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Abstract We conducted a retrospective study of 1055 patients with urinary stones who attended our single center from September 2017 to June 2024. Clinical data and laboratory indicators of patients were evaluated and compared with stone components. The most common type in our study was calcium oxalate (CaOx) stones (76.6%), followed by infection stones (13.2%) and uric acid (UA) stones (7.8%). Among the 1055 specimens, 899 (85.2%) cases were mixed component stones, of which calcium oxalate monohydrate (COM) and calcium oxalate dihydrate (COD) mixture were the most frequent (34.8%). There were only 156 cases (14.8%) of pure-component stones, of which anhydrous UA was the most frequent (7.0%). There were 738 males and 317 females, with a male-to-female ratio of 2.33:1. Male dominance was evident in CaOx stones (79.0 vs. 71.0%, P = 0.005). Female dominance was noted in infection stones (21.1 vs. 9.8%, P

Abstract Film color and editing are crucial elements in filmmaking, posing significant questions about their effective use in eliciting emotional responses from viewers. While prior research has explored the impacts of color and editing independently, their combined effect remains largely unexplored, leaving the open question of how these elements together affect emotional perception. This study investigates the combined impact of film color and editing on emotion perception, utilizing both subjective behavioral scales and objective functional magnetic resonance imaging (fMRI) techniques. It employs two experiments with a two-factor design to assess the interactions between film color (colored and black-and-white) and film editing (fearful, neutral, and happy levels) on emotional perceptions. Under the direction of a professional filmmaker, a series of film sequences was created for six experimental conditions. In Experiment 1, 117 participants watched the film sequences and subjectively rated the emotional valence of the neutral face in the sequence, uncovering a significant interaction effect between film color and editing on the valence rating of the neutral face. In Experiment 2, 67 participants watched similar film sequences in an MRI scanner to analyze their brain activation patterns. Distinct activations were identified in regions including the insula, anterior cingulate cortices (ACC), and middle frontal gyrus, where a region-of-interest (ROI) analysis of the left ACC revealed an interaction effect on neural responses. These results underscore the integral role of color and editing in influencing viewers’ emotion perception using two types of measurements. This research provides novel insights into the behavioral and neural responses to filmmaking elements that underpin film reception and offers practical implications for filmmakers, encouraging a more holistic approach to considering color and editing to further enrich the audience’s emotional experiences at the pre-production stage of filmmaking.

Abstract Pyroptosis, an immunogenic programmed cell death, could efficiently activate tumor immunogenicity and reprogram immunosuppressive microenvironment for boosting cancer immunotherapy. However, the overexpression of SLC7A11 promotes glutathione biosynthesis for maintaining redox balance and countering pyroptosis. Herein, we develop intermetallics modified with glucose oxidase (GOx) and soybean phospholipid (SP) as pyroptosis promoters (Pd2Sn@GOx-SP), that not only induce pyroptosis by cascade biocatalysis for remodeling tumor microenvironment and facilitating tumor cell immunogenicity, but also trigger disulfidptosis mediated by cystine accumulation to further promote tumor pyroptosis in female mice. Experiments and density functional theory calculations show that Pd2Sn nanorods with an intermediate size exhibit stronger photothermal and enzyme catalytic activity compared with the other three morphologies investigated. The peroxidase-mimic and oxidase-mimic activities of Pd2Sn cause potent reactive oxygen species (ROS) storms for triggering pyroptosis, which could be self-reinforced by photothermal effect, hydrogen peroxide supply accompanied by glycometabolism, and oxygen production from catalase-mimic activity of Pd2Sn. Moreover, the increase of NADP+/NADPH ratio induced by glucose starvation could pose excessive cystine accumulation and inhibit glutathione synthesis, which could cause disulfidptosis and further augment ROS-mediated pyroptosis, respectively. This two-pronged treatment strategy could represent an alternative therapeutic approach to expand anti-tumor immunotherapy.

Abstract Long-term exposure to hyperglycemic conditions leads to β-cell dysfunction, particularly mitochondrial dysfunction, and inflammatory and oxidative stress responses, which are considered the primary causes of β-cell death and the hallmarks of diabetes. Plant-active ingredients may play a key role in glycemic control. Epigallocatechin gallate (EGCG) is a characteristic catechin derived from tea that possesses anti-diabetic properties. Nonetheless, its underlying mechanisms remain elusive. Herein, the protective role of EGCG on high glucose (33 mM)-induced pancreatic beta cell dysfunction and its possible molecular mechanisms were investigated. Briefly, MIN6 cells were treated with glucose and EGCG (10 µM, 20 µM, and 40 µM) for 48 h. Our results revealed that EGCG dose-dependently restored mitochondrial membrane potential and concomitantly alleviated cell apoptosis. Mechanistically, the expression level of apoptotic protein BAX and Dynamic related protein 1 (DRP1) was significantly downregulated following EGCG treatment, whereas that of the anti-apoptotic protein BCL-2 was significantly upregulated. Taken together, EGCG alleviated high glucose-induced pancreatic beta cell dysfunction by targeting the DRP1-related mitochondrial apoptosis pathway and thus can serve as a nutritional intervention for the preservation of beta cell dysfunction in patients with type 2 diabetes mellitus.

