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Learning design has become increasingly important in the context of expanding and dynamic digital learning environments. More traditional teaching approaches are no longer sufficient to engage learners in these changing learning environments. Teachers and aspiring learning designers therefore increasingly need learning design expertise, which takes time to develop. This paper responds to this challenge by outlining a fishbone digital learning design method, which is aligned with updated versions of Bloom's taxonomy for the digital world, as a scaffolded approach to developing basic learning design expertise. The study integrates three practical tools into one learning design method to ensure constructive alignment. The findings contribute to digital educational development and teacher professional development by proposing a practical and easy to adapt learning design method.

This study aims to develop and evaluate a Chinese language course designed to enhance college students' critical thinking skills through the integration of deep learning theory and Outcome-Based Education (OBE). The research specifically addresses two questions: (1) What are the characteristics of a Chinese language course that integrates Deep Learning Theory and OBE? (2) What are the effects of this course on promoting critical thinking skills among undergraduate students? The study employs a quasi-experimental design, involving 120 undergraduate students divided into a control group and a test group from Nan fang College, Guangzhou, China. The control group received conventional teaching methods, while the test group participated in the newly developed course. Data were collected through pre-tests and post-tests using California critical thinking skills test (Chinese version), as well as semi-structured interviews. Results indicate a significant improvement in the critical thinking skills of students in the test group compared to the control group. The test group showed higher mean scores and lower standard deviations in post-test results, demonstrating the effectiveness of the course in enhancing critical thinking abilities. Qualitative data from interviews supported these findings, highlighting increased student engagement and deeper understanding of course materials. The findings suggest that this integrated approach can be effectively implemented in other educational contexts to achieve similar outcomes.

The undeniable potential benefits of learning analytics (LA) in education have led to growing investment in developing and integrating LA systems into K-12 schools. Yet, the actual integration and adoption depend on levels of teachers' acceptance and usage. This study aims to propose a conceptual model to reveal the decisive factors affecting teachers' adoption of the LA system for evaluating teachers' sustainable LA usage through the integration of Information System Success and the Technology Acceptance Model. The variables used were system performance quality (SP), information quality (IQ), perceived usefulness (PU), and intention to use (IU) via the partial least square structural equation modeling (PLS-SEM). Furthermore, the moderation effect of teachers' AI literacy level (LIT) between dependent variables (SP and IQ) and PU was analyzed. The results indicated SP (sub-constructed by accessibility and human awareness) and IQ (comprised of reliability and relevancy) have statistically positive influences on PU and IU, where LIT played a moderating role between IQ and PU. This study contributes to our understanding of teachers' perceptions regarding LA system integration through a theoretically grounded analysis of empirical data from the K-12 school education context and highlights important areas of development for better LA integration into teachers' practice.

Gliosarcoma (GS) is a rare subtype of glioblastoma multiforme, characterized by a shorter clinical course and poorer prognosis compared to glioblastoma. Here, we report the case of a 50-year-old male patient who presented with episodic loss of consciousness and left-sided limb weakness for one month. MRI revealed a complex neoplastic lesion in the right fronto-parietal region. Postoperative pathology confirmed GS, and the patient underwent adjuvant radiotherapy and chemotherapy. This case highlights the characteristic features of GS through a combination of imaging and pathological findings, providing valuable insights for radiologists.

In the virtual geographic environment, conducting status analysis on urban structures and similar objects is crucial for enhancing their detailed management level. However, it is challenging to directly convert the same object across various software systems with different modalities (such as spatial analysis, BIM design, numerical simulation etc.). Therefore, the effective conversion of multi-modal models becomes pivotal. Due to the characteristics of inconsistent spatial description and complex association relationship among multimodal models, resulting in low knowledge reuse rate, poor accuracy of unit mapping, and low efficiency of state sharing in the process of model conversion. Aiming at these problems, this article delves into the knowledge-driven semantic conversion techniques for multi-modal models from a geospatial viewpoint. The mapping relationships between multimodal models in terms of spatial, geometric, and semantic information were first clarified. Subsequently, a structural matching template based on knowledge reuse was established, and a knowledge-guided algorithm for multimodal model transformation was designed. Finally, using a suspension bridge as a case study, a prototype system was developed and experimental analysis was conducted. The experimental results show that the method proposed in this article can accurately convert between BIM models, numerical analysis models, and GIS scene models, with spatial coordinate accuracy controlled within 1 mm and a conversion efficiency increase of more than 10 times. This can effectively enhance the integrated performance of models in applications such as digital geospatial twin scenarios.

Abstract Objectives To evaluate the effects of short-acting cycloplegic agents, tropicamide and compound tropicamide, on ocular biological parameters and choroid thickness. Methods In this study, seventy pediatric subjects aged 6 to 13 years were randomly assigned to two groups: the tropicamide group and compound tropicamide group. Ocular biological parameters and choroidal thickness (CT) and subfoveal choroid thickness (SFCT) were measured in both groups and were retested 40 min after drug administration. The tropicamide eye drops were administered into the conjunctival sac every 5 min with 1 drop, for a total of 4 doses. Compound tropicamide was administered in the same way as tropicamide. Ocular biological parameters included refraction (spherical equivalent, SE), intraocular pressure (IOP), axial length (AL), anterior chamber depth (ACD), lens thickness (LT), central corneal thickness (CCT), and white to white (WTW). The CT is the regional inferior choroidal thickness of nine sectors centered on the macular fovea and automatically generated using an ETDRS grid. And the SFCT is the choroidal thickness at the subfoveal point of the macular region. Results After application of tropicamide and compound tropicamide to induce the ciliary muscle paralysis, SE, AL, and LT decreased, while ACD, CCT, and WTW increased compared to baseline(all P values 0.05). The CT in the nasal quadrant before and after ciliary paralysis was significantly thinner than other areas, the CT in the temporal quadrant was significantly thicker than others, and the CT in the inner quadrant was higher than the CT in the outer quadrant. In the tropicamide group: CT was significantly increased in the remaining quadrants except the inner inferior(I) and outer superior(S) quadrants (p 0.05). Additionally, AL and SFCT were negatively correlated. Conclusions Some ocular biological parameters were altered after application of short-acting cycloplegic agent tropicamide and compound tropicamide to paralyze the ciliary muscle. Compared with compound tropicamide, tropicamide eye drops can reduce axial length while increasing choroid thickness.

