Global burden of liver cirrhosis 1990-2019 and 20 years forecast: results from the global burden of disease study 2019.

BACKGROUND: Cirrhosis is a disease that imposes a heavy burden worldwide, but its incidence varies widely by region. Therefore, we analysed data on the incidence and mortality of cirrhosis in 204 countries and territories from 1990-2019 and projected the disease development from 2019-2039. METHODS: Data on the incidence and mortality of liver cirrhosis from 1990 to 2019 were acquired from the public Global Burden of Disease (GBD) study. In addition, the average annual percentage change (AAPC) and estimated annual percentage change (EAPC) of the age-standardized rate (ASR) of cirrhosis in different regions were calculated. The estimates of risk factor exposure were summarized, and the proportion of causes and risk factors of liver cirrhosis and their relationship with the human development index (HDI) and socio-demographic index (SDI) were analysed. Trends in the incidence of cirrhosis in 2019-2039 were predicted using Nordpred and BAPC models. RESULTS: Globally, the ASR of cirrhosis incidence decreased by 0.05% per year from 25.7/100,000 in 1990 to 25.3/100,000 in 2019. The mortality risk associated with cirrhosis is notably lower in females than in males (13 per 100,000 vs 25 per 100,000). The leading cause of cirrhosis shifted from hepatitis B to C. Globally, alcohol use increased by 14%. In line, alcohol use contributed to 49.3% of disability-adjusted life years (DALYs) and 48.4% of global deaths from liver cirrhosis. Countries with a low ASR in 1990 experienced a faster increase in cirrhosis, whereas in 2019, the opposite was observed. In countries with high SDI, the ASR of cirrhosis is generally lower. Finally, projections indicate that the number and incidence of cirrhosis will persistently rise from 2019-2039. CONCLUSIONS: Cirrhosis poses an increasing health burden. Given the changing etiology, there is an imperative to strengthen the prevention of hepatitis C and alcohol consumption, to achieve early reduce the incidence of cirrhosis.

This study is an updated assessment of liver cirrhosis prevalence trends in 204 countries worldwide and the first to project trends over the next 20 years.The disease burden of cirrhosis is still increasing, and despite the decline in ASR, the number and prevalence of cirrhosis will continue to increase over the next two decades after 2019.It is alarming that the global surge in alcohol use is accompanied by an increase in DALYs and deaths due to liver cirrhosis.Liver cirrhosis remains a noteworthy public health event, and our study can further guide the development of national healthcare policies and the implementation of related interventions.

Smooth-Muscle-Cell-Specific Deletion of CD38 Protects Mice from AngII-Induced Abdominal Aortic Aneurysm through Inhibiting Vascular Remodeling.

Abdominal aortic aneurysm (AAA) is a serious vascular disease which is associated with vascular remodeling. CD38 is a main NAD+-consuming enzyme in mammals, and our previous results showed that CD38 plays the important roles in many cardiovascular diseases. However, the role of CD38 in AAA has not been explored. Here, we report that smooth-muscle-cell-specific deletion of CD38 (CD38SKO) significantly reduced the morbidity of AngII-induced AAA in CD38SKOApoe-/- mice, which was accompanied with a increases in the aortic diameter, medial thickness, collagen deposition, and elastin degradation of aortas. In addition, CD38SKO significantly suppressed the AngII-induced decreases in α-SMA, SM22α, and MYH11 expression; the increase in Vimentin expression in VSMCs; and the increase in VCAM-1 expression in smooth muscle cells and macrophage infiltration. Furthermore, we demonstrated that the role of CD38SKO in attenuating AAA was associated with the activation of sirtuin signaling pathways. Therefore, we concluded that CD38 plays a pivotal role in AngII-induced AAA through promoting vascular remodeling, suggesting that CD38 may serve as a potential therapeutic target for the prevention of AAA.

Safety and efficacy of dexmedetomidine vs. midazolam in complex gastrointestinal endoscopy: A systematic review and meta-analysis.