Mitochondria are crucial organelles that play a central role in cellular metabolism and programmed cell death in eukaryotic cells. Mitochondrial autophagy (mitophagy) is a selective process where damaged mitochondria are encapsulated and degraded through autophagic mechanisms, ensuring the maintenance of both mitochondrial and cellular homeostasis. Excessive programmed cell death in neurons can result in functional impairments following cerebral ischemia and trauma, as well as in chronic neurodegenerative diseases, leading to irreversible declines in motor and cognitive functions. Neuroinflammation, an inflammatory response of the central nervous system to factors disrupting homeostasis, is a common feature across various neurological events, including ischemic, infectious, traumatic, and neurodegenerative conditions. Emerging research suggests that regulating autophagy may offer a promising therapeutic avenue for treating certain neurological diseases. Furthermore, existing literature indicates that various small molecule autophagy regulators have been tested in animal models and are linked to neurological disease outcomes. This review explores the role of mitophagy in programmed neuronal death and its connection to neuroinflammation.

Ovarian cancer is one of the most common gynecological malignancies. The current first-line treatment strategies for advanced ovarian cancer include surgery, chemotherapy, and maintenance therapy. Bevacizumab and poly (ADP-ribose) polymerase inhibitors (PARPi) are primary maintenance treatments for advanced ovarian cancer. Previously, many patients declined these therapies before medicare coverage because of high costs. Bevacizumab and apatinib are anti-tumor angiogenic agents. In this case study, we describe a patient with advanced ovarian cancer who underwent neoadjuvant chemotherapy, interval debulking surgery, and adjuvant chemotherapy. She declined bevacizumab and PARPi maintenance therapy owing to the prohibitive expenses. The patient was administered off-label apatinib and achieved a progression-free survival of 54 months. Thus, apatinib may offer substantial therapeutic value as a first-line maintenance therapy in advanced ovarian cancer.

In this study, a multiscale model is developed through secondary development (UMAT and UEXTERNALDB) in Abaqus with the objective of simulating the thermal deformation process with dynamic recrystallization behavior. The model couples the finite element method (FEM) with the multiphase field model (MPFM), thereby establishing bidirectional coupling between macroscopic mechanical behavior and microstructural evolution. A comparison between the single-element hot compression simulation and experimental results demonstrates that the model accurately simulates both the macroscopic mechanical behavior and microstructural evolution during the thermal deformation process, thereby exhibiting high precision. Simulations of the reduction pretreatment (RP) process under different reduction amounts and billet surface temperatures demonstrate that increasing the reduction amount and billet surface temperature significantly enhances both plastic deformation and the volume fraction of dynamic recrystallization in the billet core. This results in the closure of core voids and the refinement of the core microstructure, thereby providing valuable guidance for the development of optimal reduction pretreatment (RP) processes.

The optimal surgical intervention for lateral patellar instability remains a topic of controversy despite satisfactory clinical outcomes and low re‐dislocation rates reported in numerous studies following medial patellofemoral ligament reconstruction (MPFLR) with and without tibial tubercle transfer (TTT). The purpose of this systematic review and meta‐analysis is to investigate the hypothesis that combining MPFLR with TTT provides reduced complication rates and improved clinical outcomes to isolated MPFLR in patients with lateral patellar instability. We conducted a comprehensive systematic review and meta‐analysis of comparative trials involving MPFLR with and without TTT, sourcing data from PubMed, the Cochrane Library, Embase, and Web of Science. The primary clinical outcomes analyzed included the Kujala score, the Lysholm score, complication rates, and the Caton–Deschamps index (CDI). Random or fixed effects were used for the meta‐analysis. Postoperatively, there were no significant differences observed in the Kujala and Lysholm scores between MPFLR and MPFLR + TTT (p = 0.053). At the final follow‐up, the CDI had decreased 0.015 (95% CI −0.044, 0.013; p = 0.289) points in the MPFLR group, with no statistical significance. In contrast, the MPFLR + TTT group demonstrated a significant decrease of 0.207 (95% CI −0.240, −0.174; p = 0.000) points in CDI. Notably, the complication rate was higher in the MPFLR + TTT group compared to the MPFLR‐only group (RR = 2.472; 95% CI 1.638, 3.731; p = 0.000). Both MPFLR and MPFLR + TTT procedures yield significant improvements in the Kujala and Lysholm scores. However, the MPFLR + TTT approach results in an apparent improvement in CDI and corrects patellar maltracking, particularly in cases involving high tibial tuberosity‐trochlear groove (TT‐TG) (>20 mm) or patella alta (CDI > 1.2), while MPFLR alone cannot. It is essential to consider the higher complication rate of MPFLR + TTT, which suggests that MPFLR alone may be sufficient for patients without high TT‐TG or patella alta.

