Reactive Oxygen Species-Responsive Delivery of a Notch Inhibitor to Alleviate Nonalcoholic Steatohepatitis by Inhibiting Hepatic de Novo Lipogenesis and Inflammation.

With the increased prevalence of nonalcoholic steatohepatitis (NASH) in the world, effective pharmacotherapy in clinical practice is still lacking. Previous studies have shown that dibenzazepine (DBZ), a Notch inhibitor, could alleviate NASH development in a mouse model. However, low bioavailability, poor water solubility, and extrahepatic side effects restrict its clinical application. To overcome these barriers, we developed a reactive oxygen species (ROS)-sensitive nanoparticle based on the conjugation of bilirubin to poly(ethylene glycol) (PEG) chains, taking into account the overaccumulation of hepatic ROS in the pathologic state of nonalcoholic steatohepatitis (NASH). The PEGylated bilirubin can self-assemble into nanoparticles in an aqueous solution and encapsulate insoluble DBZ into its hydrophobic cavity. DBZ nanoparticles (DBZ Nps) had good stability, rapidly released DBZ in response to H2O2, and effectively scavenged intracellular ROS of hepatocytes. After systemic administration, DBZ Nps could accumulate in the liver of the NASH mice, extend persistence in circulation, and improve the bioavailability of DBZ. Furthermore, DBZ Nps significantly improved glucose intolerance, relieved hepatic lipid accumulation and inflammation, and ameliorated NASH-induced liver fibrosis. Additionally, DBZ Nps had no significant extrahepatic side effects. Taken together, our results highlight the potential of the ROS-sensitive DBZ nanoparticle as a promising therapeutic strategy for NASH.

Canagliflozin alleviates pulmonary hypertension by activating PPARγ and inhibiting its S225 phosphorylation.

Pulmonary hypertension (PH) is a progressive fatal disease with no cure. Canagliflozin (CANA), a novel medication for diabetes, has been found to have remarkable cardiovascular benefits. However, few studies have addressed the effect and pharmacological mechanism of CANA in the treatment of PH. Therefore, our study aimed to investigate the effect and pharmacological mechanism of CANA in treating PH. First, CANA suppressed increased pulmonary artery pressure, right ventricular hypertrophy, and vascular remodeling in both mouse and rat PH models. Network pharmacology, transcriptomics, and biological results suggested that CANA could ameliorate PH by suppressing excessive oxidative stress and pulmonary artery smooth muscle cell proliferation partially through the activation of PPARγ. Further studies demonstrated that CANA inhibited phosphorylation of PPARγ at Ser225 (a novel serine phosphorylation site in PPARγ), thereby promoting the nuclear translocation of PPARγ and increasing its ability to resist oxidative stress and proliferation. Taken together, our study not only highlighted the potential pharmacological effect of CANA on PH but also revealed that CANA-induced inhibition of PPARγ Ser225 phosphorylation increases its capacity to counteract oxidative stress and inhibits proliferation. These findings may stimulate further research and encourage future clinical trials exploring the therapeutic potential of CANA in PH treatment.

Transcriptomic sex differences in postmortem brain samples from patients with psychiatric disorders.

Many psychiatric disorders exhibit sex differences, but the underlying mechanisms remain poorly understood. We analyzed transcriptomics data from 2,160 postmortem adult prefrontal cortex brain samples from the PsychENCODE consortium in a sex-stratified study design. We compared transcriptomics data of postmortem brain samples from patients with schizophrenia (SCZ), bipolar disorder (BD), and autism spectrum disorder (ASD) to transcriptomics data of postmortem control brains from individuals without a known history of psychiatric disease. We found that brain samples from females with SCZ, BD and ASD showed a higher burden of transcriptomic dysfunction than did brain samples from males with these disorders. This observation was supported by the larger number of differentially expressed genes (DEGs) and a greater magnitude of gene expression changes observed in female versus male brain specimens. Additionally, female patient brain samples showed greater overall connectivity dysfunction, defined by a higher proportion of gene co-expression modules with connectivity changes and higher connectivity burden, indicating a greater degree of gene co-expression variability. We identified several gene co-expression modules enriched in sex-biased DEGs and identified genes from a genome-wide association study that were involved in immune and synaptic functions across different brain cell types. We found a number of genes as hubs within these modules including those encoding SCN2A, FGF14, and C3. Our results suggest that in the context of psychiatric diseases, males and females exhibit different degrees of transcriptomic dysfunction, and implicate immune and synaptic-related pathways in these sex differences.