OBJECTIVE: This study aims to perform a meta-analysis to evaluate the safety and efficacy of dexmedetomidine versus midazolam for complex digestive endoscopy procedures, with the goal of offering comprehensive clinical evidence. METHODS: Following predefined inclusion criteria, five databases were systematically searched, with a focus on identifying randomized controlled trials (RCTs) that compared the administration of dexmedetomidine and midazolam during complex digestive endoscopy procedures. The statistical software Stata 15.1 was employed for meticulous data analysis. RESULTS: Sixteen RCTs were encompassed, involving a total of 1218 patients. In comparison to the midazolam group, dexmedetomidine administration was associated with a reduced risk of respiratory depression (RR=0.25, 95 %CI: 0.11-0.56) and hypoxemia (RR=0.22, 95 %CI: 0.12-0.39). Additionally, the dexmedetomidine group exhibited lower incidence rates of choking (RR=0.27, 95 %CI: 0.16-0.47), physical movement (RR=0.16, 95 %CI: 0.09-0.27), and postoperative nausea and vomiting (RR=0.56,95 %CI: 0.34-0.92). Patients and endoscopists in the dexmedetomidine group reported higher levels of satisfaction (patient satisfaction: SMD=0.73, 95 %CI: 0.26-1.21; endoscopist satisfaction: SMD=0.84, 95 %CI: 0.24-1.44). The incidence of hypotension and anesthesia recovery time did not significantly differ between the two groups (hypotension: RR=1.73,95 %CI:0.94-3.20; anesthesia recovery time: SMD=0.02, 95 %Cl: 0.44-0.49). It is noteworthy that the administration of dexmedetomidine was associated with a significant increase in the incidence of bradycardia in patients. CONCLUSION: Compared to midazolam, dexmedetomidine exhibits a favorable safety profile for use in complex gastrointestinal endoscopy by significantly reducing the risk of respiratory depression and hypoxemia. Despite this, dexmedetomidine is associated with a higher incidence of bradycardia. These findings underscore the need for further research through larger, multi-center studies to thoroughly investigate dexmedetomidine's safety and efficacy.

Exploring the allelopathic autotoxicity mechanism of ginsenosides accumulation under ginseng decomposition based on integrated analysis of transcriptomics and metabolomics.

Continuous cropping obstacles seriously constrained the sustainable development of the ginseng industry. The allelopathic autotoxicity of ginsenosides is the key "trigger" of continuous cropping obstacles in ginseng. During harvest, the ginseng plants could be broken and remain in the soil. The decomposition of ginseng residue in soil is one of the important release ways of ginsenosides. Therefore, the allelopathic mechanism of ginsenosides through the decomposed release pathway needs an in-depth study. To investigate this allelopathic regulation mechanism, the integrated analysis of transcriptomics and metabolomics was applied. The prototype ginsenosides in ginseng were detected converse to rare ginsenosides during decomposition. The rare ginsenosides caused more serious damage to ginseng hairy root cells and inhibited the growth of ginseng hairy roots more significantly. By high-throughput RNA sequencing gene transcriptomics study, the significantly differential expressed genes (DEGs) were obtained under prototype and rare ginsenoside interventions. These DEGs were mainly enriched in the biosynthesis of secondary metabolites and metabolic pathways, phytohormone signal transduction, and protein processing in endoplasmic reticulum pathways. Based on the functional enrichment of DEGs, the targeted metabolomics analysis based on UPLC-MS/MS determination was applied to screen endogenous differential metabolized phytohormones (DMPs). The influence of prototype and rare ginsenosides on the accumulation of endogenous phytohormones was studied. These were mainly involved in the biosynthesis of diterpenoid, zeatin, and secondary metabolites, phytohormone signal transduction, and metabolic pathways. After integrating the transcriptomics and metabolomics analysis, ginsenosides could regulate the genes in phytohormone signaling pathways to influence the accumulation of JA, ABA, and SA. The conclusion was that the prototype ginsenosides were converted into rare ginsenosides by ginseng decomposition and released into the soil, which aggravated its allelopathic autotoxicity. The allelopathic mechanism was to intervene in the response regulation of genes related to the metabolic accumulation of endogenous phytohormones in ginseng. This result provides a reference for the in-depth study of continuous cropping obstacles of ginseng.

Prohibitin 1 inhibits cell proliferation and induces apoptosis via the p53-mediated mitochondrial pathway in vitro.