Abstract Background Diabetes mellitus (DM) and periodontitis are two prevalent diseases with mutual influence. Accumulation of advanced glycation end products (AGEs) in hyperglycemia may impair cell function and worsen periodontal conditions. N 6-methyladenosine (m6A) is an important post-transcriptional modification in RNAs that regulates cell fate determinant and progression of diseases. However, whether m6A methylation participates in the process of periodontitis with diabetes is unclear. Thus, we aimed to investigate the effects of AGEs on bone marrow mesenchymal stem cells (BMSCs), elucidate the m6A modification mechanism in diabetes-associated periodontitis. Methods Periodontitis with diabetes were established by high-fat diet/streptozotocin injection and silk ligation. M6A modifications in alveolar bone were demonstrated by RNA immunoprecipitation sequence. BMSCs treated with AGEs, fat mass and obesity associated (FTO) protein knockdown and sclerostin (SOST) interference were evaluated by quantitative polymerase chain reaction, western blot, immunofluorescence, alkaline phosphatase and Alizarin red S staining. Results Diabetes damaged alveolar bone regeneration was validated in vivo. In vitro experiments showed AGEs inhibited BMSCs osteogenesis and influenced the FTO expression and m6A level in total RNA. FTO knockdown increased the m6A levels and reversed the AGE-induced inhibition of BMSCs differentiation. Mechanically, FTO regulated m6A modification on SOST transcripts, and AGEs affected the binding of FTO to SOST transcripts. FTO knockdown accelerated the degradation of SOST mRNA in presence of AGEs. Interference with SOST expression in AGE-treated BMSCs partially rescued the osteogenesis by activating Wnt Signaling. Conclusions AGEs impaired BMSCs osteogenesis by regulating SOST in an m6A-dependent manner, presenting a promising method for bone regeneration treatment of periodontitis with diabetes.

Abstract Background Neuroinflammation is one of the most important pathogeneses in secondary brain injury after traumatic brain injury (TBI). Neutrophil extracellular traps (NETs) forming neutrophils were found throughout the brain tissue of TBI patients and elevated plasma NET biomarkers correlated with worse outcomes. However, the biological function and underlying mechanisms of NETs in TBI-induced neural damage are not yet fully understood. Here, we used Cl-amidine, a selective inhibitor of NETs to investigate the role of NETs in neural damage after TBI. Methods Controlled cortical impact model was performed to establish TBI. Cl-amidine, 2′3′-cGAMP (an activator of stimulating Interferon genes (STING)), C-176 (a selective STING inhibitor), and Kira6 [a selectively phosphorylated inositol-requiring enzyme-1 alpha [IRE1α] inhibitor] were administrated to explore the mechanism by which NETs promote neuroinflammation and neuronal apoptosis after TBI. Peptidyl arginine deiminase 4 (PAD4), an essential enzyme for neutrophil extracellular trap formation, is overexpressed with adenoviruses in the cortex of mice 1 day before TBI. The short-term neurobehavior tests, magnetic resonance imaging (MRI), laser speckle contrast imaging (LSCI), Evans blue extravasation assay, Fluoro-Jade C (FJC), TUNEL, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative-PCR were performed in this study. Results Neutrophils form NETs presenting in the circulation and brain at 3 days after TBI. NETs inhibitor Cl-amidine treatment improved short-term neurological functions, reduced cerebral lesion volume, reduced brain edema, and restored cerebral blood flow (CBF) after TBI. In addition, Cl-amidine exerted neuroprotective effects by attenuating BBB disruption, inhibiting immune cell infiltration, and alleviating neuronal death after TBI. Moreover, Cl-amidine treatment inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization at 3 days after TBI. Mechanistically, STING ligand 2′3′-cGAMP abolished the neuroprotection of Cl-amidine via IRE1α/ASK1/JNK signaling pathway after TBI. Importantly, overexpression of PAD4 promotes neuroinflammation and neuronal death via the IRE1α/ASK1/JNK signaling pathway after TBI. However, STING inhibitor C-176 or IRE1α inhibitor Kira6 effectively abolished the neurodestructive effects of PAD4 overexpression after TBI. Conclusion Altogether, we are the first to demonstrate that NETs inhibition with Cl-amidine ameliorated neuroinflammation, neuronal apoptosis, and neurological deficits via STING-dependent IRE1α/ASK1/JNK signaling pathway after TBI. Thus, Cl-amidine treatment may provide a promising therapeutic approach for the early management of TBI. Graphical Abstract

Abstract Endoplasmic reticulum (ER) stress and ER stress-mediated apoptosis play an important role during secondary brain damage after traumatic brain injury (TBI). Increased neutrophil extracellular traps (NETs) formation has been demonstrated to be associated with neurological damage after TBI. However, the correlation between ER stress and NETs remains unclear, and the specific function of NETs in neurons has not been defined. In this study, we found that the levels of NETs circulating biomarkers were remarkably elevated in the plasma of TBI patients. We then inhibited NETs formation by peptidylarginine deiminase 4 (PAD4, a critical enzyme for NETs formation) deficiency and discovered that ER stress activation and ER stress-mediated neuronal apoptosis were reduced. The degradation of NETs via DNase I showed similar outcomes. Furthermore, overexpression of PAD4 aggravated neuronal ER stress and ER stress-associated apoptosis, while TLR9 antagonist administration abrogated the damage caused by NETs. In addition to in vivo experiments, in vitro experiments revealed that treatment with a TLR9 antagonist alleviated NETs-induced ER stress and apoptosis in HT22 cells. Collectively, our results indicated that ER stress as well as the accompanying neuronal apoptosis can be ameliorated by disruption of NETs and that suppression of the TLR9-ER stress signaling pathway may contribute to positive outcomes after TBI.