Species-specific design of artificial promoters by transfer-learning based generative deep-learning model.

Native prokaryotic promoters share common sequence patterns, but are species dependent. For understudied species with limited data, it is challenging to predict the strength of existing promoters and generate novel promoters. Here, we developed PromoGen, a collection of nucleotide language models to generate species-specific functional promoters, across dozens of species in a data and parameter efficient way. Twenty-seven species-specific models in this collection were finetuned from the pretrained model which was trained on multi-species promoters. When systematically compared with native promoters, the Escherichia coli- and Bacillus subtilis-specific artificial PromoGen-generated promoters (PGPs) were demonstrated to hold all distribution patterns of native promoters. A regression model was developed to score generated either by PromoGen or by another competitive neural network, and the overall score of PGPs is higher. Encouraged by in silico analysis, we further experimentally characterized twenty-two B. subtilis PGPs, results showed that four of tested PGPs reached the strong promoter level while all were active. Furthermore, we developed a user-friendly website to generate species-specific promoters for 27 different species by PromoGen. This work presented an efficient deep-learning strategy for de novo species-specific promoter generation even with limited datasets, providing valuable promoter toolboxes especially for the metabolic engineering of understudied microorganisms.

Using Multiple Imputation to Account for the Uncertainty Due to Missing Data in the Context of Factor Retention.

Although parallel analysis has been found to be an accurate method for determining the number of factors in many conditions with complete data, its application under missing data is limited. The existing literature recommends that, after using an appropriate multiple imputation method, researchers either apply parallel analysis to every imputed data set and use the number of factors suggested by most of the data copies or average the correlation matrices across all data copies, followed by applying the parallel analysis to the average correlation matrix. Both approaches for pooling the results provide a single suggested number without reflecting the uncertainty introduced by missing values. The present study proposes the use of an alternative approach, which calculates the proportion of imputed data sets that result in k (k = 1, 2, 3 . . .) factors. This approach will inform applied researchers of the degree of uncertainty due to the missingness. Results from a simulation experiment show that the proposed method can more likely suggest the correct number of factors when missingness contributes to a large amount of uncertainty.

Exploring the causal relationship between gut microbiota and frailty: a two-sample mendelian randomization analysis.

Background: Frailty is a complex geriatric syndrome that seriously affects the quality of life of older adults. Previous observational studies have reported a strong relationship of frailty with the gut microbiota; however, further studies are warranted to establish a causal link. Accordingly, we aimed to conduct a bidirectional Mendelian randomization study to assess the causal relationship between frailty, as measured by the frailty index, and gut microbiota composition. Methods: Instrumental variables for the frailty index (N = 175, 226) and 211 gut bacteria (N = 18,340) were obtained through a genome-wide association study. A two-sample Mendelian randomization analysis was performed to assess the causal relationship of gut microbiota with frailty. Additionally, we performed inverse Mendelian randomization analyses to examine the direction of causality. Inverse variance weighting was used as the primary method in this study, which was supplemented by horizontal pleiotropy and sensitivity analyses to increase confidence in the results. Results: Bacteroidia (b = -0.041, SE = 0.017, p = 0.014) and Eubacterium ruminantium (b = -0.027, SE = 0.012, p = 0.028) were protective against frailty amelioration. Additionally, the following five bacteria types were associated with high frailty: Betaproteobacteria (b = 0.049, SE = 0.024, p = 0.042), Bifidobacterium (b = 0.042, SE = 0.016, p = 0.013), Clostridium innocuum (b = 0.023, SE = 0.011, p = 0.036), E. coprostanoligenes (b = 0.054, SE = 0.018, p = 0.003), and Allisonella (b = 0.032, SE = 0.013, p = 0.012). Contrastingly, frailty affected Butyrivibrio in the gut microbiota (b = 1.225, SE = 0.570, p = 0.031). The results remained stable within sensitivity and validation analyses. Conclusion: Our findings strengthen the evidence of a bidirectional causal link between the gut microbiota and frailty. It is important to elucidate this relationship to optimally enhance the care of older adults and improve their quality of life.

