Enzyme-Activated Biomimetic Vesicles Confining Mineralization for Bone Maturation.

Inspired by the crucial role of matrix vesicles (MVs), a series of biomimetic vesicles (BVs) fabricated by calcium glycerophosphate (CaGP) modified polyurethane were designed to mediate the mineralization through in situ enzyme activation for bone therapy. In this study, alkaline phosphatase (ALP) was harbored in the porous BVs by adsorption (Ad-BVs) or entrapment (En-BVs). High encapsulation of ALP on En-BVs was effectively self-activating by calcium ions of CaGP-modified PU that specifically hydrolyzed the organophosphorus (CaGP) to inorganic phosphate, thus promoting the formation of the highly oriented bone-like apatite in vitro. Enzyme-catalyzed kinetics confirms the regulation of apatite crystallization by the synergistic action of self-activated ALP and the confined microcompartments of BVs. This leads to a supersaturated microenvironment, with the En-BVs group exhibiting inorganic phosphate (Pi) levels 4.19 times higher and Ca2+ levels 3.67 times higher than those of simulated body fluid (SBF). Of note, the En-BVs group exhibited excellent osteo-inducing differentiation of BMSCs in vitro and the highest maturity with reduced bone loss in rat femoral defect in vivo. This innovative strategy of biomimetic vesicles is expected to provide valuable insights into the enzyme-activated field of bone therapy.

Clinical value of BRE-AS1 in myocardial infarction and its role in myocardial infarction-induced cardiac muscle cell apoptosis.

Objectives. The aim of this study was to investigate the expression of long non-coding RNA (lncRNA) brain and reproductive organ-expressed protein (BRE) antisense RNA 1 (BRE-AS1) in patients with acute myocardial infarction (AMI) and its effect on ischemia/reperfusion (I/R)-induced oxidative stress and apoptosis of cardiomyocytes. Methods. Serum BRE-AS1 levels in patients with AMI was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The diagnostic and prognostic values of BRE-AS1 were evaluated. H9c2 cells were treated with hypoxia/reoxygenation to establish an in vitro myocardial infarction cell model. The levels of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 were detected by enzyme-linked immunosorbent assay (ELISA). Levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were determined by commercial kits. Cell counting kit-8 (CCK-8) and flow cytometry were used to evaluate the cell viability and cell apoptosis. Results. The expression of BRE-AS1 in serum of patients with AMI is upregulated, which shows the clinical diagnostic value for AMI. In the I/R injury cell model, the knockout of BRE-AS1 can significantly alleviate the increase in TNF-α, IL-1ß, and IL-6 levels, inhibit the production of LDH and MDA, increase the activities of SOD and GSH-Px, promote the cell viability and suppress cell apoptosis. Conclusions. Abnormally elevated BRE-AS1 has a high diagnostic value for AMI as well as a prognostic value for major adverse cardiovascular events (MACEs). The elevation of BRE-AS1 promoted oxidative stress injury and cell apoptosis in vitro.

Impacts of aspirin use on the prognosis of patients with myocardial infarction and pneumonia.

BACKGROUND: We aimed to explore the impact of aspirin use on the risk of readmission and mortality in patients with myocardial infarction and pneumonia. METHODS: This was a cohort study including 703 participants with severe pneumonia and myocardial infarction included in the Medical Information Mart for Intensive Care (MIMIC)-III and the MIMIC-IV. Kaplan-Meier survival analysis was used to show the readmission and survival probability of patients with or without aspirin. In addition, univariate and multivariable models were used to investigate the impact of aspirin on the risk of readmission or mortality of patients. Subgroup analyses were conducted in terms of age, gender, antibiotic use, vancomycin and ampicillin use. RESULTS: Average follow-up was one year, 22% of patients experienced readmission, and 72% patients survived. After the confounders were adjusted for, a 0.46-fold decreased risk of readmission (hazard ratio [HR]=0.46, 95% confidence interval [CI]: 0.27-0.78) and a 0.58-fold decreased risk of one-year mortality (HR=0.56, 95%CI: 0.42-0.82) were observed favoring aspirin use. Subgroup analyses revealed that aspirin was, however, associated with an increased risk of mortality in patients not receiving vancomycin treatment (HR=1.79, 95%CI: 1.08-2.97). CONCLUSIONS: Our findings suggest that clinicians should consider using aspirin in patients with severe myocardial infarction and pneumonia was recommended.