BACKGROUND: Prohibitin 1 (PHB1) has been identified as an antiproliferative protein that is highly conserved and ubiquitously expressed, and it participates in a variety of essential cellular functions, including apoptosis, cell cycle regulation, proliferation, and survival. Emerging evidence indicates that PHB1 may play an important role in the progression of hepatocellular carcinoma (HCC). However, the role of PHB1 in HCC is controversial. AIM: To investigate the effects of PHB1 on the proliferation and apoptosis of human HCC cells and the relevant mechanisms in vitro. METHODS: HCC patients and healthy individuals were enrolled in this study according to the inclusion and exclusion criteria; then, PHB1 levels in the sera and liver tissues of these participates were determined using ELISA, RT-PCR, and immunohistochemistry. Human HepG2 and SMMC-7721 cells were transfected with the pEGFP-PHB1 plasmid and PHB1-specific shRNA (shRNA-PHB1) for 24-72 h. Cell proliferation was analysed with an MTT assay. Cell cycle progression and apoptosis were analysed using flow cytometry (FACS). The mRNA and protein expression levels of the cell cycle-related molecules p21, Cyclin A2, Cyclin E1, and CDK2 and the cell apoptosis-related molecules cytochrome C (Cyt C), p53, Bcl-2, Bax, caspase 3, and caspase 9 were measured by real-time PCR and Western blot, respectively. RESULTS: Decreased levels of PHB1 were found in the sera and liver tissues of HCC patients compared to those of healthy individuals, and decreased PHB1 was positively correlated with low differentiation, TNM stage III-IV, and alpha-fetoprotein ≥ 400 µg/L. Overexpression of PHB1 significantly inhibited human HCC cell proliferation in a time-dependent manner. FACS revealed that the overexpression of PHB1 arrested HCC cells in the G0/G1 phase of the cell cycle and induced apoptosis. The proportion of cells in the G0/G1 phase was significantly increased and the proportion of cells in the S phase was decreased in HepG2 cells that were transfected with pEGFP-PHB1 compared with untreated control and empty vector-transfected cells. The percentage of apoptotic HepG2 cells that were transfected with pEGFP-PHB1 was 15.41% ± 1.06%, which was significantly greater than that of apoptotic control cells (3.65% ± 0.85%, P < 0.01) and empty vector-transfected cells (4.21% ± 0.52%, P < 0.01). Similar results were obtained with SMMC-7721 cells. Furthermore, the mRNA and protein expression levels of p53, p21, Bax, caspase 3, and caspase 9 were increased while the mRNA and protein expression levels of Cyclin A2, Cyclin E1, CDK2, and Bcl-2 were decreased when PHB1 was overexpressed in human HCC cells. However, when PHB1 was upregulated in human HCC cells, Cyt C expression levels were increased in the cytosol and decreased in the mitochondria, which indicated that Cyt C had been released into the cytosol. Conversely, these effects were reversed when PHB1 was knocked down. CONCLUSION: PHB1 inhibits human HCC cell viability by arresting the cell cycle and inducing cell apoptosis via activation of the p53-mediated mitochondrial pathway.

A novel EIF3C-related CD8+ T-cell signature in predicting prognosis and immunotherapy response of nasopharyngeal carcinoma.

PURPOSE: At present, dysfunctional CD8+ T-cells in the nasopharyngeal carcinoma (NPC) tumor immune microenvironment (TIME) have caused unsatisfactory immunotherapeutic effects, such as a low response rate of anti-PD-L1 therapy. Therefore, there is an urgent need to identify reliable markers capable of accurately predicting immunotherapy efficacy. METHODS: Utilizing various algorithms for immune-infiltration evaluation, we explored the role of EIF3C in the TIME. We next found the influence of EIF3C expression on NPC based on functional analyses and RNA sequencing. By performing correlation and univariate Cox analyses of CD8+ Tcell markers from scRNA-seq data, we identified four signatures, which were then used in conjunction with the lasso algorithm to determine corresponding coefficients in the resulting EIF3C-related CD8+ T-cell signature (ETS). We subsequently evaluated the prognostic value of ETS using univariate and multivariate Cox regression analyses, Kaplan-Meier curves, and the area under the receiver operating characteristic curve (AUROC). RESULTS: Our results demonstrate a significant relationship between low expression of EIF3C and high levels of CD8+ T-cell infiltration in the TIME, as well as a correlation between EIF3C expression and progression of NPC. Based on the expression levels of four EIF3C-related CD8+ T-cell marker genes, we constructed the ETS predictive model for NPC prognosis, which demonstrated success in validation. Notably, our model can also serve as an accurate indicator for detecting immunotherapy response. CONCLUSION: Our findings suggest that EIF3C plays a significant role in NPC progression and immune modulation, particularly in CD8+ T-cell infiltration. Furthermore, the ETS model holds promise as both a prognostic predictor for NPC patients and a tool for adjusting individualized immunotherapy strategies.