AbstractBackground The clinical manifestations of maintenance haemodialysis (MHD) outpatients diagnosed with coronavirus disease 2019 (COVID-19) are highly heterogeneous. They are prone to progress to severe conditions, and they often require hospitalization. To better guide the management of MHD outpatients, this retrospective observational study assessed risk factors for hospitalization of MHD patients after a diagnosis of COVID-19.Methods The demographic data, comorbidities, laboratory indicators and imaging data of 128 MHD outpatients at our haemodialysis centre with confirmed COVID-19 infection from December 2022 to January 2023 were collected. The relationships between these factors and hospitalization of patients were analyzed.Results Among the 128 patients, 25 (19.53%) were hospitalized. One of the 25 inpatients was mechanically ventilated, and two of them died. Multivariate logistic regression analysis showed that the hospitalization rate was correlated with age, comorbid diabetes and peripheral blood lymphocyte count.Conclusion Older age, comorbid diabetes and lower lymphocyte count are important risk factors for hospitalization of MHD outpatients after a diagnosis of COVID-19. Focusing on these factors may help in early identification of patients who may need to be admitted due to potential disease progression.

The spread through air spaces (STAS) is one of the aggressive behaviors of lung adenocarcinoma. It is a risk factor for recurrence and an indicator of poor prognosis after sublobectomy. The association between computed tomography (CT)-based features and STAS can predict the STAS status of patients with lung adenocarcinoma, and thus, assist in the clinical selection of the appropriate type of surgery. This article reviewed the aggressiveness of STAS in lung adenocarcinoma and the current research on the preoperative CT prediction of STAS, as well as related new techniques.

Abstract Introducing nitrogen vacancies is an effective method to improve the catalytic performance of g‐C3N4‐based photocatalysts, whereas understanding how nitrogen vacancies types affect the catalytic performance remains unclear. Herein, two different types of nitrogen vacancies were successfully introduced into g‐C3N4 by pyrolysis of melamine under argon and ammonia atmosphere with subsequent HNO3 oxidation. The pyrolysis atmosphere is found to have a significant influence on the introduced nitrogen vacancies type, where tertiary nitrogen groups (N3C) and sp2‐hybridized nitrogen atoms (N2C) were the preferred sites for the formation of nitrogen vacancies under ammonia and argon pyrolysis, respectively. Moreover, nitrogen vacancies from N3C are experimentally and theoretically demonstrated to facilitate the narrowed band gap and the improved oxygen absorption capability. As expected, the optimal catalyst exhibits high H2O2 yield of 451.8 µM, which is 3.8 times higher than the pristine g‐C3N4 (119.0 µM) after 4 h and good stability after10 photocatalytic runs.

An open critical-size bone defect is a major medical problem because of the difficulty in self-healing, leading to an increased risk of bacterial infection owing to wound exposure, resulting in treatment failure. Herein, a composite hydrogel was synthesized by chitosan, gallic acid, and hyaluronic acid, termed “CGH.” Hydroxyapatite was modified with polydopamine (PDA@HAP) and introduced to CGH to obtain a mussel-inspired mineralized hydrogel (CGH/PDA@HAP). The CGH/PDA@HAP hydrogel exhibited excellent mechanical performances, including self-healing and injectable properties. Owing to its three-dimensional porous structure and polydopamine modifications, the cellular affinity of the hydrogel was enhanced. When adding PDA@HAP into CGH, Ca2+ and PO43- could release and then promoted differentiation of BMSCs into osteoblasts. Without any osteogenic agent or stem cells, the area of new bone at the site of defect was enhanced and the newly formed bone had a dense trabecular structure after implanting of the CGH/PDA@HAP hydrogel for 4 and 8 weeks. Moreover, the growth of Staphylococcus aureus and Escherichia coli was effectively inhibited through the grafting of gallic acid onto chitosan. Above, this study provides a reasonable alternative strategy to manage open bone defects.

Background: The limited regenerative potential of periodontal tissue remains a challenge in orthodontic treatment, especially with respect to alveolar bone remodeling. The dynamic balance between the bone formation of osteoblasts and the bone resorption of osteoclasts controls bone homeostasis. The osteogenic effect of low-intensity pulsed ultrasound (LIPUS) is widely accepted, so LIPUS is expected to be a promising method for alveolar bone regeneration. Osteogenesis is regulated by the acoustic mechanical effect of LIPUS, while the cellular perception, transduction mode and response regulation mechanism of LIPUS stimuli are still unclear. This study aimed to explore the effects of LIPUS on osteogenesis by osteoblast-osteoclast crosstalk and the underlying regulation mechanism.Methods: The effects of LIPUS on orthodontic tooth movement (OTM) and alveolar bone remodeling were investigated via rat model by histomorphological analysis. Mouse bone marrow mesenchymal stem cells (BMSCs) and bone marrow monocytes (BMMs) were purified and used as BMSC-derived osteoblasts and BMM-derived osteoclasts, respectively. The osteoblast-osteoclast co-culture system was used to evaluate the effect of LIPUS on cell differentiation and intercellular crosstalk by Alkaline phosphatase (ALP), Alizarin Red S (ARS), tartrate-resistant acid phosphatase (TRAP) staining, real-time quantitative PCR, western blotting and immunofluorescence.Results: LIPUS was found to improve OTM and alveolar bone remodeling in vivo, promote differentiation and EphB4 expression in BMSC-derived osteoblasts in vitro, particularly when cells were directly co-cultured with BMM-derived osteoclasts. LIPUS enhanced EphrinB2/EphB4 interaction between osteoblasts and osteoclasts in alveolar bone, activated the EphB4 receptor on osteoblasts membrane, transduced LIPUS-related mechanical signals to the intracellular cytoskeleton, and gave rise to the nuclear translocation of YAP in Hippo signaling pathway, thus regulating cell migration and osteogenic differentiation.Conclusions: This study shows that LIPUS modulates bone homeostasis by osteoblast-osteoclast crosstalk via EphrinB2/EphB4 signaling, which benefits the balance between OTM and alveolar bone remodeling.