The central retinal thickness and its related genotype in ABCA4-related retinopathy.

PURPOSE: To further explore the influence of genotype, including mutation type and structural domain, on the severity of macular atrophy, we measured the central retinal thickness (CRT) in patients with ABCA4-related retinopathy. METHODS: A total of 66 patients were included in the cohort. This was a retrospective investigation. The patients were tested using whole exon sequencing and ophthalmic exams, including slip lamp exams, best-corrected visual acuity, optical coherence tomography, fundus photo, and fundus autofluorescence. RESULTS: In this study, we discovered that mutations on nucleotide binding domains (NBD) lead to less CRT (45.00 ± 25.25µm, 95% CI: 31.54-58.46) had significantly less CRT than the others (89.75 ± 71.17µm, 95% CI: 30.25-149.25, p = 0.032), and could accelerate the rate of CRT decrease. CONCLUSIONS: Our study provides new perspectives in the understanding of ABCA4-related retinopathy.

Enhanced Charge Transfer in Quasi-2D Perovskite by Formamidinium Cation Gradient Incorporation for Efficient and Stable Solar Cells.

Quasi-2D perovskites have attracted much attention in perovskite photovoltaics due to their excellent stability. However, their photoelectric conversion efficiency (PCE) still lags 3D counterparts, particularly with high short-circuit current (JSC) loss. The quantum confinement effect is pointed out to be the sole reason, which introduces widened bandgap and poor exciton dissociation, and undermines the light capture and charge transport. Here, the gradient incorporation of formamidinium (FA) cations into quasi-2D perovskite is proposed to address this issue. It is observed that FA prefers to incorporate into the larger n value phases near the film surface compared to the smaller n value phases in the bulk, resulting in a narrow bandgap and gradient structure within the film. Through charge dynamic analysis using in situ light-dark Kelvin probe force microscopy and transient absorption spectroscopy, it is demonstrated that incorporating 10% FA significantly facilitates efficient charge transfer between low n-value phases in the bulk and high n-value nearby film surface, leading to reduced charge accumulation. Ultimately, the device based on (AA)2(MA0.9FA0.1)4Pb5I16, where AA represents n-amylamine renowned for its exceptional environmental stability as a bulky organic ligand, achieves an impressive power conversion efficiency (PCE) of 18.58% and demonstrates enhanced illumination and thermal stability.

Generation of an induced pluripotent stem cell line (SJTUGHi003-A) from a patient with Sorsby fundus dystrophy carrying c.484G>A mutation in TIMP3 gene.

Sorsby fundus dystrophy (SFD) is a rare autosomal dominant disorder with macular dystrophy and severe visual loss. Mutations in TIMP3 gene has been related to SFD with mechanisms unclear. We have successfully reprogrammed the peripheral blood mononuclear cells (PBMCs) from an SFD patient carrying c.484G>A mutation in TIMP3 gene to induced pluripotent stem cells (iPSCs) and characterized their pluripotency and genetic stability. This line may serve as a useful tool to explore the role of TIMP3 in SFD pathogenesis.

Passivation of Sodium Benzenesulfonate at the Buried Interface of a High-Performance Wide-Bandgap Perovskite Solar Cell.

The phase segregation of wide-bandgap perovskite is detrimental to a device's performance. We find that Sodium Benzenesulfonate (SBS) can improve the interface passivation of PTAA, thus addressing the poor wettability issue of poly[bis(4-phenyl)(2,4,6-trimethylphenyl)amine](PTAA). This improvement helps mitigate interface defects caused by poor contact between the perovskite and PTAA, reducing non-radiative recombination. Additionally, enhanced interface contact improves the crystallinity of the perovskite, leading to higher-quality perovskite films. By synergistically controlling the crystallization and trap passivation to reduce the phase segregation, SBS-modified perovskite solar cells (PSCs) achieved a power conversion efficiency (PCE) of 20.27%, with an open-circuit voltage (Voc) of 1.18 V, short-circuit current density (Jsc) of 20.93 mA cm-2, and fill factor (FF) of 82.31%.