DNA-methylome-derived epigenetic fingerprint as an immunophenotype indicator of durable clinical immunotherapeutic benefits in head and neck squamous cell carcinoma.

BACKGROUND: Cancer immunotherapy provides durable response and improves survival in a subset of head and neck squamous cell carcinoma (HNSC) patients, which may due to discriminative tumor microenvironment (TME). Epigenetic regulations play critical roles in HNSC tumorigenesis, progression, and activation of functional immune cells. This study aims to identify an epigenetic signature as an immunophenotype indicator of durable clinical immunotherapeutic benefits in HNSC patients. METHODS: Unsupervised consensus clustering approach was applied to distinguish immunophenotypes based on five immune signatures in The Cancer Genome Atlas (TCGA) HNSC cohort. Two immunophenotypes (immune 'Hot' and immune 'Cold') that had different TME features, diverse prognosis, and distinct DNA methylation patterns were recognized. Immunophenotype-related methylated signatures (IPMS) were identified by the least absolute shrinkage and selector operation algorithm. Additionally, the IPMS score by deconvolution algorithm was constructed as an immunophenotype classifier to predict clinical outcomes and immunotherapeutic response. RESULTS: The 'Hot' HNSC immunophenotype had higher immunoactivity and better overall survival (p = 0.00055) compared to the 'Cold' tumors. The immunophenotypes had distinct DNA methylation patterns, which was closely associated with HNSC tumorigenesis and functional immune cell infiltration. 311 immunophenotype-related methylated CpG sites (IRMCs) was identified from TCGA-HNSC dataset. IPMS score model achieved a strong clinical predictive performance for classifying immunophenotypes. The area under the curve value (AUC) of the IPMS score model reached 85.9% and 89.8% in TCGA train and test datasets, respectively, and robustness was verified in five HNSC validation datasets. It was also validated as an immunophenotype classifier for predicting durable clinical benefits (DCB) in lung cancer patients who received anti-PD-1/PD-L1 immunotherapy (p = 0.017) and TCGA-SKCM patients who received distinct immunotherapy (p = 0.033). CONCLUSIONS: This study systematically analyzed DNA methylation patterns in distinct immunophenotypes to identify IPMS with clinical prognostic potential for personalized epigenetic anticancer approaches in HNSC patients. The IPMS score model may serve as a reliable epigenome prognostic tool for clinical immunophenotyping to guide immunotherapeutic strategies in HNSC.

Metagenomic insight into the acidophilic functional communities driving elemental geochemical cycles in an acid mine drainage lake.

Acidophiles play a key role in the generation, evolution and attenuation of acid mine drainage (AMD), which is characterized by strong acidity (pH<3.5) and high metal concentrations. In this study, the seasonal changes of acidophilic communities and their roles in elemental cycling in an AMD lake (pH∼3.0) in China were analyzed through metagenomics. The results showed eukaryotic algae thrived in the lake, and Coccomyxa was dominant in January (38.1%) and May (33.9%), while Chlorella in July (9.5%). The extensive growth of Chlamydomonas in December (22.7%) resulted in an ultrahigh chlorophyll a concentration (587 µg/L), providing abundant organic carbon for the ecosystem. In addition, the iron-oxidizing and nitrogen-fixing bacterium Ferrovum contributed to carbon fixation. Ammonia oxidation likely occurred in the acidic lake, as was revealed by archaea Ca. Nitrosotalea. To gain a competitive advantage in the nutrient-poor environment, some acidophiles exhibited facultative characteristics, e.g. the most abundant bacterium Acidiphilium utilized both organic and inorganic carbon, and obtained energy from organic matter, inorganic sulfur, and sunlight simultaneously. It was suggested that sunlight, rather than chemical energy of reduced iron-sulfur was the major driver of elemental cycling in the AMD lake. The results are beneficial to the development of bioremediation strategies for AMD.