The Influence of Crosslinker Architecture on Dynamic Covalent Hydrogel Viscoelasticity.

Dynamic covalent crosslinked (DCC) hydrogels represent a significant advance in biomaterials for regenerative medicine and mechanobiology. These gels typically offer viscoelasticity and self-healing properties that more closely mimic in vivo tissue mechanics than traditional, predominantly elastic, covalent crosslinked hydrogels. Despite their promise, the effects of varying crosslinker architecture - side chain versus telechelic crosslinks - on the viscoelastic properties of DCC hydrogels have not been thoroughly investigated. This study introduces hydrazone-based alginate hydrogels and examines how side-chain and telechelic crosslinker architectures impact hydrogel viscoelasticity and stiffness. In side-chain crosslinked gels, higher polymer concentrations, enhances stiffness and decelerates stress relaxation, while an off-stoichiometric hydrazine-to-aldehyde ratio leads to reduced stiffness and shorter relaxation time. In telechelic crosslinked gels, maximal stiffness and stress relaxation occurs at intermediate crosslinker concentrations for both linear and star crosslinkers, with higher crosslinker valency further increasing stiffness and decreasing relaxation rates. Our result suggested different ranges of stiffness and stress relaxation are accessible with the different crosslinker architectures, with side-chain crosslinking leading to gels with slower stress relaxation times relative to the other architectures, and star crosslinked gels providing increased stiffness and slower stress relaxation relative to linear crosslinked gels. The mechanical properties of hydrogels with star crosslinking are more robust to changes induced by competing chemical reactions compared to linear crosslinking. Our research underscores the pivotal role of crosslinker architecture in defining hydrogel stiffness and viscoelasticity, providing crucial insights for the design of DCC hydrogels with tailored mechanical properties for specific biomedical applications.

Real-world performance of indobufen versus aspirin after percutaneous coronary intervention: insights from the ASPIRATION registry.

BACKGROUND: Indobufen is widely used in patients with aspirin intolerance in East Asia. The OPTION trial launched by our cardiac center examined the performance of indobufen based dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). However, the vast majority of patients with acute coronary syndrome (ACS) and aspirin intolerance were excluded. We aimed to explore this question in a real-world population. METHODS: Patients enrolled in the ASPIRATION registry were grouped according to the DAPT strategy that they received after PCI. The primary endpoints were major adverse cardiovascular and cerebrovascular events (MACCE) and Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. Propensity score matching (PSM) was adopted for confounder adjustment. RESULTS: A total of 7135 patients were reviewed. After one-year follow-up, the indobufen group was associated with the same risk of MACCE versus the aspirin group after PSM (6.5% vs. 6.5%, hazard ratio [HR] = 0.99, 95% confidence interval [CI] = 0.65 to 1.52, P = 0.978). However, BARC type 2, 3, or 5 bleeding was significantly reduced (3.0% vs. 11.9%, HR = 0.24, 95% CI = 0.15 to 0.40, P < 0.001). These results were generally consistent across different subgroups including aspirin intolerance, except that indobufen appeared to increase the risk of MACCE in patients with ACS. CONCLUSIONS: Indobufen shared the same risk of MACCE but a lower risk of bleeding after PCI versus aspirin from a real-world perspective. Due to the observational nature of the current analysis, future studies are still warranted to further evaluate the efficacy of indobufen based DAPT, especially in patients with ACS. TRIAL REGISTRATION: Chinese Clinical Trial Register ( https://www.chictr.org.cn ); Number: ChiCTR2300067274.

Telomere dysfunction alters intestinal stem cell dynamics to promote cancer.