Potential value of CT-based comprehensive nomogram in predicting occult lymph node metastasis of esophageal squamous cell paralaryngeal nerves: a two-center study.

PURPOSE: The aim of this study is to construct a combined model that integrates radiomics, clinical risk factors and machine learning algorithms to predict para-laryngeal lymph node metastasis in esophageal squamous cell carcinoma. METHODS: A retrospective study included 361 patients with esophageal squamous cell carcinoma from 2 centers. Radiomics features were extracted from the computed tomography scans. Logistic regression, k nearest neighbor, multilayer perceptron, light Gradient Boosting Machine, support vector machine, random forest algorithms were used to construct radiomics models. The receiver operating characteristic curve and The Hosmer-Lemeshow test were employed to select the better-performing model. Clinical risk factors were identified through univariate logistic regression analysis and multivariate logistic regression analysis and utilized to develop a clinical model. A combined model was then created by merging radiomics and clinical risk factors. The performance of the models was evaluated using ROC curve analysis, and the clinical value of the models was assessed using decision curve analysis. RESULTS: A total of 1024 radiomics features were extracted. Among the radiomics models, the KNN model demonstrated the optimal diagnostic capabilities and accuracy, with an area under the curve (AUC) of 0.84 in the training cohort and 0.62 in the internal test cohort. Furthermore, the combined model exhibited an AUC of 0.97 in the training cohort and 0.86 in the internal test cohort. CONCLUSION: A clinical-radiomics integrated nomogram can predict occult para-laryngeal lymph node metastasis in esophageal squamous cell carcinoma and provide guidance for personalized treatment.

Generation of an induced pluripotent stem cell line (SJTUGHi001-A) from a patient with Retinitis Pigmentosa carrying c.77C > T mutation in RAX2 gene.

Retinitis pigmentosa (RP) is a group of genetically heterogeneous retinopathy resulting in irreversible loss of vision. Mutations in RAX2 gene has been related to RP with mechanisms unclear. Here, we generated a human induced pluripotent stem cell (iPSC) line from peripheral blood mononuclear cells of a RP patient carrying c.77C > T mutation in RAX2 gene. This cell line was induced by integration-free episomal vectors and validated for pluripotency and differentiation capacity, which may serve as a model to study the role of RAX2 in RP pathogenesis.

Establishment of the induced pluripotent stem cell line SJTUGHi002-A from a CNGA1-related recessive retinitis pigmentosa patient.

Retinitis pigmentosa (RP) is the most common inherited retinal diseases, characterized by photoreceptor cell death and retinal pigment epithelial atrophy. Mutations in cyclic nucleotide gated channel subunit alpha 1 (CNGA1) have been reported to cause retinitis pigmentosa. Here, we established the human induced pluripotent stem cell line (iPSC) SJTUGHi002-A, generated from peripheral blood mononuclear cells of a 36-year-old male RP patient, who carried a homozygous frameshift variant in CNGA1 gene (c.265delC; p.L89Ffs*4). The cell line can serve as a patient-derived disease model for exploring the pathogenesis and drug development of CNGA1-RP.

Corn stigma ameliorates hyperglycemia in zebrafish and GK rats of type 2 diabetes.