Knockoffs-SPR: Clean Sample Selection in Learning With Noisy Labels.

A noisy training set usually leads to the degradation of the generalization and robustness of neural networks. In this article, we propose a novel theoretically guaranteed clean sample selection framework for learning with noisy labels. Specifically, we first present a Scalable Penalized Regression (SPR) method, to model the linear relation between network features and one-hot labels. In SPR, the clean data are identified by the zero mean-shift parameters solved in the regression model. We theoretically show that SPR can recover clean data under some conditions. Under general scenarios, the conditions may be no longer satisfied; and some noisy data are falsely selected as clean data. To solve this problem, we propose a data-adaptive method for Scalable Penalized Regression with Knockoff filters (Knockoffs-SPR), which is provable to control the False-Selection-Rate (FSR) in the selected clean data. To improve the efficiency, we further present a split algorithm that divides the whole training set into small pieces that can be solved in parallel to make the framework scalable to large datasets. While Knockoffs-SPR can be regarded as a sample selection module for a standard supervised training pipeline, we further combine it with a semi-supervised algorithm to exploit the support of noisy data as unlabeled data. Experimental results on several benchmark datasets and real-world noisy datasets show the effectiveness of our framework and validate the theoretical results of Knockoffs-SPR.

Global burden of inflammatory bowel disease 1990-2019: A systematic examination of the disease burden and twenty-year forecast.

BACKGROUND: Inflammatory bowel disease (IBD) is an idiopathic intestinal disease with various levels and trends in different countries and regions. Understanding the current burden and trends of IBD in various geographical locations is essential to establish effective strategies for prevention and treatment. We report the average annual percentage change (AAPC) and estimated annual percentage change (EAPC) in age-standardized rates (ASR) of IBD in different regions based on the Global Burden of Disease (GBD) study from 1990-2019, and the relationships between IBD and the human development index (HDI) and socio-demographic index (SDI). The prevalence trends of IBD were predicted by gender from 2019-2039. AIM: To comprehensively investigate IBD data, providing further insights into the management of this chronic disease. METHODS: We collected the information on the incidence of IBD from the GBD study from 1990-2019 to calculate the AAPC and EAPC in ASR of IBD in different regions. The relationships between IBD, HDI, and SDI were analyzed. The Nordpred and Bayesian age-period-cohort models were used to predict the prevalence trends of IBD by gender from 2019-2039, and the reliability of the results was validated. Statistics of all the data in this study were performed using R software (version 4.2.1). RESULTS: North America consistently had the highest IBD ASR, while Oceania consistently had the lowest. East Asia had the fastest average annual growth in ASR (2.54%), whereas Central Europe had the fastest decline (1.38%). Countries with a low age-standardized incidence rates in 1990 showed faster growth in IBD while there was no significant correlation in 2019. Additionally, IBD increased faster in countries with a low age-standardized death rates in 1990, whereas the opposite was true in 2019. Analysis of SDI and IBD ASR showed that countries with a high SDI generally had a higher IBD ASR. Finally, the projections showed a declining trend in the incidence of IBD from 2019-2039, but a gradual increase in the number of cases. CONCLUSION: As the global population increases and ages, early monitoring and prevention of IBD is important to reduce the disease burden, especially in countries with a high incidence of IBD.

Hepatoprotective effects of aspirin on diethylnitrosamine-induced hepatocellular carcinoma in rats by reducing inflammation levels and PD-L1 expression.