Abstract This study evaluates the cost-effectiveness of adding durvalumab to chemotherapy, with subsequent maintenance either with olaparib (DOCT) or without olaparib (DCT), versus chemotherapy alone (CT) as a first-line treatment for advanced endometrial cancer (EC) in the United States, stratified by mismatch repair deficiency (dMMR) and proficiency (pMMR). A Markov model based on DUO-E Phase III trial data simulated disease progression and outcomes. Total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER) were evaluated. Sensitivity analysis assessed model robustness. For dMMR EC, costs (QALYs) were $1,204,763.33 (5.49), $590,732.13 (4.61), and $1,495,528.15 (3.68) for DOCT, DCT, and CT, respectively, with ICER of $584,140.94/QALYs (DOCT vs. CT) and $476,946.43/QALYs (DCT vs. CT). For pMMR EC, costs (QALYs) were $421,126.70 (3.00), $400,470.92 (2.45), and $133,424.52 (1.69), with ICER of $219,601.20/QALYs (DOCT vs. CT) and $351,777.86/QALYs (DCT vs. CT). In the overall population, costs (QALYs) were $607,921.80 (3.89), $417,637.19 (2.82), and $141,594.38 (2.16), with ICER of $269,195.01/QALYs (DOCT vs. CT) and $416,098.68/QALYs (DCT vs. CT). From a U.S. payer perspective, DOCT and DCT regimens are not cost-effective compared to CT for advanced or recurrent EC, including dMMR and pMMR subgroups, at a $150,000/QALY threshold.

Abstract Cuproptosis differs from other forms of cell death, such as apoptosis, necroptosis, and ferroptosis, in its unique molecular mechanisms and signaling pathways. In this review, we delve into the cellular metabolic pathways of copper, highlighting the role of copper in biomolecule synthesis, mitochondrial respiration, and antioxidant defense. Furthermore, we elucidate the relationship between cuproptosis-related genes (CRGs) and cancer prognosis, analyzing their expression patterns across various tumor types and their impact on patient outcomes. Our review also uncovers the potential therapeutic applications of copper chelators, copper ionophores, and copper-based nanomaterials in oncology. In addition, we discuss the emerging role of cuproptosis in remodeling the tumor microenvironment, enhancing immune cell infiltration, and converting “cold tumors” into “hot tumors” that respond better to immunotherapy. In short, this review underscores the pivotal importance of cuproptosis in cancer biology and highlights its translational potential as a novel therapeutic target.

Abstract Background Human responses and acclimation to the environmental stresses of high altitude and low oxygen are multifaceted and regulated by multiple genes. However, the mechanism of how the body adjusts in a low-oxygen environment is not yet clear. Results Hence, we performed RNA sequencing (RNA-seq) and ATAC sequencing (ATAC-seq) to observe the changes of transcriptome and chromatin accessibility in the peripheral blood of eight individuals at 1 h post adaptation in a simulated plateau environment with 3500 m and 4500 m altitude, respectively. Differential expression analysis and the Boruta algorithm identified differentially expressed genes (DEGs) and differentially accessible regions (DARs) associated with hypoxia adaptation. Specifically, RNA-seq identified 93 and 7 DEGs after 1 h post adaptation with 3500 m altitude and 45 and 8 DEGs after 1 h adaptation with 4500 m. Additionally, ATAC-seq screened 12 and 4 DARs in 3500 m altitude adaption and 15 and 5 DARs in 4500 m altitude adaption. Moreover, the combined analysis of RNA-seq and ATAC-seq revealed that 10 hub genes were independently identified from the protein–protein interaction (PPI) network for each altitude. Gene enrichment analysis displayed that most hub genes were related with hypoxia pathways. Conclusions Our results can provide the reference for the early response of the organism to hypoxic adaptation.

Abstract Compromised vascular integrity facilitates the cancer cells extravasation and metastasis. However, the mechanisms leading to a disruption in vascular integrity in colorectal cancer (CRC) remain unclear. In this study, PCDH17 expression was higher in the vascular endothelial cells of colon cancer with distant metastasis, and the rates of PCDH17+ endothelial cells (ECs) was associated with the M stage in clinical pathological characteristics analysis and correlated with a poor survival prognosis. The liver and lung metastatic dissemination of MC-38 was significantly decreased in PCDH17–/–mice. The ubiquitination and degradation of VEGFR2 was prevented by the interaction between PCDH17 and the E3 ubiquitin ligase MARCH5, which causing the separation of internalized VE-cadherin, and increased the vascular permeability and metastasis of CRC. These results highlight the importance of PCDH17 in maintaining vascular integrity, which has emphasis for endothelial barrier function in metastatic cancer. PCDH17 has the potential to be a marker for predicting tumor metastasis as well as a viable treatment target for CRC.

Abstract Background This study aimed to investigate the potential relationship between the newly defined adiposity metric, the Body Roundness Index (BRI), which assesses central obesity, and the development of new-onset hyperuricemia. Methods In the Kailuan cohort study from 2006 to 2019, 91,804 eligible participants were included. A multivariate Cox regression model was used to test the correlation between BRI and hyperuricemia. At the same time, the restricted cubic spline was applied to solve the dose-response relationship between BRI and the risk of hyperuricemia.Then, stratified analysis was carried out using multivariate Cox regression according to age, sex, hs-CRP level, TG level, education level, smoking status and hypertension status. Results The results showed that the risk of new-onset hyperuricemia was significantly increased in the highest quartile compared with the lowest quartile. After adjusting for confounders, compared with Q1, the HR (95% CI) for new-onset hyperuricemia was 1.24 (1.18–1.30), 1.32 (1.25–1.40), and 1.40 (1.29–1.52) for Q2, Q3, and Q4, respectively. Restricted cubic spline analysis showed a J-curve relationship between baseline BRI levels and new-onset hyperuricaemia. Age, sex, hs-CRP level, TG level, income level, education level, smoking, and hypertension each had a multiplicative interaction with BRI at baseline. Conclusion We found that elevated BRI increased the risk of developing new-onset hyperuricaemia. In addition, the association between elevated BRI and the risk of new-onset hyperuricemia showed dependency on age, sex, hs-CRP level, TG level, education level, smoking status and hypertension status.

Abstract Background Antiretroviral drugs are essential for preventing mother-to-child transmission (MTCT) of HIV in HIV-infected pregnant women. However, ART treatment for HIV-infected pregnant women with multidrug resistance remains a major challenge. Effective and safe ART regimens for preventing MTCT should be tailored to this special population. Albuvirtide (ABT) is along-acting fusion inhibitor with proven efficacy and safety in adults with multidrug-resistant HIV. Herein, for the first time, we report the use of an ABT-based ART regimen in pregnant women infected with multidrug-resistant HIV. Case presentation A 25-year-old female HIV patient with an estimated gestational age of 14 weeks who received the TDF + 3TC + EFV regimen. The tests revealed an HIV- RNA concentration of 1730 copies/mL, a CD4 T lymphocyte (CD4 cell) concentration of 145 cells/µL and genotypic resistance to NRTI and NNRTI. The patient showed a decreased viral load (30 copies/mL) and increased CD4 cells (215 cells/µL) after 12 weeks of ABT + 3TC/DTG treatment. Her physical condition was good, and no drug- related adverse reactions occurred. By the prenatal period (40 weeks), HIV RNA became undetectable, and CD4 cells had risen to 348 cells/µL. Finally, the patient delivered a healthy female baby who was negative for HIV, and the follow-up showed normal growth. Conclusions In our case, ABT-based antiretroviral regimen was effective in suppressing viral load (VL) in pregnancy, and there is no reported safety issues for the mother or the baby. Albuvirtide use in pregnancy might represent a strategy to avoid in utero transmission of MDR-HIV, but further investigation is warranted.