Abstract Purpose FAI (femoroacetabular impingement syndrome) is a common cause of hip pain, resulting in a decreased life quality. This study aims to compare the postoperative clinical outcome between arthroscopic surgery (AT) and conservative treatment (CT). Method The six studies were selected from PubMed, Embase and OVID database. The data were extracted and analyzed by RevMan5.3. Mean differences and 95% confidence intervals were calculated. RevMan5.3 was used to assess the risk of bias. Result Six observational studies were assessed. The methodological quality of the trials indicated five of six studies had a low risk of bias and one article had a high risk of bias. The differences were statistically significant between AT and CT for HOS (follow-up for 6 months), iHOT-33 (follow-up for 6 months) improvement, iHOT-33 (follow-up for 12 months) improvement, iHOT-33 (follow-up for 12 months), EQ-5D-5L index score (follow-up for 12 months) and AT showed higher benefits than CT. Meanwhile no statistically significant were found in iHOT-33 (follow-up for 6 months), EQ-5D-5L index score (follow-up for 6 months), EQ5D-VAS (follow-up for 6 months) and EQ5D-VAS (follow-up for 12 months). Conclusion AT and CT both can have clinical effects when facing FAI. In our meta-analysis, hip arthroscopy is statistically superior to conservative treatment in both long-term and short-term effects.

BackgroundBone marrow stimulation (BMS) has been considered a well-established method for treating knee and ankle osteochondral lesions. Some studies have also shown that BMS can promote healing of the repaired tendon and enhance biomechanical properties during rotator cuff repair. Our purpose was to compare the clinical outcomes of arthroscopic repair rotator cuff (ARCR) with and without BMS.MethodsA systematic review with meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PubMed, Embase, Web of Science, Google scholar, ScienceDirect, and the Cochrane Library were searched from inception to March 20, 2022. Data on retear rates, shoulder functional outcomes, visual analog score and range of motion were pooled and analyzed. Dichotomous variables were presented as odds ratios (OR), and continuous variables were presented as mean differences (MD). Meta-analyses were conducted with Review Manager 5.3.ResultsEight studies involving 674 patients were included, with mean follow-up period ranging from 12 to 36.8 months. Compared to ARCR alone, the intraoperative combination of the BMS resulted in lower retear rates (P

BackgroundSpontaneous quadriceps tendon rupture (QTR) is a rare complication of uremia. Secondary hyperparathyroidism (SHPT) is considered the leading cause of QTR in uremia patients. QTR in patients with uremia and SHPT are treated with active surgical repair along with the treatment of SHPT using medication or parathyroidectomy (PTX). The impact of PTX for SHPT on tendon healing remains unclear. The purpose of this study was to introduce surgical procedures for QTR and to determine the functional recovery of the repaired quadriceps tendon (QT) after PTX.MethodsBetween Jan 2014 and Dec 2018, eight uremia patients underwent PTX after a ruptured QT was repaired by figure-of-eight trans-osseous sutures with an overlapping tightening suture technique. Biochemical indices were measured before and one year after PTX to evaluate the control of SHPT. The changes in bone mineral density (BMD) were determined by comparing x-ray images at pre-PTX and during follow-up. The assessment of the functional recovery of the repaired QT was conducted at the last follow-up using multiple functional parameters.ResultsEight patients (fourteen tendons) were retrospectively evaluated at an average follow-up of 3.46 ± 1.37 years after PTX. ALP and iPTH levels one year after PTX were significantly lower than at pre-PTX (P = 0.017, P

BackgroundPancreatic ductal adenocarcinoma (PDAC), the most prevalent type of pancreatic cancer, is a highly lethal malignancy with poor prognosis. Polypeptide N-acetylgalactosaminyltransferase-6 (GALNT6) is frequently overexpressed in PDAC. However, the role of GALNT6 in the PDAC remains unclear.MethodsThe expression of GALNT6 in pancreatic cancer and normal tissues were analyzed by bioinformatic analyses and immunohistochemistry. CCK8 and colony formation were used to detect cell proliferation. Flow cytometry was applied to detect cell cycle.The pyroptosis was detected by scanning electron microscopy. The mRNA expression was detected by qRT-PCR. The protein expression and localization were detected by western blot and immunofluorescence assay. ELISA was used to detect the levels of inflammatory factors.ResultsThe expression of GALNT6 was associated with advanced tumor stage, and had an area under curve (AUC) value of 0.919 in pancreatic cancer based on the cancer genome atlas (TCGA) dataset. Knockdown of GALNT6 inhibited cell proliferation, migration, invasion and cell cycle arrest of PDAC cells. Meanwhile, knockdown of GALNT6 increased the expression levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-18 (IL-18), the release of inflammasome and an increasing of Gasdermin D (GSDMD), N-terminal of GSDMD (GSDMD-N), Gasdermin E (GSDME) and N-terminal of GSDME (GSDME-N) in PDAC cells. GALNT6 suppressed the expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and GSDMD by glycosylation of NF-κB and inhibiting the nucleus localization of NF-κB. Additionally, GALNT6 promotes the degradation of GSDME by O-glycosylation.ConclusionWe found that GALNT6 is highly expressed in pancreatic cancer and plays a carcinogenic role. The results suggested that GALNT6 regulates the pyroptosis of PDAC cells through NF-κB/NLRP3/GSDMD and GSDME signaling. Our study might provides novel insights into the roles of GALNT6 in PDAC progression.