ETHNOPHARMACOLOGICAL RELEVANCE: Cornstigma (CS), derived from the stigma and style of gramineous plant Zeamays. The medicinal use of CS can be traced back to DianNanMateriaMedica. LingnanMedicinalPlantsCompendium records its effectiveness in ameliorating diabetes. Diabetes is a metabolic disorder characterized by hyperglycemia and the consequent chronic complications of kidney, heart, brain and other organs, which pose a significant threat to human health. CS has shown great potential in relieving hyperglycemia associated with diabetes. However, the mechanism of CS in treating diabetes remains unclear. AIM OF THE STUDY: To explore the pathogenesis of diabetes and the mechanism of CS improving hyperglycemia in diabetes. MATERIALS AND METHODS: We measured apigenin and luteolin contents in CS by UPLC/MS/MS method. Selecting Wistar rats as normal group, and GK rats as model group. For rats, we detected glucose and lipid metabolism indicators, including GHb, AST, ALT, U-Glu, UA, U-TP, U-ALB, and ACR after treatment. For zebrafish, we utilized alloxan and sucrose to establish the diabetes model. Measuring zebrafish blood glucose is employed to evaluate the hypoglycemic capability of CS. In order to explore the mechanism of CS in treating diabetes, we sequenced the transcriptome of zebrafish, compared differentially expressed genes of normal, diabetic, and CS-treated group, and validated multiple enrichment pathways by PCR. RESULTS: CS can improve blood glucose levels in both GK rats and diabetic zebrafish. For rats, CS partially restored glucose and lipid metabolism indicators. Transcriptome data from zebrafish showed a close correlation with steroid biosynthesis. The RNA-Sequencing was consistent with PCR results, indicating that CS downregulated gene (fdft1,lss,cyp51) expression concerned with steroid biosynthesis pathway in the diabetes model. CONCLUSION: CS effectively improved blood glucose levels, regulated glucose and lipid metabolism by suppressing gene expression in steroid biosynthesis pathway, and ameliorated hyperglycemia. Our research provides valuable insights for CS in the treatment of diabetes, and proposes a new strategy for selecting clinical medications for diabetes.

Prevalence and optical coherence tomography analyses of outer retinal tubulations in Chinese population with inherited retinal diseases.

BACKGROUND: To investigate the prevalence of outer retinal tubulation (ORT) and its correlations with optical coherence tomography (OCT) parameters in Chinese population with inherited retinal diseases (IRDs). METHODS: This retrospective study enrolled consecutive patients identified with IRDs and referred for genetic testing between February 2016 and April 2021. Clinical characteristics from medical records and features of cross-sectional B-scans were reviewed and analysed. The associations of patient-specific and ocular features with the presence of ORT were evaluated using univariate and multivariate analyses. RESULTS: Two hundred and three patients (401 eyes) with a mean age of 49.7 ± 16.7 years were enrolled. ORT was observed in 41 eyes (10.2%), including 26 of 28 eyes (92.9%) with Bietti crystalline corneoretinal dystrophy (BCD), 14 of 338 eyes (4.1%) with retinitis pigmentosa (RP), and 1 of 26 eyes (3.8%) in eyes with cone-rod dystrophy. Eyes with ORT showed significantly worse visual acuity than those without ORT (P = 0.002). Multivariate analysis indicated that the presence of ORT was positively correlated with choroidal atrophy and inner nuclear layer (INL) cysts (P < 0.01). ORTs were detected more frequently in eyes with BCD than RP (P = 0.024), most of which located exclusively within the extrafoveal area. Large choroidal vessels were detected underneath the corresponding ORTs in both patients with BCD and RP. CONCLUSIONS: The prevalence of ORT varies among different IRDs phenotypes, with the highest prevalence in BCD. The presence of choroidal atrophy and INL cysts may be associated with an increased risk of ORT formation in patients with IRD.

GENETIC FACTORS AND CHARACTERISTICS ON SPECTRAL-DOMAIN OPTICAL COHERENCE TOMOGRAPHY ARE ASSOCIATED WITH CHOROIDAL THICKNESS IN ABCA4 -RELATED RETINOPATHY.