Abstract Peripheral nerve injury (PNI)-induced neuropathic pain (NP) is a severe disease with high prevalence in clinics. Gene reprogramming and tissue remodeling in the dorsal root ganglia (DRG) and spinal cord (SC) drive the development and maintenance of neuropathic pain (NP). However, our understanding of the NP-associated spatial molecular processing landscape of SC and the non-synaptic interactions between DRG neurons and SC cells remains limited. We here integrate spatial transcriptomics (ST) with single-nucleus RNA-sequencing (snRNA-seq) and bulk RNA-sequencing (bulk RNA-seq) to characterize regional pathological heterogeneity of the SC under NP conditions. First, the SC of NP mice manifests unique spatial atlases of genes, cell populations, cell-cell cross-talks, signaling pathways, and transcriptional regulatory networks compared to sham mice. We further report that injured DRG sensory neurons and the corresponding ventral horn of the SC show similar expression patterns after PNI. In addition, for the first time, we systematically exhibit “cross-talk omics” between the DRG neurons and SC dorsal horn neurons and glial cells, indicating an altered communication profile under NP conditions. Together, our findings decode the spatial and cellular heterogeneity of molecular pathological mechanisms underlying NP, providing a foundation for designing therapeutic targets for this disorder.

Abstract Background Lynch syndrome (LS)-associated colorectal cancer (CRC) always ascribes to pathogenic germline mutations in mismatch repair (MMR) genes. However, the penetrance of CRC varies among those with the same MMR gene mutation. Thus, we hypothesized that the gut microbiota is also involved in CRC development in LS families. Methods This prospective, observational study was performed from December 2020 to March 2023. We enrolled 72 individuals from 9 LS families across six provinces in China and employed 16S rRNA gene amplicon sequencing to analyze the fecal microbiota components among LS-related CRC patients (AS group), their spouses (BS group), mutation carriers without CRC (CS group), and non-mutation carriers (DS group) using alpha and beta diversity indices. Results There were no apparent differences in age or gender among the four groups. Alpha and beta diversity indices exhibited no significant differences between the AS and BS groups, verifying the role of germline mutations in the occurrence of CRC in LS families. Beta diversity analysis exhibited significant differences between the AS and CS groups, revealing the importance of the gut microbiota for the occurrence of CRC in LS families. A greater difference (both alpha and beta diversity indices) was shown between the AS and DS groups, demonstrating the combined impact of the gut microbiota and genetic germline mutations on the occurrence of CRC in LS families. Compared with those in the CS and DS groups, we identified ten microbial genera enriched in the AS group, and one genus (Bacteroides) decreased in the AS group. Among the elevated genera in the AS group, Agathobacter, Coprococcus and Prevotellaceae_NK3B31_group were butyrate-producing genera. Conclusion This study found the development of CRC in the LS families can be attributed to the combined effects of gene germline mutations as well as the gut microbiota and provided novel insights into the prevention and treatment of CRC in the LS families.

Abstract This is a randomized, double-blind, placebo-controlled phase 3 clinical trial (ClinicalTrials.gov, NCT04878016) conducted in 54 hospitals in China. Adults who were histologically diagnosed and never treated for extensive-stage small cell lung cancer (ES-SCLC) were enrolled. Eligible Patients were randomly assigned (1:1) to receive four cycles (21 days as one cycle) of intravenous carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle) and etoposide (100 mg/m² of body-surface area, on days 1–3 of each cycle) with either socazolimab (5 mg/kg, day 1 of each cycle) or matching placebo, following maintenance therapy with socazolimab or placebo. From July 15, 2021, to May 12, 2022, 498 eligible patients were randomly assigned to receive socazolimab (250 patients) or placebo (248 patients) combined with chemotherapy. As of October 13, 2023, patients treated with socazolimab presented significant overall survival (OS) benefit (13.90 months) compared with the placebo plus EC group (11.58 months) (hazard ratio for death, 0.799; 95% CI, 0.652–0.979; p = 0.0158). The median progression free survival (PFS) was 5.55 months in the socazolimab plus EC group, prolonging disease progression or death by nearly 1.2 months (5.55 months vs 4.37 months, hazard ratio for progression or death, 0.569; 95% CI, 0.457–0.708; p

Abstract. With the aging of the global population, older people living with HIV (OPLWH) have emerged as a focal point in HIV/AIDS research. Although antiretroviral therapy has demonstrated positive effects in OPLWH, concerns persist regarding overall poor immune reconstitution and elevated rates of age-related comorbidities, such as cardiovascular disease, bone disease, and cognitive impairment. This review aims to elucidate the mechanisms underlying immunosenescence and the interaction of immunosenescence with HIV infection, further exploring its role in the pathogenesis of HIV infection during aging. Aging-induced involution of the immune system, along with chronic inflammation and infection, can induce immunosenescence, leading to immune dysfunction that impairs the effective control of HIV infection. In addition, HIV infection induces immunosenescence through persistent inflammation and immune activation, even under treatment. The combined effects of aging and HIV infection accelerate the progression of immunosenescence in OPLWH, increasing their susceptibility to multiple age-related diseases. The unfavorable prognosis observed among OPLWH is largely attributed to increased levels of immunosenescence. A comprehensive understanding of the relationship between immunosenescence and HIV infection is crucial for developing targeted therapeutic strategies for this vulnerable population.

Abstract Background To analyze the demographic characteristics of retinopathy of prematurity (ROP) in China, attempting to propose optimized screening criteria and hopefully providing valuable information for future updates to the ROP guideline. Methods A multicenter, retrospective-cohort study was conducted. The study included infants born between January 1, 2018, and July 31, 2023, who underwent ROP screening and were diagnosed with ROP at seven screening centers in China. Examinations were carried out in accordance with the ROP guidelines in 2014: infants with a gestational age (GA)

Abstract Unsymmetric disulfides are prevalent in natural products and are essential in medicinal chemistry and materials science, but their robust synthesis poses significant challenges. In this paper, we report an expeditous transition-metal-free methodology for synthesizing unsymmetric disulfides through the addition of perthiyl radicals to alkenes. This study marks the use of generating perthiyl radicals by reacting SO2 with unactivated alkyl (pseudo)halides (Cl/Br/I/OTs). Various primary, secondary and tertiary alkyl (pseudo)halides substituted with different functional groups successfully function as suitable reactants. The formation of perthiyl radicals and their involvement in the reaction process are verified through mechanistic studies and DFT calculations. Overall, this method leverages readily available alkyl electrophiles and alkenes alongside SO2 in a single reaction setup to efficiently form both carbon-sulfur and sulfur-sulfur bonds simultaneously.