IntroductionPediatric growth hormone deficiency (GHD) is a disease resulting from impaired growth hormone/insulin-like growth factor-1 (IGF-1) axis but the effects of GHD on children’s cognitive function, brain structure and brain function were not yet fully illustrated.MethodsFull Wechsler Intelligence Scales for Children, structural imaging, diffusion tensor imaging, and resting-state functional magnetic resonance imaging were assessed in 11 children with GHD and 10 matched healthy controls.Results(1) The GHD group showed moderate cognitive impairment, and a positive correlation existed between IGF-1 levels and cognitive indices. (2) Mean diffusivity was significantly increased in both corticospinal tracts in GHD group. (3) There were significant positive correlations between IGF-1 levels and volume metrics of left thalamus, left pallidum and right putamen but a negative correlation between IGF-1 levels and cortical thickness of the occipital lobe. And IGF-1 levels negatively correlated with fractional anisotropy in the superior longitudinal fasciculus and right corticospinal tract. (4) Regional homogeneity (ReHo) in the left hippocampus/parahippocampal gyrus was negatively correlated with IGF-1 levels; the amplitude of low-frequency fluctuation (ALFF) and ReHo in the paracentral lobe, postcentral gyrus and precentral gyrus were also negatively correlated with IGF-1 levels, in which region ALFF fully mediates the effect of IGF-1 on working memory index.ConclusionMultiple subcortical, cortical structures, and regional neural activities might be influenced by serum IGF-1 levels. Thereinto, ALFF in the paracentral lobe, postcentral gyrus and precentral gyrus fully mediates the effect of IGF-1 on the working memory index.

Cork spot is a common physiological disorder in pear fruits, which has been found in some pear cultivars. Mineral nutrition imbalance in fruit is regarded as the principal influence factor for disorder incidence, with some ongoing confusion and controversy. In our research, we explored the cork spot characteristics in Japanese pear ‘Akizuki’ (Pyrus pyrifolia Nakai), adopted metabolome and mineral content analysis for healthy and disordered fruits, and made a correlation analysis of mineral and metabolites. Cork spots are mainly distributed on the outer flesh beneath the fruit peel. In cork spotted tissues, superoxide (SOD) and peroxidase (POD) activities, as well as malondialdehyde (MDA) content, increased. A total of 1024 known metabolites were identified from all the samples and more changes in metabolism were detected between normal and cork spotted flesh tissues. Correlation analysis displayed that Ca, especially the Mg/Ca in fruits, could be used to predict whether an orchard will develop cork spot disorder; Mg and B were associated with the appearance of symptoms, and the contents of Zn, Fe, and Mg, as well as Mg/B and Zn/B, might be strongly tied to the formation of cork spots in pears. This research provides insights into the occurrence of pear cork spot disorder and clarifies the role of minerals.

Abstract Background Inflammatory cardiomyopathy (IC) is a syndrome with chronic myocarditis and cardiac remodeling. This study aimed to explore predicting factors of adverse outcomes in patients with IC secondary to idiopathic inflammatory myopathy (IIM‐IC). Methods By means of a single‐center retrospective study, 52 patients with IIM‐IC at Peking Union Medical College Hospital were identified from January 1999 to June 2019. Electrocardiogram and echocardiography data were analyzed for the primary outcome (defined as all‐cause death) and secondary outcomes (defined as re‐hospitalization of heart failure and all‐cause death), using regression and survival analysis. Results The prevalence of atrial fibrillation, ventricular tachycardia, Q‐wave abnormality, left ventricular conduction abnormalities, and reduced left ventricular ejection fraction (LVEF) (≤40%) were 65.4%, 67.3%, 67.3%, 61.6%, and 50.5%. After a median follow‐up of 2 years (IQR 0.8–3.0), 26 cases were readmitted due to heart failure. Twenty‐two deaths were recorded, including 20 cardiogenic deaths. Among the patients with adverse events, the incidence of poor R‐wave progression, low‐voltage of the limb leads, Q‐wave abnormality, QRS duration >130 ms, left ventricular enlargement, and impaired systolic function were higher. Kaplan–Meier analysis showed that Q‐wave abnormality, limb leads low‐voltage, LVEF ≤40%, and left ventricular end‐diastolic dimension >60 mm were correlated with shorter survival. However, multivariate Cox regression analysis revealed that only Q‐wave abnormality (HR = 12.315) and LVEF ≤40% (HR = 5.616) were independent risk factors for all‐cause death. Conclusion Q‐wave abnormality and reduced LVEF are predictive of poor prognosis in patients with IIM‐IC.