PURPOSE: To investigate the possible correlation factors of choroidal thickness in ABCA4 -related retinopathy. METHODS: A total of 66 patients were included in the cohort. It is a retrospective, cross-sectional laboratory investigation. The patients were tested using whole-exon sequencing and ophthalmic examinations, including slit-lamp examinations, best-corrected visual acuity, spectral-domain optical coherence tomography, fundus photograph, and fundus autofluorescence. RESULTS: Besides demographic characteristics (age, onset age, duration), we selected genetic factors and ocular characteristics on spectral-domain optical coherence tomography as the candidates related to choroidal thickness. Mutation type (inframe mutation or premature termination codon), epiretinal membrane, retinal pigment epithelium- Bruch membrane integrity, and macular curvature changes were identified as related factors to choroidal thickness in ABCA4 -related retinopathy after the adjustment of Logistic LASSO regression. CONCLUSION: Mutation type, epiretinal membrane, retinal pigment epithelium-Bruch membrane integrity, and macular curvature changes are related factors to choroidal thinning. These findings could provide us a further understanding for the pathological process and clinical features of ABCA4 mutation.

Blockade of TNF-α/TNFR2 signalling suppresses colorectal cancer and enhances the efficacy of anti-PD1 immunotherapy by decreasing CCR8+ T regulatory cells.

Enrichment of regulatory T cells (Tregs) in the tumour microenvironment (TME) has been recognized as one of the major factors in the initiation and development of resistance to immune checkpoint inhibitors. C-C motif chemokine receptor 8 (CCR8), a marker of activated suppressive Tregs, has a significant impact on the functions of Tregs in the TME. However, the regulatory mechanism of CCR8 in Tregs remains unclear. Here, we reveal that a high level of TNF-α in the colorectal cancer (CRC) microenvironment upregulates CCR8 expression in Tregs via the TNFR2/NF-κB signalling pathway and the FOXP3 transcription factor. Furthermore, in both anti-PD1-responsive and anti-PD1-unresponsive tumour models, PD1 blockade induced CCR8+ Treg infiltration. In both models, Tnfr2 depletion or TNFR2 blockade suppressed tumour progression by reducing CCR8+ Treg infiltration and thus augmented the efficacy of anti-PD1 therapy. Finally, we identified that TNFR2+CCR8+ Tregs but not total Tregs are positively correlated with adverse prognosis in CRC and gastric cancer. Our work reveals the regulatory mechanisms of CCR8 in Tregs and identifies TNFR2 as a promising target for immunotherapy.

A novel microdeletion of 517 kb downstream of the PAX6 gene in a Chinese family with congenital aniridia.

BACKGROUND: To identify the disease-causing gene in a Chinese family affected with congenital aniridia. METHODS: Patients underwent systematic ophthalmic examinations such as anterior segment photography, fundus photography, optical coherence tomography, and fundus fluorescein angiography. The proband was screened for pathogenic variants by whole exome sequencing (WES) and copy number variant (CNV) analysis. Real-time quantitative PCR (RT-qPCR) was applied to confirm the CNV results. Breakpoints were identified by long-range PCR followed by Sanger sequencing. RESULTS: All seven members of this Chinese family, including four patients and three normal individuals, were recruited for this study. All patients showed bilateral congenital aniridia with nystagmus, except the son of the proband, who presented with bilateral partial coloboma of the iris. A novel heterozygous deletion (chr11:31,139,019-31,655,997) containing the 3' regulatory enhancers of the PAX6 gene was detected in this family. We also reviewed the reported microdeletions downstream of PAX6 in patients with aniridia. CONCLUSIONS: We identified a novel microdeletion, 517 kb in size located about 133 kb downstream of the PAX6 gene, responsible for congenital aniridia in this Chinese family, which expands the spectrum of aniridia-associated mutations in PAX6.

Nomogram of uveal melanoma as prediction model of metastasis risk.

Background: Since the poor prognosis of uveal melanoma with distant metastasis, we intended to screen out possible biomarkers for uveal melanoma metastasis risk and establish a nomogram model for predicting the risk of uveal melanoma (UVM) metastasis. Methods: Two datasets of UVM (GSE84976, GSE22138) were selected. Data was analyzed by R language, CTD database and GEPIA. Results: The co-upregulated genes of two datasets, HTR2B, CHAC1, AHNAK2, and PTP4A3 were identified using a Venn diagram. These biomarkers are combined with clinical characteristics, and Lasso regression was conducted to filter the metastasis-related biomarkers. HTR2B, CHAC1, AHNAK2, PTP4A3, tumor thickness, and retinal detachment (RD) were selected to establish the nomogram. Conclusion: Our study provides a comprehensive predictive model and personalized risk estimation tool for assessment of 3-year metastasis risk of UVM with a better accuracy.