Abstract Thermal conductivity and electrical resistivity at ultralow temperatures and high magnetic fields are studied in the topological compensated semimetals TaAs2, NbAs2, and NdSb. A striking phenomenon is observed where the thermal conductivity shows a T 4 scaling at very low temperatures, while the resistivity shows a T-independent residual term. This indicates a strong violation of the Wiedemann–Franz (WF) law, since the field dependence of κ shows that the low-temperature thermal conductivity is dominated by electronic transport. The obtained Lorenz ratio is hundreds of times lower than Sommerfeld’s value even when approaching the zero-temperature limit. The strong downward deviation of the WF law at very low temperatures point to a non-Fermi liquid state in these materials. In addition, the giant thermal quantum oscillations accompanied by antiphase characteristics have been observed. Our findings not only point to a possible non-Fermi liquid ground state of these topological compensated semimetals, but also reveal an unusual T 4 temperature dependence for the electronic thermal conductivity.

Abstract Background Heavy metal exposure is an emerging environmental risk factor linked to cardiovascular disease (CVD) through its effects on vascular ageing. However, the relationship between heavy metal exposure and vascular age have not been fully elucidated. Methods This cross-sectional study analyzed data from 3,772 participants in the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2016. We measured urinary concentrations of nine heavy metals and assessed their associations with vascular age, estimated pulse wave velocity (ePWV) and heart vascular age (HVA). Additionally, sex-stratified analyses, Weighted Quantile Sum (WQS) regression and Bayesian Kernel Machine Regression were conducted to explore the effects of individual and mixed metal exposures. Results Exposure to metals such as cadmium (Cd) cesium (Cs), cobalt (Co), and lead (Pb) was significantly associated with increased vascular age, with odds ratios (OR) ranging from 1.05 to 3.48 in full adjusted models. Sex-stratified analyses indicated that individual metal including cobalt (Co) and cadmium (Cd) exposures had a more substantial impact on males. WQS analysis consistently showed combined heavy metals exposure had stronger associations with increased vascular age in men (OR for HVA = 3.89, 95% CI 2.91–5.28). Conclusions This study highlights a significant association between heavy metal exposure and increased vascular age. Stratified analyses illustrated men might be more susceptible to the combined effects of multiple heavy metal exposure. The findings underscore the importance of considering sex-specific responses and interventions measures in cardiovascular risk assessments and managements. Further research is needed to validate these findings and to develop more precise public health strategies targeting environmental risks. Graphical Abstract

Accurate knowledge of mesospheric winds and waves is essential for studying the dynamics and climate in the mesosphere and lower thermosphere (MLT) region. In this study, we conduct a comparative analysis of the mesosphere tidal results obtained from two adjacent meteor radars at low latitudes in Kunming, China, from November 2013 to December 2014. These two radars operate at different frequencies of 37.5 MHz and 53.1 MHz, respectively. However, overall good agreement is observed between the two radars in terms of horizontal winds and tide observations. The results show that the dominant tidal waves of the zonal and meridional winds are diurnal and semidiurnal tides. Moreover, we conduct an exhaustive statistical analysis to compare the tidal amplitudes and vertical wavelengths recorded by the dual radar systems, which reveals a high degree of alignment in tidal dynamics. The investigation includes variances and covariances of tidal amplitudes, which demonstrate remarkable consistency across measurements from both radars. This finding highlights clear uniformity in the mesospheric tidal patterns observed at low latitudes by the two neighboring meteor radars. Results of the comparative analysis specifically underscore the significant correlation in vertical wavelength measurements, validating the robustness of radar observations for tidal research.

Abstract Purpose This study aims to examine the correlation between specific clinical parameters, such as axial eye length, and the onset of ocular hypertension “OH” following the use of silicone oil filling in patients with high myopia. Method In this retrospective analysis, we reviewed 214 eyes from 432 patients diagnosed with severe myopia, all of whom underwent vitrectomy and were treated with silicone oil filling. The study aimed to document the incidence and timing of postoperative ocular hypertension “OH” while assessing various factors, including demographic details, medical history, additional surgical interventions, and findings from supplementary examinations (such as axial length, silicone oil emulsification, and anterior chamber penetration). Binary logistic regression was employed as the primary statistical method to identify significant predictors and their relationship with “OH”. This approach allowed for a comprehensive analysis of the impact of the duration of silicone oil presence in the eye on “OH” occurrence, providing a detailed understanding of the factors influencing post-surgical outcomes. Result The study revealed a statistically significant increase in postoperative axial length (29.21 ± 0.85 mm) compared to the preoperative length (28.31 ± 0.82 mm), corresponding to an incidence rate of 37.38% (80 cases) for “OH”. Logistic regression analysis identified the following variables as significantly associated with an increased risk of “OH” post-silicone oil filling: scleral buckling, aphakic status, silicone oil emulsification, and silicone oil penetration into the anterior chamber. The odds ratios (OR) for these variables were 1.397, 0.672, 1.859, and 1.364, respectively, indicating their predictive value for “OH” risk. Conclusion The development of “OH” post-silicone oil filling is strongly correlated with changes in the anterior segment anatomy and the dynamics of aqueous humor flow, particularly in eyes without the natural lens. Recognizing these risk factors highlights the importance of thorough preoperative evaluation and individualized postoperative care to reduce the incidence of OH in patients with high myopia, thereby improving surgical outcomes.

Abstract Deep learning methods have shown significant potential in tool wear lifecycle analysis. However, there are fewer open source datasets due to the high cost of data collection and equipment time investment. Existing datasets often fail to capture cutting force changes directly. This paper introduces QIT-CEMC, a comprehensive dataset for the full lifecycle of titanium (Ti6Al4V) tool wear. QIT-CEMC utilizes complex circumferential milling paths and employs a rotary dynamometer to directly measure cutting force and torque, alongside multidimensional data from initial wear to severe wear. The dataset consists of 68 different samples with approximately 5 million rows each, includes vibration, sound, cutting force and torque. Detailed wear pictures and measurement values are also provided. It is a valuable resource for time series prediction, anomaly detection, and tool wear studies. We believe QIT-CEMC will be a crucial resource for smart manufacturing research.