Telomere dynamics are linked to aging hallmarks, and age-associated telomere loss fuels the development of epithelial cancers. In Apc-mutant mice, the onset of DNA damage associated with telomere dysfunction has been shown to accelerate adenoma initiation via unknown mechanisms. Here, we observed that Apc-mutant mice engineered to experience telomere dysfunction show accelerated adenoma formation resulting from augmented cell competition and clonal expansion. Mechanistically, telomere dysfunction induces the repression of EZH2, resulting in the derepression of Wnt antagonists, which causes the differentiation of adjacent stem cells and a relative growth advantage to Apc-deficient telomere dysfunctional cells. Correspondingly, in this mouse model, GSK3ß inhibition countered the actions of Wnt antagonists on intestinal stem cells, resulting in impaired adenoma formation of telomere dysfunctional Apc-mutant cells. Thus, telomere dysfunction contributes to cancer initiation through altered stem cell dynamics, identifying an interception strategy for human APC-mutant cancers with shortened telomeres.

Investigation of Metabolic and Inflammatory Disorder in the Aging FGF21 Knockout Mouse.

Aging is a physiological condition accomplished with persistent low-grade inflammation and metabolic disorders. FGF21 has been reported to act as a potent longevity determinant, involving inflammatory response and energy metabolism. In this study, we engineered aging FGF21 knockout mice of 36-40 weeks and observed that FGF21 deficiency manifests a spontaneous inflammatory response of lung and abnormal accumulation of lipids in liver. On one hand, inflamed state in lungs and increased circulating inflammatory cytokines were found in FGF21 knockout mice of 36-40 weeks. To evaluate the ability of FGF21 to suppress inflammation, a subsequent study found that FGF21 knockout aggravated LPS-induced pulmonary exudation and inflammatory infiltration in mice, while exogenous administration of FGF21 reversed these malignant phenotypes by enhancing microvascular endothelial junction. On the other hand, FGF21 knockout induces fatty liver in aging mice, characterized by excessive accumulation of triglycerides within hepatocytes. Further quantitative metabolomics and lipidomics analysis revealed perturbed metabolic profile in liver lacking FGF21, including disrupted glucose and lipids metabolism, glycerophospholipid metabolism, and amino acid metabolism. Taken together, this investigation reveals the protective role of FGF21 during aging by weakening the inflammatory response and balancing energy metabolism.

Local Confinement Effects of Block Copolymers Driving Self-Assembly of Nanoparticles into Discrete Pancake-Shaped Superlattices.

The utilization of polymer conformations to construct a variety of superlattices is a common method within the field. However, this technique often results in only long-range ordering rather than the formation of distinct superlattices. In this study, a well-organized array of discrete pancake-shaped superlattices (DPSs) is successfully obtained through the utilization of air-liquid interface self-assembly, facilitated by the confined environment created by a block copolymer. It is crucial to note that both the self-assembly behavior and resulting morphologies of the DPSs can be precisely tuned by adjusting several experimental parameters, most notably the concentration and molecular architecture of the block copolymers. Furthermore, this work provides valuable insights into the formation processes and mechanisms underpinning the DPSs. The approach described here is both straightforward and efficacious, establishing a strong foundation for subsequent research and the development of non-close-packed superlattice structures.

Macroscopic Superlattice Membranes Self-Assembled from Gold Nanobipyramids with Precisely Tunable Tip Arrangements for SERS.

A persistent challenge in utilizing Au nanocrystals for surface-enhanced Raman spectroscopy (SERS) lies in achieving controllable superstructures that maximize SERS performance. Here, a novel strategy is proposed to enhance the SERS performance by precisely adjusting the tip arrangements of Au nanobipyramids (BPs) in two-dimensional (2D) superlattices (SLs). This is achieved through ligand-exchange of Au BPs, followed by liquid-air interfacial assembly, resulting in large-area, transferrable SL membranes. The key to controlling the arrangement of Au BPs in the SLs is the regulation of the amount of free ligands added during self-assembly, which allows for the precise formation of various configurations such as tilted SLs, tip-on-tip SLs, and tip-to-tip SLs. Among these configurations, tip-on-tip SLs exhibit the highest enhancement factor for SERS, reaching an impressive value of 1.95×108, with uniform and consistent SERS signals across a large area. The experimental findings are further corroborated by simulations using the finite element method. This study establishes an efficient method for engineering the microstructure of 2D SLs composed of Au BPs, highlighting the importance of fine-tuning the tip arrangements of Au BPs to regulate SERS performance.