Aspirin, as a widely used anti-inflammatory drug, has been shown to exert anti-cancer effects in a variety of cancers. PD-L1 is widely expressed in tumor cells and inhibits anti-tumor immunity. This study aims to clarify whether aspirin exerts its anti-hepatocellular carcinoma (HCC) effect by inhibiting PD-L1 expression. The rat model of HCC was established by drinking 0.01% diethylnitrosamine (DEN), and aspirin was given by gavage. The gross and blood biochemical indexes of rats were analyzed. CD4 and CD8 expression in liver tissues were investigated by immunohistochemistry. CCK8 assay was used to detect the inhibitory effect of aspirin on the proliferation of HCC cells. The regulatory effect of aspirin on PD-L1 expression was analyzed by western blot. As a result, the tumor number and liver weight ratio in the DEN + ASA group were lower than those in the DEN group (P = 0.006, P = 0.046). Compared with the DEN group, the expression of CD4 in the DEN + ASA group was significantly increased, while CD8 was decreased (all P < 0.01). Biochemical indexes showed that there were differences in all indexes between the DEN and control group (P < 0.05). The levels of DBIL, ALP, and TT in the DEN + ASA group were lower than those in the DEN group (P = 0.038, P = 0.042, P = 0.031). In the DEN group, there was an obvious fibrous capsule around the tumor, and the portal vein was dilated. The pathological changes were mild in the DEN + ASA group. Compared with the DEN group, the expression of PD-L1 in liver tissue of the DEN + ASA group was decreased (P = 0.0495). Cytological experiments further showed that aspirin could inhibit the proliferation and PD-L1 expression in Hep G2 and Hep 3B cells. In conclusion, aspirin can inhibit the proliferation of HCC cells and reduce tumor burden by reducing inflammation and targeting PD-L1.

Isochromenylium/Isoquinolinium-Mediated One-Pot Annulation to Hexahydropyrazinoisoquinolines. Synthesis of Quinocarcinol.

A novel annulation protocol has been successfully developed in this work for the quick generation of 1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinolines from easily accessible o-alkynylbenzaldehydes. Various hexahydropyrazinoisoquinolines, including those previously unavailable with electron-deficient substituents, have been achieved via the newly developed continuously operational isochromenylium/isoquinolinium-mediated procedure. It also perfectly served as a key step to generate the basic skeleton in the new total synthesis of quinocarcinol, accompanied by the development and application of a direct late-stage stereoselective sp3 C-H hydroxymethylation.

Microstructure Optimization for Design of Porous Tantalum Scaffolds Based on Mechanical Properties and Permeability.

Porous tantalum (Ta) implants have important clinical application prospects due to their appropriate elastic modulus, and their excellent bone growth and bone conduction ability. However, porous Ta microstructure designs generally mimic titanium (Ti) implants commonly used in the clinic, and there is a lack of research on the influence of the microstructure on the mechanical properties and penetration characteristics, which will greatly affect bone integration performance. This study explored the effects of different microstructure parameters, including the fillet radius of the middle plane and top planes, on the mechanics and permeability properties of porous Ta diamond cells through simulation, and put forward an optimization design with a 0.5 mm midplane fillet radius and 0.3 mm top-plane fillet radius in order to significantly decrease the stress concentration effect and improve permeability. On this basis, the porous Ta structures were prepared by Laser Powder Bed Fusion (LPBF) technology and evaluated before and after microstructural optimization. The elastic modulus and the yield strength were increased by 2.31% and 10.39%, respectively. At the same time, the permeability of the optimized structure was also increased by 8.25%. The optimized microstructure design of porous Ta has important medical application value.

Functional analysis of ZmG6PE reveals its role in responses to low-phosphorus stress and regulation of grain yield in maize.

A previous metabolomic and genome-wide association analysis of maize screened a glucose-6-phosphate 1-epimerase (ZmG6PE) gene, which responds to low-phosphorus (LP) stress and regulates yield in maize's recombinant inbred lines (RILs). However, the relationship of ZmG6PE with phosphorus and yield remained elusive. This study aimed to elucidate the underlying response mechanism of the ZmG6PE gene to LP stress and its consequential impact on maize yield. The analysis indicated that ZmG6PE required the Aldose_epim conserved domain to maintain enzyme activity and localized in the nucleus and cell membrane. The zmg6pe mutants showed decreased biomass and sugar contents but had increased starch content in leaves under LP stress conditions. Combined transcriptome and metabolome analysis showed that LP stress activated plant immune regulation in response to the LP stress through carbon metabolism, amino acid metabolism, and fatty acid metabolism. Notably, LP stress significantly reduced the synthesis of glucose-1-phosphate, mannose-6-phosphate, and ß-alanine-related metabolites and changed the expression of related genes. ZmG6PE regulates LP stress by mediating the expression of ZmSPX6 and ZmPHT1.13. Overall, this study revealed that ZmG6PE affected the number of grains per ear, ear thickness, and ear weight under LP stress, indicating that ZmG6PE participates in the phosphate signaling pathway and affects maize yield-related traits through balancing carbohydrates homeostasis.