Abstract The spatiotemporal nonstationarity of shared bicycle usage, a sustainable and eco-friendly mode of transportation, is believed to be influenced by the built environment. However, the specific spatial and temporal impacts of built environment factors on shared bicycle trips are not yet fully understood. This study investigates the relationship between the built environment and shared bicycle ridership in Shenzhen, a city where the distribution of shared bicycles is relatively dense, by utilizing multisource urban big data. Key independent variables were selected based on the “5Ds” dimensions of the built environment, and the performance of two models—Geographically Weighted Regression (GWR) and Geographically and Temporally Weighted Regression (GTWR)—were compared. The analysis evaluates the impact of the built environment on the density of shared bicycle ridership, incorporating both spatial and temporal dimensions. The results of the study found that the GTWR model used in this paper can effectively explain the spatio-temporal heterogeneity of built environment-related variables on shared bicycle trips with high goodness of fit. And the regression fit coefficients of the model show that the effects of different built environment indicators on the density of shared bicycle ridership are significantly different in both time and space. Among them, road network density, catering POI density, traffic POI density and POI diversity have a facilitating effect on shared bicycle travels, particularly during peak hours on weekdays and in central urban areas. Shopping POI density shows different effects on shared bike use in different times and spaces. While the distance from the city center and the nearest distance to the bus station have a suppressive effect on shared bicycle use, they show opposite degrees of influence in the spatial distribution. The results can provide more precise guidance for future rational transportation strategies or sustainable urban planning.

Abstract Background Older people living with HIV-1 (PLWH) experience a dual burden from the combined effects of aging and HIV-1 infection, resulting in significant immune dysfunction. Despite receiving HAART, immune reconstitution is not fully optimized. The objective of this study was to investigate the impact of aging and HAART on T cell subsets and function in PLWH across different age groups, thereby providing novel insights into the prognosis of older PLWH. Method This study was conducted at Yunnan AIDS Care Center, China, to explore the immunological responses of old PLWH to HAART and compared with the middle-age and the younger. Blood samples were collected from 146 PLWH to analyze T cell subsets and their functions, with a particular emphasis on markers related to T cell differentiation, activation, exhaustion, inflammation, and cellular function, using multicolor flow cytometry analysis. Results Older age may have a greater effect on long-term CD4+T cell recovery. Compared with young and middle-aged PLWH, older PLWH presented distinct alterations in their immune profile, including a decline in the Naïve CD4+T and CD8+T cell subsets, an expansion of effector memory cells, and other potential immune risk phenotypes, such as activation, exhaustion, and up-regulation of aging markers. In addition, we observed a significant association between the CD4 + EM3 subset and the CD8 + EM2 subset with HIV-1 progression, independent of age, suggesting their potential as reliable markers for assessing immune reconstitution in all PLWH. Conclusion Our study extends previous findings showing that older participants exhibit a wide range of late differentiation, senescence, or exhaustion phenotypes in cells, including all the CD4+T and CD8+T subsets, consistent with an immunosenescent phenotype. This may accelerate poor immune recovery in older PLWH. Identifying new strategies to improve the immune risk phenotypes of older PLWH may help improve their immune reconstitution outcomes. The CD4 + EM3 subset and the CD8 + EM2 subset should be studied as additional markers of late presentation.

Abstract Background Hainan is a tropical island in China with a large migratory population. Study have reported that the blood pressure of Hainan elderly hypertensive migratory population decreased significantly, which may be related to the improvement of environment and quality of life (QoL). Understanding the changes of QoL of these people before and after coming to Hainan and its influencing factors can provide a basis for the prevention and control of hypertension. Methods A cross-sectional study of elderly hypertensive migratory population were conducted in Chengmai Mangrove Bay community of Hainan from December 2021 to January 2022. Convenience sampling was used to recruit elderly hypertensive migratory individuals reside stay of longer than one month. After obtaining informed consent, we investigated the demographic characteristics of the participants and evaluated their QoL with the SF-36 twice; one round of the SF-36 was about their hometown, and the other round was about living in Hainan for 1 month. The Cronbach’s α coefficient and KMO value of SF-36 were both greater than 0.8, indicating good reliability and validity. The difference in blood pressure between that observed in Hainan and that observed in their hometowns was used to determine whether the Body Pain change in the subjects decreased or did not decrease after migrating to Hainan. Univariate analysis was performed via paired t tests and Kendall’s tau-b tests, and multiple linear regression analysis and logistic regression analysis were used to analyse the factors influencing the QoL of the participants. Results A total of 305 hypertensive migratory individuals participated in this study. Among them, there were 148 males (48.52%) and 157 females (51.48%), with a mean age of 68.61 ± 9.39 years. The postmigration scores for the 8 subscales of QoL, the global score, the Physical Component Score, and the Mental Component Score were all higher than the scores for their hometowns (P

Abstract Background Medical professionals who are engaged in palliative care commonly experience negative emotions resulting from the pain and grief experienced by patients and family members, which results in enormous psychological pressure for professionals, and the risk related to job burnout is significantly greater. Objective We aimed to explore the factors influencing job burnout and resilience among palliative care professionals. Methods We conducted a qualitative study using semistructured interviews and purposeful sampling methods. Face-to-face interviews were carried out from September 2023-April 2024 in the palliative care ward of one of the top three hospitals in a province of China. A total of 22 palliative care professionals were interviewed. The interview data were coded and relevant topics were extracted and summarized from two perspectives: factors influencing job burnout among palliative care professionals and resilience to job burnout. Data analysis was guided by Colaizzi’s seven-step method. Results This study identified personal, work, institutional, and social factors affecting job burnout among palliative care professionals in China. Personal factors include the original intention of engaging in palliative care, psychological qualities, and ways of coping with stress. Work factors include work intensity and environment and the characteristics and nature of palliative care work. Institutional and social factors include promotion mechanisms, wages and benefits, government policy support and professional recognition, as well as cultural conflicts from traditional China. The factors that affect resilience include personal internal factors and external factors. Personal internal factors come from good self-regulation and emotional balance, while external factors come from an increasingly sophisticated social support system and effective intervention measures to cope with job burnout. Conclusion Our research found that many factors affect the job burnout and resilience of palliative care professionals. Promoting the construction of a professional team in palliative medicine, rational allocation of human resources, improving the welfare benefits of professionals, enhancing their social status, safeguarding their legitimate rights and interests, establishing effective emotional and social support systems, and implementing effective intervention measures in cultural contexts are all effective ways to reduce work fatigue and enhance resilience. Future research needs to investigate intervention measures to address or prevent burnout.