OsGLP8-7 interacts with OsPRX111 to detoxify excess copper in rice.

Lignin is a phenolic biopolymer generated from phenylpropanoid pathway in the secondary cell wall and is required for defense of plants against various stress. Although the fact of stress-induced lignin deposition has been clearly demonstrated, it remains largely elusive how the formation of lignin is promoted under Cu stress. The present study showed that OsGLP8-7, an extracellular glycoprotein of rice (Oryza sativa L.), plays an important function against Cu stress. The loss function of OsGLP8-7 results in Cu sensitivity whereas overexpression of OsGLP8-7 scavenges Cu-induced superoxide anion (O2•-). OsGLP8-7 interacts with apoplastic peroxidase111 (OsPRX111) and elevates OsPRX111 stability when exposed to excess Cu. In OsGLP8-7 overexpressing (OE) lines, the retention of Cu within cell wall limiting Cu uptake into cytoplasm is attributed to the enhanced lignification required for Cu tolerance. Exogenous application of a lignin inhibitor can impair the Cu tolerance of transgenic Arabidopsis lines overexpressing OsGLP8-7. In addition, co-expression of OsGLP8-7 and OsPRX111 genes in tobacco leaves leads to an improved lignin deposition compared to leaves expressing each gene individually or the empty vector. Taken together, our findings provided the convincing evidences that the interaction between OsGLP8-7 and OsPRX111 facilitates effectively lignin polymerization, thereby contributing to Cu tolerance in rice.

Glycine betaine modulates extracellular polymeric substances to enhance microbial salinity tolerance.

High salinity inhibits microbial activity in the bioremediation of saline wastewater. To alleviate osmotic stress, glycine betaine (GB), an osmoprotectant, is added to enhance the secretion of extracellular polymeric substances (EPS). These EPS are pivotal in withstanding environmental stressors, yet the intricate interplay between GB supplementation and microbial responses through EPS modifications-encompassing composition, molecular architecture, and electrochemical features-remains elusive in hypersaline conditions. Here we show microbial strategies for salinity endurance by investigating the impact of GB on the dynamic alterations of EPS properties. Our findings reveal that GB supplementation at 3.5% salinity elevates the total EPS (T-EPS) content from 12.50 ± 0.05 to 24.58 ± 0.96 mg per g dry cell weight. The observed shift in zeta potential from -28.95 to -6.25 mV at 0% and 3.5% salinity, respectively, with GB treatment, indicates a reduction in electrostatic repulsion and compaction. Notably, the EPS protein secondary structure transition from ß-sheet to α-helix, with GB addition, signifies a more compact protein configuration, less susceptible to salinity fluctuations. Electrochemical analyses, including cyclic voltammetry (CV) and differential pulse voltammetry (DPV), reveal GB's role in promoting the release of exogenous electron shuttles, such as flavins and c-type cytochromes (c-Cyts). The enhancement in DPV peak areas (QDPV) with GB addition implies an increase in available extracellular electron transfer sites. This investigation advances our comprehension of microbial adaptation mechanisms to salinity through EPS modifications facilitated by GB in saline habitats.

Unsupervised ensemble-based phenotyping enhances discoverability of genes related to left-ventricular morphology.

Recent genome-wide association studies have successfully identified associations between genetic variants and simple cardiac morphological parameters derived from cardiac magnetic resonance images. However, the emergence of large databases, including genetic data linked to cardiac magnetic resonance facilitates the investigation of more nuanced patterns of cardiac shape variability than those studied so far. Here we propose a framework for gene discovery coined unsupervised phenotype ensembles. The unsupervised phenotype ensemble builds a redundant yet highly expressive representation by pooling a set of phenotypes learnt in an unsupervised manner, using deep learning models trained with different hyperparameters. These phenotypes are then analysed via genome-wide association studies, retaining only highly confident and stable associations across the ensemble. We applied our approach to the UK Biobank database to extract geometric features of the left ventricle from image-derived three-dimensional meshes. We demonstrate that our approach greatly improves the discoverability of genes that influence left ventricle shape, identifying 49 loci with study-wide significance and 25 with suggestive significance. We argue that our approach would enable more extensive discovery of gene associations with image-derived phenotypes for other organs or image modalities.