Background: The treatment of cartilage damage is a hot topic at present, and cell therapy is an emerging alternative therapy. Stem cells derived from peripheral blood have become the focus of current research due to the ease of obtaining materials and a wide range of sources.Methods: We used a text search strategy using the [“mesenchymal stem cells” (MeSH term) OR “MSC” OR “BMMSC” OR “PBMSC” OR” PBMNC” OR “peripheral blood stem cells”] AND (cartilage injury [MeSH term] OR “cartilage” OR “chondral lesion”). After searching the literature, through the inclusion and exclusion criteria, the last included articles were systematically reviewed.Result: We found that peripheral blood-derived stem cells have chondrogenic differentiation ability and can induce chondrogenic differentiation and repair in vivo and have statistical significance in clinical and imaging prognosis. It is an improvement of academic differences. Compared with the bone marrow, peripheral blood is easier to obtain, widely sourced, and simple to obtain. In the future, peripheral blood will be a more potential cell source for cell therapy in the treatment of cartilage damage.Conclusion: Stem cells derived from peripheral blood can repair cartilage and are an important resource for the treatment of cartilage damage in the future. The specific mechanism and way of repairing cartilage need further study.

Abstract The high-resistive grain boundaries are the bottleneck for Li+ transport in Li7La3Zr2O12 (LLZO) solid electrolytes. Herein, high-conductive LLZO thin films with cubic phase and amorphous domains between crystalline grains are prepared, via annealing the repetitive LLZO/Li2CO3/Ga2O3 multi-nanolayers at 600 °C for 2 h. The amorphous domains may provide additional vacant sites for Li+, and thus relax the accumulation of Li+ at grain boundaries. The significantly improved ionic conductivity across grain boundaries demonstrates that the high energy barrier for Li+ migration caused by space charge layer is effectively reduced. Benefiting from the Li+ transport paths with low energy barriers, the presented LLZO thin film exhibits a cutting-edge value of ionic conductivity as high as 6.36 × 10−4 S/cm, which is promising for applications in thin film lithium batteries.

The repairment of critical-sized bone defects is a serious problem that stimulates the development of new biomaterials. In this study, nanohydroxyapatite (nHA)-doped porous polyetheretherketone (pPEEK) were successfully fabricated by the thermally induced phase separation method and hydrothermal treatment. Structural analysis was performed by X-ray diffraction. The water contact angles and scanning electron microscopy were measured to assess physical properties of surfaces. The mechanical strength of the composites is also determined. Microcomputed tomography is used to characterize the nHA content of the composites. The in vitro bioactivity of the composites with or without nHA was investigated by using murine pre-osteoblasts MC3T3-E1, and the results of cytotoxicity and cell proliferation assays revealed that the cytocompatibility of all specimens was good. Adherence assays were employed to examine the adhesion and morphology of cells on different materials. However, nHA-doped composites induced cell attachment and cell spreading more significantly. Osteogenic differentiation was investigated using alkaline phosphatase activity and alizarin red staining, and these in vitro results demonstrated that composites containing nHA particles enhanced osteoblast differentiation. Its effectiveness for promoting osteogenesis was also confirmed in an in vivo animal experiment using a tibial defective rat model. After 8 weeks of implantation, compared to the pure PEEK and pPEEK without nHA groups, the nHA-pPEEK group showed better osteogenic activity. The results indicate that the nHA-pPEEK composites are possibly a well-designed bone substitute for critical-sized bone defects by promoting bone regeneration and osteointegration successfully.

BackgroundMyocardial fibrosis is an important pathophysiologic mechanism of cardiac involvement that leads to increased mortality in patients with autoimmune diseases (AIDs). The aim of this study was to evaluate the association between myocardial strain from speckle-tracking echocardiography (STE) and fibrosis on cardiovascular magnetic resonance (CMR) and to further explore their prognostic implications in patients with AIDs.MethodsWe prospectively included 102 AIDs patients with clinically suspected cardiac involvement and 102 age- and sex-matched healthy individuals. Patients underwent CMR for evaluation of myocardial fibrosis by late gadolinium enhancement (LGE) and T1 mapping. A semiquantitative evaluation based on the extent of LGE was used to calculate the total (tLGEs) and segmental (sLGEs) LGE score. Global longitudinal strain (GLS) was evaluated by STE in all subjects. All patients were regularly followed up every 6 months. The primary endpoint was the composite incidence of all-cause death and cardiovascular hospitalization.ResultsCompared to healthy controls, AIDs patients had impaired GLS (−17.9 ± 5.1% vs. −21.2 ± 2.5%, p < 0.001). LGE was detected in 70% of patients. Patients with LGE presented worse GLS (−17.1 ± 5.3% vs. −19.6 ± 4.1%, p = 0.018) than those without LGE. On multivariate logistic analysis, GLS ≥ −15% was an independent predictor of LGE presence (OR = 4.98, 95%CI 1.35–18.33, p = 0.016). Moreover, a marked and stepwise impairment of segmental longitudinal strain (−19.3 ± 6.6 vs. −14.9 ± 6.5 vs. −8.9 ± 6.3, p < 0.001) was observed as sLGEs increased. During a median follow-up time of 25 months, 6 patients died, and 14 patients were hospitalized for cardiovascular reasons. Both GLS ≥ −15% (HR 3.56, 95%CI 1.28–9.86, p = 0.015) and tLGEs ≥ 6 (HR 4.13, 95%CI 1.43–11.92, p = 0.009) were independently associated with the primary endpoint.ConclusionsIn AIDs patients, impaired myocardial strain on STE could reflect the presence and extent of myocardial fibrosis and provide incremental prognostic value in addition to LGE in the prediction of adverse outcomes.