Abstract Background Understanding the stepwise progression of esophageal squamous cell carcinoma (ESCC) is crucial for developing customized strategies for early detection and optimal clinical management. Herein, we aimed to unravel the transcriptional and immunologic alterations occurring during malignant transformation and identify clinically significant biomarkers of ESCC. Methods Digital spatial profiling (DSP) was performed on 11 patients with early-stage ESCC (pT1) to explore the transcriptional alterations in epithelial, immune cell, and non-immune cell stromal compartments across regions of distinct histology, including normal tissues, low- and high-grade dysplasia, and cancerous tissues. Furthermore, single-cell spatial transcriptomics was performed using the CosMx Spatial Molecular Imaging (SMI) system on 4 additional patients with pT1 ESCC. Immunohistochemical (IHC) analysis was performed on consecutive histological sections of 20 pT1 ESCCs. Additionally, public bulk and single-cell RNA-sequencing (scRNA-seq) datasets were analyzed, and in vitro and in vivo functional studies were conducted. Results Spatial transcriptional reprogramming and dynamic cell signaling pathways that determined ESCC progression were delineated. Increased infiltration of macrophages from normal tissues through dysplasia to cancerous tissues occurred. Macrophage subtypes were characterized using the scRNA-seq dataset. Cell–cell communication analysis of scRNA-seq and SMI data indicated that the migration inhibitory factor (MIF)-CD74 axis may exhibit pro-tumor interactions between macrophages and epithelial cells. DSP, SMI, and IHC data demonstrated that DTX3L expression in epithelial cells and BST2 expression in stromal cells increased gradually with ESCC progression. Functional studies demonstrated that DTX3L or BST2 knockdown inhibited ESCC proliferation and migration and decreased M2 polarization of tumor-associated macrophages. Conclusions Spatial profiling comprehensively characterized the molecular and immunological hallmarks from normal tissue to ESCC, guiding the way to a deeper understanding of the tumorigenesis and progression of this disease and contributing to the prevention of ESCC. Within this exploration, we uncovered biomarkers that exhibit a robust correlation with ESCC progression, offering potential new avenues for insightful therapeutic approaches.

ObjectiveTo investigate the effect of idiopathic pulmonary fibrosis (IPF) on the prognosis of patients with non-small cell lung cancer ( NSCLC ). MethodsA total of 98 patients with NSCLC who underwent radical surgery in Honghui Hospital, Xi’an Jiaotong University from March 2018 to March 2019 were selected, and were divided into the IPF group and the non-IPF group. The clinicpathological and surgical data were compared between the two groups. The follow-up time was up to March 31, 2024. The endpoint event was NSCLC-related death or NSCLC recurrence, and the death and recurrence during the follow-up period were recorded. Kaplan-Meier survival curve and log-rank test were used to compare survival rate between the two groups. Cox regression analysis was used to analyze the related factors affecting postoperative death and NSCLC recurrence. ResultsOf the 98 patients included, 45 (45.92%) had IPF. Compared with the non-IPF group, the patients were older, proportion of female patients and preoperative serum C-reactive protein (CRP) level were higher, and the preoperative serum albumin level was lower in the IPF group (P＜0.05). The median follow-up time was 3.7（0.7, 5.6）years. The 1-, 3-, 5-year overall survival rates and recurrence-free survival rates of patients in the IPF group were shorter than those in the non-IPF group (P＜0.05). Cox regression analysis showed that high-degree differentiation and IPF were risk factors for survival of NSCLC patients (P＜0.05), and vascular infiltration, bigger tumor and IPF were risk factors resulting in NSCLC recurrence (P＜0.05). Conclusions For NSCLC patients, IPF can significantly shorten the overall survival and recurrence-free survival, and is a common risk factor resulting in postoperative death and recurrence.

Abstract In the age of stock planning, urban vitality is a key indication of a city’s health and vitality. Using the central city of Tianjin as an example, the study uses multi-source data, such as Weibo check-ins, points of interest, etc., to quantify urban vitality. The Light GBM-SHAP model is chosen to measure the non-linear effects of each indicator on urban vitality in four dimensions: crowd vitality, economic vitality, facility vitality, and environmental vitality. The study also applies spatial visualization and spatial statistical analysis to analyze the vitality of the central city of Tianjin in terms of time and space scales. The findings indicate that: (1) There is clear temporal and geographical variation in the vitality distribution in Tianjin’s core urban region. Over time, spring, particularly April, is marked by a surge of vitality brought on by the tourist season and holiday effects; there is a double-peak time in the morning and evening, and the nighttime vitality is particularly strong; and, in terms of space, urban vitality tends to decline from the Heping District outward. (2) Public facility density, living facility density, and building density are the three indicators that most strongly influence urban vitality; each indication has a negligible impact on the temporal dimension of urban vitality. (3) The indicators in Tianjin’s core urban region have a substantial impact on urban vitality. Their threshold effect and non-linear influence are evident, and managing the indicators within a suitable range may effectively promote urban vitality. The study’s findings might serve as a foundation for Tianjin’s core city’s urban planning and design.

Abstract Two-dimensional (2D) semiconductors, combining remarkable electrical properties and mechanical flexibility, offer fascinating opportunities for flexible integrated circuits (ICs). Despite notable progress, so far the showcased 2D flexible ICs have been constrained to basic logic gates and ring oscillators with a maximum integration scale of a few thin film transistors (TFTs), creating a significant disparity in terms of circuit scale and functionality. Here, we demonstrate medium-scale flexible ICs integrating both combinational and sequential elements based on 2D molybdenum disulfide (MoS2). By co-optimization of the fabrication processes, flexible MoS2 TFTs with high device yield and homogeneity are implemented, as well as flexible NMOS inverters with robust rail-to-rail operation. Further, typical IC modules, such as NAND, XOR, half-adder and latch, are created on flexible substrates. Finally, a medium-scale flexible clock division module consisting of 112 MoS2 TFTs is demonstrated based on an edge-triggered Flip-Flop circuit. Our work scales up 2D flexible ICs to medium-scale, showing promising developments for various applications, including internet of everything, health monitoring and implantable electronics.

Abstract The anthroponotic Cryptosporidium hominis differs from the zoonotic C. parvum in its lack of infectivity to animals, but several divergent subtypes have recently been found in nonhuman primates and equines. Here, we sequence 17 animal C. hominis isolates and generate a new IbA12G3 genome at the chromosome level. Comparative analysis with 222 human isolates shows significant genetic divergence of the animal isolates, with genetic recombination among them. They have additional subtelomeric insulinase and MEDLE genes. In interferon-γ knockout mice, three monkey isolates show differences in infectivity and induce higher and longer oocyst shedding than a reference C. parvum isolate. Deletion of the MEDLE genes significantly reduces the growth and pathogenicity of a virulent strain in mice. Co-infection of two fluorescence-tagged C. hominis subtypes produces bicolored oocysts, supporting the conclusion that mixed subtype infections can lead to genetic recombination. These data provide insight into potential determinants of host infectivity in Cryptosporidium, and a convenient animal model for biological studies of C. hominis.