Expeditious Synthesis of Gwanakoside A and the Chloronaphthol Glycoside Congeners.

The synthesis of gwanakoside A, a chlorinated naphthol bis-glycoside, and its analogues was achieved through stepwise chlorination and donor-equivalent controlled regioselective phenol glycosylation with glycosyl N-phenyltrifluoroacetimidates as donors. Gwanakoside A displayed considerable inhibitory effects against various cancer cells and Staphylococcus aureus strains.

Development and validation of nomograms to predict clinical outcomes of preeclampsia.

Background: Preeclampsia (PE) is one of the most severe pregnancy-related diseases; however, there is still a lack of reliable biomarkers. In this study, we aimed to develop models for predicting early-onset PE, severe PE, and the gestation duration of patients with PE. Methods: Eligible patients with PE were enrolled and divided into a training (n = 253) and a validation (n = 108) cohort. Multivariate logistic and Cox models were used to identify factors associated with early-onset PE, severe PE, and the gestation duration of patients with PE. Based on significant factors, nomograms were developed and evaluated using the area under the curve (AUC) and a calibration curve. Results: In the training cohort, multiple gravidity experience (p = 0.005), lower albumin (ALB; p < 0.001), and higher lactate dehydrogenase (LDH; p < 0.001) were significantly associated with early-onset PE. Abortion history (p = 0.017), prolonged thrombin time (TT; p < 0.001), and higher aspartate aminotransferase (p = 0.002) and LDH (p = 0.003) were significantly associated with severe PE. Abortion history (p < 0.001), gemellary pregnancy (p < 0.001), prolonged TT (p < 0.001), higher mean platelet volume (p = 0.014) and LDH (p < 0.001), and lower ALB (p < 0.001) were significantly associated with shorter gestation duration. Three nomograms were developed and validated to predict the probability of early-onset PE, severe PE, and delivery time for each patient with PE. The AUC showed good predictive performance, and the calibration curve and decision curve analysis demonstrated clinical practicability. Conclusion: Based on the clinical features and peripheral blood laboratory indicators, we identified significant factors and developed models to predict early-onset PE, severe PE, and the gestation duration of pregnant women with PE, which could help clinicians assess the clinical outcomes early and design appropriate strategies for patients.

TAK-242 improves sepsis-associated acute kidney injury in rats by inhibiting the TLR4/NF-κB signaling pathway.

OBJECTIVE: This study was designed to observe the effect of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway activity on sepsis-associated acute kidney injury (SA-AKI), thereby providing new considerations for the prevention and treatment of SA-AKI. METHODS: The rats were divided into Sham, cecal ligation and puncture (CLP), CLP + vehicle, and CLP + TAK-242 groups. Except the Sham group, a model of CLP-induced sepsis was established in other groups. After 24 h, the indicators related to kidney injury in blood samples were detected. The pathological changes in the kidneys were observed by hematoxylin-eosin staining, and tubular damage was scored. Oxidative stress-related factors, mitochondrial dysfunction-related indicators in each group were measured; the levels of inflammatory factors in serum and kidney tissue of rats were examined. Finally, the expression of proteins related to the TLR4/NF-κB signaling pathway was observed by western blot. RESULTS: Compared with the CLP + vehicle and CLP + TAK-242 groups, the CLP + TAK-242 group reduced blood urea nitrogen (BUN), creatinine (Cr), cystatin-C (Cys-C), reactive oxygen species (ROS), malondialdehyde (MDA), and inflammatory factors levels (p < 0.01), as well as increased superoxide dismutase (SOD) activity of CLP rats (p < 0.01). Additionally, TAK-242 treatment improved the condition of CLP rats that had glomerular and tubular injuries and mitochondrial disorders (p < 0.01). Further mechanism research revealed that TAK-242 can inhibit the TLR4/NF-κB signaling pathway activated by CLP (p < 0.01). Above indicators after TAK-242 treatment were close to those of the Sham group. CONCLUSION: TAK-242 can improve oxidative stress, mitochondrial dysfunction, and inflammatory response by inhibiting the activity of TLR4/NF-κB signaling pathway, thereby preventing rats from SA-AKI.

