratio of live and dead cells, qRT-PCR and Western blot were used to identify the mRNA and protein levels of genes in cells, immunofluorescence staining was used to analyze the localization of Nrf2 in cells, RNA-seq was used to analyze changes in mRNA expression profile, and combined with the FerrDb database, ferroptosis-related molecules were screened to elucidate the impact of NEK2 on the sensitivity of gastric cancer cells to ferroptosis. We found that inhibition of NEK2 could enhance the sensitivity of gastric cancer cells to RSL3 and Erastin-induced ferroptosis, which was reflected in the combination of inhibition of NEK2 and ferroptosis induction compared with ferroptosis induction alone: cell viability and GSH level were further decreased, while the proportion of dead cells, Fe2+ level, ROS level, lipid oxidation level, MDA level, GSSG level and GSSG/GSH ratio were further increased. Mechanism studies have found that inhibiting NEK2 could promote the expression of HMOX1, a gene related to ferroptosis, and enhance the sensitivity of gastric cancer cells to ferroptosis by increasing HMOX1. Further mechanism studies have found that inhibiting NEK2 could promote the ubiquitination and proteasome degradation of Keap1, increase the level of Nrf2 in the nucleus, and thus promote the expression of HMOX1. This study confirmed that NEK2 can regulate HMOX1 expression through Keap1/Nrf2 signal, and then affect the sensitivity of gastric cancer cells to ferroptosis, enriching the role and mechanism of NEK2 in gastric cancer.