Stretchable piezoelectric biocrystal thin films.

Stretchability is an essential property for wearable devices to match varying strains when interfacing with soft tissues or organs. While piezoelectricity has broad application potentials as tactile sensors, artificial skins, or nanogenerators, enabling tissue-comparable stretchability is a main roadblock due to the intrinsic rigidity and hardness of the crystalline phase. Here, an amino acid-based piezoelectric biocrystal thin film that offers tissue-compatible omnidirectional stretchability with unimpaired piezoelectricity is reported. The stretchability was enabled by a truss-like microstructure that was self-assembled under controlled molecule-solvent interaction and interface tension. Through the open and close of truss meshes, this large scale biocrystal microstructure was able to endure up to 40% tensile strain along different directions while retained both structural integrity and piezoelectric performance. Built on this structure, a tissue-compatible stretchable piezoelectric nanogenerator was developed, which could conform to various tissue surfaces, and exhibited stable functions under multidimensional large strains. In this work, we presented a promising solution that integrates piezoelectricity, stretchability and biocompatibility in one material system, a critical step toward tissue-compatible biomedical devices.

Ultrasound-Driven Healing: Unleashing the Potential of Chondrocyte-Derived Extracellular Vesicles for Chondrogenesis in Adipose-Derived Stem Cells.

Repairing cartilage defects represents a significant clinical challenge. While adipose-derived stem cell (ADSC)-based strategies hold promise for cartilage regeneration, their inherent chondrogenic potential is limited. Extracellular vesicles (EVs) derived from chondrocytes (CC-EVs) have shown potential in enhancing chondrogenesis, but their role in promoting chondrogenic differentiation of ADSCs remains poorly understood. Moreover, the clinical application of EVs faces limitations due to insufficient quantities for in vivo use, necessitating the development of effective methods for extracting significant amounts of CC-EVs. Our previous study demonstrated that low-intensity ultrasound (LIUS) stimulation enhances EV secretion from mesenchymal stem cells. Here, we identified a specific LIUS parameter for chondrocytes that increased EV secretion by 16-fold. CC-EVs were found to enhance cell activity, proliferation, migration, and 21-day chondrogenic differentiation of ADSCs in vitro, while EVs secreted by chondrocytes following LIUS stimulation (US-CC-EVs) exhibited superior efficacy. miRNA-seq revealed that US-CC-EVs were enriched in cartilage-regeneration-related miRNAs, contributing to chondrogenesis in various biological processes. In conclusion, we found that CC-EVs can enhance the chondrogenesis of ADSCs in vitro. In addition, our study introduces ultrasound-driven healing as an innovative method to enhance the quantity and quality of CC-EVs, meeting clinical demand and addressing the limited chondrogenic potential of ADSCs. The ultrasound-driven healing unleashes the potential of CC-EVs for chondrogenesis possibly through the enrichment of cartilage-regeneration-associated miRNAs in EVs, suggesting their potential role in cartilage reconstruction. These findings hold promise for advancing cartilage regeneration strategies and may pave the way for novel therapeutic interventions in regenerative medicine.

FPGA implementation for 44.2368-Gbit/s PAM8 signal transmission with pruned pre-equalization.

In this experiment, we demonstrated an intensity modulation and direct-detection (IM/DD) system based on a field-programmable gate array (FPGA). The PAM8 signals are successfully delivered at 44.2368 Gbit/s over a 45-km standard single-mode fiber (SSMF), satisfying the soft-decision forward error correction (SD-FEC) criterion of 2.4 × 10-2, and the net bit rate may reach 36.864 Gbit/s without the need of optical amplifiers. At the transmitter, we used a pruned pre-equalization algorithm to process the PAM8 signals, and the high-speed parallel PAM8 signals were processed at the receiver using 64 parallel constant modulus algorithm (CMA) and decision-directed least mean square (DD-LMS) equalizers. Additionally, we analyzed the bit error rate (BER) performance of the DD-LMS equalizer in FPGA simulation with various data lengths, both before and after equalization.