Hypoxia preconditioning of adipose stem cell-derived exosomes loaded in gelatin methacryloyl (GelMA) promote type H angiogenesis and osteoporotic fracture repair.

The challenges posed by delayed atrophic healing and nonunion stand as formidable obstacles in osteoporotic fracture treatment. The processes of type H angiogenesis and osteogenesis emerge as pivotal mechanisms during bone regeneration. Notably, the preconditioning of adipose-derived stem cell (ADSC) exosomes under hypoxic conditions has garnered attention for its potential to augment the secretion and functionality of these exosomes. In the present investigation, we embarked upon a comprehensive elucidation of the underlying mechanisms of hypo-ADSC-Exos within the milieu of osteoporotic bone regeneration. Our findings revealed that hypo-ADSC-Exos harboured a preeminent miRNA, namely, miR-21-5p, which emerged as the principal orchestrator of angiogenic effects. Through in vitro experiments, we demonstrated the capacity of hypo-ADSC-Exos to stimulate the proliferation, migration, and angiogenic potential of human umbilical vein endothelial cells (HUVECs) via the mediation of miR-21-5p. The inhibition of miR-21-5p effectively attenuated the proangiogenic effects mediated by hypo-ADSC-Exos. Mechanistically, our investigation revealed that exosomal miR-21-5p emanating from hypo-ADSCs exerts its regulatory influence by targeting sprouly1 (SPRY1) within HUVECs, thereby facilitating the activation of the PI3K/AKT signalling pathway. Notably, knockdown of SPRY1 in HUVECs was found to potentiate PI3K/AKT activation and, concomitantly, HUVEC proliferation, migration, and angiogenesis. The culminating stage of our study involved a compelling in vivo demonstration wherein GelMA loaded with hypo-ADSC-Exos was validated to substantially enhance local type H angiogenesis and concomitant bone regeneration. This enhancement was unequivocally attributed to the exosomal modulation of SPRY1. In summary, our investigation offers a pioneering perspective on the potential utility of hypo-ADSC-Exos as readily available for osteoporotic fracture treatment.

Longitudinal patient-reported outcomes after minimally invasive McKeown esophagectomy for patients with esophageal squamous cell carcinoma.

PURPOSE: Surgery for esophageal squamous cell carcinoma (ESCC) is characterized by a poor prognosis and high complication rate, resulting in a heavy symptom burden and poor health-related quality of life (QOL). We evaluated longitudinal patient-reported outcomes (PROs) to analyze the correlations between symptoms and QOL and their changing characteristics during postoperative rehabilitation. METHODS: We investigated patients with ESCC who underwent minimally invasive McKeown esophagectomy at Sichuan Cancer Hospital between April 2019 and December 2019. Longitudinal data of the clinical characteristics and PROs were collected. The MD Anderson Symptom Inventory and European Organization for Research and Treatment of Cancer (EORTC) QOL questionnaires were used to assess symptoms and QOL and compare the trajectories of PROs during the investigation. RESULTS: A total of 244 patients with ESCC were enrolled in this study. Regarding QOL, role and emotional functions returned to baseline at 1 month after surgery, and cognitive and social functions returned to baseline at 3 months after surgery. However, physical function and global QOL did not return to baseline at 1 year after surgery. At 7 days and 1, 3, 6, and 12 months after surgery, the main symptoms of the patients were negatively correlated with physical, role, emotional, cognitive, and social functions and the overall health status (P < 0.05). CONCLUSION: Patients with ESCC experience reduced health-related QOL and persisting symptoms after minimally invasive McKeown esophagectomy, but a recovery trend was observed within 1 month. The long-term QOL after esophagectomy is acceptable.