CYP-mediated fast metabolism may lead to poor bioavailability, fast drug clearance and significant drug interaction. Thus, metabolic stability screening in human liver microsomes (HLM) followed by metabolic soft-spot identification (MSSID) is routinely conducted in drug discovery. Liver microsomal incubations of testing compounds with fixed single or multiple incubation time(s) and quantitative and qualitative analysis of metabolites using high-resolution mass spectrometry are routinely employed in MSSID assays. The major objective of this study was to develop and validate a simple, effective, and high-throughput assay for determining metabolic soft-spots of testing compounds in liver microsomes using a single variable incubation time and LC/UV/MS. Model compounds (verapamil, dextromethorphan, buspirone, mirtazapine, saquinavir, midazolam, amodiaquine) were incubated at 3 or 5 µM with HLM for a single variable incubation time between 1 and 60 min based on predetermined metabolic stability data. As a result, disappearances of the parents were around 20–40%, and only one or a few primary metabolites were generated as major metabolite(s) without notable formation of secondary metabolites. The unique metabolite profiles generated from the optimal incubation conditions enabled LC/UV to perform direct quantitative estimation for identifying major metabolites. Consequently, structural characterization by LC/MS focused on one or a few major primary metabolite(s) rather than many metabolites including secondary metabolites. Furthermore, generic data-dependent acquisition methods were utilized to enable Q-TOF and Qtrap to continuously record full MS and MS/MS spectral data of major metabolites for post-acquisition data-mining and interpretation. Results from analyzing metabolic soft-spots of the seven model compounds demonstrated that the novel MSSID assay can substantially simplify metabolic soft-spot identification and is well suited for high-throughput analysis in lead optimization.

BackgroundThe transcriptional factor peroxisome proliferator–activated receptor γ (PPARγ) is an important therapeutic target for the treatment of type 2 diabetes. However, the role of the PPARγ transcriptional activity remains ambiguous in its metabolic regulation.MethodsBased on the crystal structure of PPARγ bound with the DNA target of PPARγ response element (PPRE), Arg134, Arg135, and Arg138, three crucial DNA binding sites for PPARγ, were mutated to alanine (3RA), respectively. In vitro AlphaScreen assay and cell-based reporter assay validated that PPARγ 3RA mutant cannot bind with PPRE and lost transcriptional activity, while can still bind ligand (rosiglitazone) and cofactors (SRC1, SRC2, and NCoR). By using CRISPR/Cas9, we created mice that were heterozygous for PPARγ-3RA (PPARγ3RA/+). The phenotypes of chow diet and high-fat diet fed PPARγ3RA/+ mice were investigated, and the molecular mechanism were analyzed by assessing the PPARγ transcriptional activity.ResultsHomozygous PPARγ-3RA mutant mice are embryonically lethal. The mRNA levels of PPARγ target genes were significantly decreased in PPARγ3RA/+ mice. PPARγ3RA/+ mice showed more severe adipocyte hypertrophy, insulin resistance, and hepatic steatosis than wild type mice when fed with high-fat diet. These phenotypes were ameliorated after the transcription activity of PPARγ was restored by rosiglitazone, a PPARγ agonist.ConclusionThe current report presents a novel mouse model for investigating the role of PPARγ transcription in physiological functions. The data demonstrate that the transcriptional activity plays an indispensable role for PPARγ in metabolic regulation.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disorder, and yet with no pharmacological treatment approved worldwide. The repositioning of old drugs provides a safe approach for drug development. Vidofludimus, an inhibitor for dihydroorotate dehydrogenase (DHODH) for the treatment of autoimmune disorders, is herein uncovered as a novel modulator for farnesoid X receptor (FXR) by biochemical and crystallographic analysis. We further revealed that vidofludimus exerts in vivo therapeutic effects on dextran sodium sulfate (DSS)-induced colitis in an FXR-dependent manner. Notably, vidofludimus also possesses remarkable beneficial effects in reducing NAFLD by targeting FXR, which may represent a unique approach in developing the treatment for NAFLD. Our findings not only reveal a promising template for the design of novel FXR ligands in treating autoimmune disorders, but also uncover a novel therapeutic effect for vidofludimus on NAFLD based on the newly established relationships among drugs, targets, and diseases.

A solid-state electrolyte with an ionic conductivity comparable to that of a liquid electrolyte is demanded of all-solid-state lithium-ion batteries. Li7La3Zr2O12 (LLZO) is considered to be a promising candidate due to its good thermal stability, high ionic conductivity, and wide electrochemical window. However, the synthesis of a stable cubic-phase LLZO thin film with enhanced densification at a relatively low thermal treatment temperature is yet to be developed. Indium is predicted to be a possible dopant to stabilize the cubic-phase LLZO (c-LLZO). Herein, via a nanolayer stacking process, a LLZO–Li2CO3–In2O3 multilayer solid electrolyte precursor was obtained. After thermal annealing at different temperatures, the effects of indium doping on the formation of c-LLZO and the ionic conductivities of the prepared LLZO–LZO thin film were systematically investigated. The highest ionic conductivity of 9.6 × 10−6 S·cm–1 was obtained at an annealing temperature of 800 °C because the incorporation of indium promoted the formation of c-LLZO and the highly conductive LLZO–LZO interfaces. At the end, a model of LLZO–LZO interface-enhancing ionic conductivity was proposed. This work provides a new approach for the development of low-temperature LLZO-based, solid-state thin-film batteries.