CRISPR/Cas-Assisted Nanoneedle Sensor for Adenosine Triphosphate Detection in Living Cells.

The clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein (Cas) (CRISPR/Cas) systems have recently emerged as powerful molecular biosensing tools based on their collateral cleavage activity due to their simplicity, sensitivity, specificity, and broad applicability. However, the direct application of the collateral cleavage activity for in situ intracellular detection is still challenging. Here, we debut a CRISPR/Cas-assisted nanoneedle sensor (nanoCRISPR) for intracellular adenosine triphosphate (ATP), which avoids the challenges associated with intracellular collateral cleavage by introducing a two-step process of intracellular target recognition, followed by extracellular transduction and detection. ATP recognition occurs by first presenting in the cell cytosol an aptamer-locked Cas12a activator conjugated to nanoneedles; the recognition event unlocks the activator immobilized on the nanoneedles. The nanoneedles are then removed from the cells and exposed to the Cas12a/crRNA complex, where the activator triggers the cleavage of an ssDNA fluorophore-quencher pair, generating a detectable fluorescence signal. NanoCRISPR has an ATP detection limit of 246 nM and a dynamic range from 1.56 to 50 µM. Importantly, nanoCRISPR can detect intracellular ATP in 30 min in live cells without impacting cell viability. We anticipate that the nanoCRISPR approach will contribute to broadening the biomedical applications of CRISPR/Cas sensors for the detection of diverse intracellular molecules in living systems.

Visual isothermal amplification detection of ASFV based on trimeric G-quadruplex cis-cleavage activity of Cas-12a.

African swine fever virus (ASFV) is a kind of DNA virus and can infect both domestic pigs and wild boars with fatality up to 100%. The contaminated meat products mainly led to the worldwide transmission of ASFV. The outbreak of ASF greatly affects the supply stability of meat products as well as the development of the global pig industry. In this study, a visual isothermal amplification detection assay for ASFV based on trimeric G-quadruplex cis-cleavage activity of Cas12a was developed. The introduction of Cas12a could discriminate the specific amplification from the non-specific amplification and improve the sensitivity. The detection limit was as low as 0.23 copies/µL. This assay had good potential in the detection of ASFV and would be helpful for the stability of meat production and supply.

Time-Dependent Changes in the Bladder Muscle Metabolome After Traumatic Spinal Cord Injury in Rats Using Metabolomics.

PURPOSE: The main treatment options of neurogenic bladder remains catheterization and long-term oral medications. Metabolic interventions have shown good therapeutic results in many diseases. To date, no studies have characterized the metabolites of the detrusor muscle during neurogenic bladder. Using metabolomics, new muscle metabolomic signatures were identified to reveal the temporal metabolic profile of muscle during disease progression. METHODS: We used 42 Sprague-Dawley rats (200±20 g, males) for T10 segmental spinal cord injury modeling and collected detrusor tissue and performed nontargeted metabolomics after sham surgery, 30-minute, 6-hour, 12-hour, 24-hour, 5-day, and 2-week postmodelling, to identify the dysregulated metabolic pathways and key metabolites. RESULTS: By comparing mzCloud, mzVault, MassList, we identified a total of 1,271 metabolites and enriched a total of 12 metabolism-related pathways with significant differences (P<0.05) based on Kyoto Encyclopedia of Genes and Genomes analysis. Metabolites in several differential metabolic pathways such as ascorbate and aldarate metabolism, Steroid hormone biosynthesis, and carbon metabolism are altered in a regular manner before and after ridge shock. CONCLUSION: Our study is the first time-based metabolomic study of rat forced urinary muscle after traumatic spinal cord injury, and we identified multiple differential metabolic pathways during injury that may improve long-term management strategies for neurogenic bladder and reduce costs in long-term treatment.