Abstract Recent advances have uncovered an exotic sliding ferroelectric mechanism, which endows to design atomically thin ferroelectrics from non-ferroelectric parent monolayers. Although notable progress has been witnessed in understanding the fundamental properties, functional devices based on sliding ferroelectrics remain elusive. Here, we demonstrate the rewritable, non-volatile memories at room-temperature with a two-dimensional (2D) sliding ferroelectric semiconductor of rhombohedral-stacked bilayer MoS2. The 2D sliding ferroelectric memories (SFeMs) show superior performances with a large memory window of >8 V, a high conductance ratio of above 106, a long retention time of >10 years, and a programming endurance greater than 104 cycles. Remarkably, flexible SFeMs are achieved with state-of-the-art performances competitive to their rigid counterparts and maintain their performances post bending over 103 cycles. Furthermore, synapse-specific Hebbian forms of plasticity and image recognition with a high accuracy of 97.81% are demonstrated based on flexible SFeMs.

The spread of natural gas in the main international natural gas markets shows characteristics of violent fluctuation, frequent mutation, and periodic evolution, which pose a great challenge to the safety and sustainable development of natural gas in China. First, this paper used the complete ensemble empirical mode decomposition with adaptive noise (CEEMDAN) model to decompose and reconstruct natural gas “Asian premium.” Based on the evolution law of each subsequence, the “Asian premium” was decomposed into four parts: speculative, geographical, energy security, and fundamental. Second, this study adopts the Bayesian model averaging (BMA) method to extract the main factors and uses the TVP-SV-VAR (time varying parameter stochastic volatility vector autoregression) model to characterize the nonlinear relationships. The results showed that the speculative motivation of suppliers and the cross-regional transportation cost of natural gas were the main reasons for the fluctuations, and the influence of oil prices on “Asian premium” was gradually reduced. The impulse response results showed that when the financial crisis hit in 2008, the impact of energy security and economic fundamentals on the “Asian premium” was more obvious. In the case of supply shortages, financial speculation and geographical factors played a more significant role in the “Asian premium” for natural gas. This study provides an important reference for price mechanism reform in China's natural gas market.

Abstract The pathogenesis of celiac disease (CeD) remains incompletely understood. Traditional diagnostic techniques for CeD include serological testing and endoscopic examination; however, they have limitations. Therefore, there is a need to identify novel noninvasive biomarkers for CeD diagnosis. We analyzed duodenal and plasma samples from CeD patients by four-dimensional data-dependent acquisition (4D-DIA) proteomics. Differentially expressed proteins (DEPs) were identified for functional analysis and to propose blood biomarkers associated with CeD diagnosis. In duodenal and plasma samples, respectively, 897 and 140 DEPs were identified. Combining weighted gene co-expression network analysis(WGCNA) with the DEPs, five key proteins were identified across three machine learning methods. FGL2 and TXNDC5 were significantly elevated in the CeD group, while CHGA expression showed an increasing trend, but without statistical significance. The receiver operating characteristic curve results indicated an area under the curve (AUC) of 0.7711 for FGL2 and 0.6978 for TXNDC5, with a combined AUC of 0.8944. Exploratory analysis using Mfuzz and three machine learning methods identified four plasma proteins potentially associated with CeD pathological grading (Marsh classification): FABP, CPOX, BHMT, and PPP2CB. We conclude that FGL2 and TXNDC5 deserve exploration as potential sensitive, noninvasive diagnostic biomarkers for CeD.

Abstract The recent worldwide outbreaks of mpox prioritize the development of a safe and effective mRNA vaccine. The contemporary mpox virus (MPXV) exhibits changing virological and epidemiological features, notably affecting populations already vulnerable to human immunodeficiency virus (HIV). Herein, we profile the immunogenicity of AR-MPXV5, a penta-component mRNA vaccine targeting five specific proteins (M1R, E8L, A29L, A35R, and B6R) from the representative contemporary MPXV clade II strain, in both naive and simian immunodeficiency virus (SIV)-infected nonhuman primates. Immunization with two doses of AR-MPXV5 to cynomolgus macaques effectively elicits antibody responses and cellular responses. Importantly, based on the challenge model with a contemporary MPXV clade II strain, AR-MPXV5 demonstrates effective efficacy in preventing skin lesions, eliminating viremia and reducing viral loads in multiple tissues after challenge in naive male animals. More importantly, AR-MPXV5 is well-tolerated in stable chronic SIV-infected rhesus monkeys, while eliciting comparable MPXV-specific humoral and cellular responses in both naive and SIV-infected monkeys. Together, these results support further clinical development of the AR-MPXV5 vaccine.

Abstract Implantable catheters are susceptible to severe complications due to non-specific protein adhesion on their surfaces. Polyethylene glycol (PEG) coatings, the gold standard for resistance to non-specific protein adhesion, present a challenge in achieving high-density grafting, which significantly restricts their use as anti-biofouling coatings. Herein, we exploited the strong interaction between polyphenols (PCs) and polycations (K6-PEG) to graft PEG onto the surface of PC-Cu (A network of metal polyphenols composed of proanthocyanidins and metal copper ions, with expectation for the coating with excellent resistance to non-specific protein adhesion (PC-Cu@K6-PEG). The introduction of K6-PEG resulted in enhanced stability and modulus of PC-Cu, as well as a reduction in the surface adhesion energy and contact angle of PC-Cu. In contrast to previously reported PEG coatings, PC-Cu@K6-PEG exhibited a markedly elevated grafting density of PEG (4.06 chains/nm²), which was more than double the highest value previously reported (1.9 chains/nm²), due to the diffusing ability of K6-PEG throughout the PC-Cu networks. PC-Cu@K6-PEG displays robust resistance to a variety of proteins, microbials, and platelet attachment, thereby preventing thrombosis. The coating ability of PC-Cu onto diverse substrates, combined with the simple, straightforward and environmentally benign process of fabricating PC-Cu@K6-PEG, suggests that this strategy has significant potential for use in anti-biofouling surfaces.