SIGLEC10+ macrophages drive gastric cancer progression by suppressing CD8+ T cell function.

Existing immune checkpoint inhibitors focus on activating T cells and show limited effectiveness in gastric cancer (GC). SIGLEC10 is identified as a novel tumor-associated macrophage-related immune checkpoint in other cancer types. However, its immunosuppressive role and clinical significance in GC remain unclear. In this study, we find a dominant expression of SIGLEC10 on CD68+ macrophages in GC. SIGLEC10 can suppress the proliferation and function of tumor-infiltrating CD8+ T cells in vitro via the Akt/P38/Erk signaling pathway. Furthermore, in ex vivo and in vivo models, SIGLEC10 blockade promotes CD8+ T cell effector function. Finally, SIGLEC10+ macrophages are positively correlated with the adverse prognosis of GC. Our study highlights that SIGLEC10 directly suppresses T cell function and serves as a promising target for immunotherapy and suggests SIGLEC10+ macrophages as a novel potential predictor of the clinical prognosis of GC.

Rapid and Sensitive Diagnosis of Leber Hereditary Optic Neuropathy Variants Using CRISPR/Cas12a Detection.

Leber hereditary optic neuropathy (LHON) is the most common maternally inherited mitochondrial disease, with >90% of cases harboring one of three point variants (m.3460G>A, m.11778G>A, and m.14484T>C). Rapid and sensitive diagnosis of LHON variants is urgently needed for early diagnosis and timely treatment after onset, which is currently limited. Herein, we adapted the Cas12a-based DNA detection platform for LHON mitochondrial variant diagnosis. Single-strand guide CRISPR RNAs and enzymatic recombinase amplification primers were first screened, the CRISPR/Cas12a system was then optimized with restriction enzymes, and finally compared with Sanger sequencing and next-generation sequencing (NGS) in multicenter clinical samples. This approach can be completed within 30 minutes using only one drop of blood and could reach a sensitivity of 1% of heteroplasmy. Among the 182 multicenter clinical samples, the CRISPR/Cas12a detection system showed high consistency with Sanger sequencing and NGS in both specificity and sensitivity. Notably, a sample harboring a de novo 3.78% m.11778G>A variant detected by NGS, but not by Sanger sequencing, was successfully confirmed using the CRISPR/Cas12a assay, which proved the effectiveness of our method. Overall, our CRISPR/Cas12a detection system provides an alternative for rapid, convenient, and sensitive detection of LHON variants, exhibiting great potential for clinical practice.

Association between previous cataract surgery and cognition among middle-aged and older Chinese: the China health and retirement longitudinal study (CHARLS).

BACKGROUND: Cataract is the primary cause of blindness globally, and surgery offers the only method by which to remove cataracts. We aimed to examine whether previous cataract surgery is associated with cognitive function. METHODS: Our study included 13,824 participants. Data from the baseline of the China Health and Retirement Longitudinal Study (CHARLS) were used. The participants were categorized into two groups: with and without previous cataract surgery. Weighted multiple linear regression was used to obtain the ß and 95% confidence intervals (CI). RESULTS: The participants who had previous cataract surgery (n = 261) scored lower in cognition, including both memory and mental state, than those without previous cataract surgery. After adjusting for socioeconomic factors and metabolic measures, a negative association was evident between previous cataract surgery and cognition (ß = -0.647, 95% CI: -1.244, - 0.049). Furthermore, the participants who were older and female demonstrated a decline in cognition, while living in cities and having higher levels education were associated with higher cognition. CONCLUSIONS: Better cognitive function was associated with less previous cataract surgery or cataract occurrence. This suggests that a period of vision loss due to cataract leads to cognitive decline, however further studies are need to dissect the impact of vision loss and cataract surgery on cognitive decline.