Abstract Erythropoiesis is a crucial process in hematopoiesis, yet it remains highly susceptible to disruption by various diseases, which significantly contribute to the global challenges of anemia and blood shortages. Current treatments like erythropoietin (EPO) or glucocorticoids often fall short, especially for hereditary anemias such as Diamond-Blackfan anemia (DBA). To uncover new erythropoiesis-stimulating agents, we devised a screening system using primary human hematopoietic stem and progenitor cells (HSPCs). We discovered that BRAF inhibitors (BRAFi), commonly used to treat BRAFV600E melanoma, can unexpectedly and effectively promote progenitor cell proliferation by temporarily delaying erythroid differentiation. Notably, these inhibitors exhibited pronounced efficacy even under cytokine-restricted conditions and in patient samples of DBA. Mechanistically, although these BRAFi inhibit the MAPK cascade in BRAFV600E mutant cells, they paradoxically act as amplifiers in wild-type BRAF cells, potently enhancing the cascade. Furthermore, we found that while the oncogenic BRAFV600E mutation disrupts hematopoiesis and erythropoiesis through AP-1 hyperactivation, BRAFi minimally impact HSPC self-renewal and differentiation. In vivo studies have shown that BRAFi can enhance human hematopoiesis and erythropoiesis in severe immunodeficient mouse models and alleviate anemia in the Rpl11 haploinsufficiency DBA model, as well as other relevant anemia models. This discovery underscores the role of the MAPK pathway in hematopoiesis and positions BRAFi as a promising therapeutic option for improving hematopoietic reconstitution and treating anemias, including DBA.

Abstract Segmentation of brain tissue from MR images provides detailed quantitative brain analysis for accurate diagnosis, detection, and classification of brain diseases, and plays an important role in neuroimaging research and clinical environments. Recently, a plethora of deep learning-based approaches have been employed to achieve brain tissue segmentation in fetuses, infants, and adults with impressive outcomes. However, owing to the existence of noise, motion artifacts, and edge blurriness in MR images, automatically segmenting brain tissue accurately from MR images is still a very challenging task. This survey examines both deep learning and MRI, providing an overview of the latest advances in fetal, infant, and adult brain tissue segmentation techniques based on deep learning. It includes the performance and quantitative analysis of the state-of-the-art methods. Over 100 scientific papers covering various technical aspects, including network architecture, prior knowledge, and attention mechanisms, were reviewed and analyzed. This article also comprehensively discusses these technologies and their potential applications in the future. Brain tissue segmentation provides detailed quantitative brain analysis for accurate diagnosis, detection, and classification of brain diseases, and plays an important role in neuroimaging research and clinical environments.

Parkinson disease (PD) is defined by the loss of dopamine (DA). Changes in the pedunculopontine nucleus (PPN), particularly in local field potential (LFP), can be attributed to deficits in DA and DA receptor expression levels. PPN is a heterogeneous nucleus consisting of cholinergic, γ-aminobutyric acid (GABAergic), and glutamatergic neurons. However, it is unclear whether low levels of DA receptors affect the activity of different PPN neuron types. We record the neuronal activity of PPN by administering the selective dopamine D1 and D2 receptor antagonists, SCH23390 and Raclopride, respectively. This study discover that the firing rates of glutamatergic neurons could be normalized, and their firing patterns were more consistent in lesioned rats treated with raclopride. Raclopride administration could correct the increased coherence and phase locking between glutamatergic spikes and beta-band oscillatory activity in lesioned rats. Raclopride administration correct the increased coherence and phase locking between glutamatergic spikes and beta-band oscillatory activity in lesioned rats.

Background: Hypochondroplasia (HCH) is a prevalent form of dwarfism linked to mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, causing missense alterations. We previous report was the first to identify FGFR3(G382D) gain-of-function variants with a positive family history as a novel cause of HCH. However, the precise contribution of FGFR3 to the pathogenesis of HCH remains elusive. Methods: We generated an Fgfr3 (V376D) mutation mouse model using CRISPR/Cas9 technology and performed proteomic analyses to investigate the molecular mechanisms and potential therapeutic targets of HCH. Radiography and micro-computed tomography were employed to assess the bone-specific phenotype in Fgfr3 (V376D)mutant mice. Immunofluorescence, western blotting, and flow cytometry were used to systematically investigate the underlying mechanisms and therapeutic targets. Results: We observed that Fgfr3 (V376D) mutant mice exhibit a bone-specific phenotype, with symmetrically short limb bones, partially resembling the dwarfism phenotype of patients with HCH. We demonstrated that the mutant-activated FGFR3 promotes heat shock protein B 6 (HSPB6)-mediated cuproptosis by inhibiting chondrocyte autophagy both in vivo and in vitro. Additionally, we revealed that FGFR3 (G382D) mutation leads to enhanced ERK signaling, increased Drp1-mediated mitochondrial fission, and upregulated cuproptosis-related protein ferredoxin 1 (FDX1). Furthermore, genetic and pharmacological inhibition of the HSPB6-ERK-Drp1-FDX1 pathway partially alleviate the phenotypes of FGFR3 mutants. Conclusions: Our study provides the first evidence for the pathogenicity of a gain-of-function mutation in FGFR3 (G382D) using mouse and cell models, and it underscores the potential of targeting the HSPB6-ERK-Drp1-FDX1 axis as a novel therapeutic approach for HCH. Translational potential of this article: We first demonstrate that impaired autophagy and enhanced cuproptosis are pivotal in the pathogenesis of HCH. This study not only enlarged the therapeutic potential of targeting cuproptosis for treating FGFR3 mutation-related HCH but also provided a novel perspective on the role of the HSPB6-ERK-Drp1-FDX1 signaling pathway in the development of HCH. Consequently, this article provides valuable insights into the mechanisms and treatment strategies for FGFR3 mutation-related chondrodysplasia.

Cr and Ti are essential elements in Ni-based superalloys for γ solid solution strengthening and γ′ precipitation strengthening, respectively, enhancing high-temperature performance. Despite the known benefits of high concentrations, the effects of lower Cr and Ti concentrations on γ′ precipitation kinetics remain unclear. This study investigates the temporal evolution of γ′ phase in Ni–Al-X (X = Cr, Ti) system, utilizing diffusion-couple alongside aberration-corrected transmission electron microscopy to unveil atomic-scale effects. Experimental results demonstrate that Cr and Ti accelerate γ′ phase formation due to competition between lattice misfit and interdiffusion. Moreover, γ′ phase forms through an order-disorder transition, regulated by alloy type. First-principles calculations indicate that Cr and Ti favor γ′ phase formation thermodynamically and kinetically. Al compressibility from Cr and Ti doping promotes γ′ formation. These insights aid in designing Ni-based superalloys with improved microstructural stability and high-temperature performance.

The concept of the generalized Perron complement concerning a nonnegative irreducible matrix was proposed by L. Z. Lu in 2002, and it was used to construct an algorithm for estimating the boundary of the spectral radius. In this study, we consider the properties of generalized Perron complements of nonnegative irreducible and diagonally dominant matrices. Moreover, we analyze the closure property of the generalized Perron complements of nonnegative irreducible $ H $-matrices under certain conditions.