Multimodal three-dimensional characterization of murine skeletal muscle micro-scale elasticity, structure, and composition: Impact of dysferlinopathy, Duchenne muscular dystrophy, and age on three hind-limb muscles.

Skeletal muscle tissue function is governed by the mechanical properties and organization of its components, including myofibers, extracellular matrix, and adipose tissue, which can be modified by the onset and progression of many disorders. This study used a novel combination of quantitative micro-elastography and clearing-enhanced three-dimensional (3D) microscopy to assess 3D micro-scale elasticity and micro-architecture of muscles from two muscular dystrophies: dysferlinopathy and Duchenne muscular dystrophy, using male BLA/J and mdx mice, respectively, and their wild-type (WT) controls. We examined three muscles with varying proportions of slow- and fast-twitch myofibers: the soleus (predominantly slow), extensor digitorum longus (EDL; fast), and quadriceps (mixed), from BLA/J and WTBLA/J mice aged 3, 10, and 24 months, and mdx and WTmdx mice aged 10 months. Both dysferlin deficiency and age reduced the elasticity and variability of elasticity of the soleus and quadriceps, but not EDL. Overall, the BLA/J soleus was 20% softer than WT and less mechanically heterogeneous (-14% in standard deviation of elasticity). The BLA/J quadriceps at 24 months was 72% softer than WT and less mechanically heterogeneous (-59% in standard deviation), with substantial adipose tissue accumulation. While mdx muscles did not differ quantitatively from WT, regional heterogeneity was evident in micro-scale elasticity and micro-architecture of quadriceps (e.g., 11.2 kPa in a region with marked pathology vs 3.8 kPa in a less affected area). These results demonstrate differing biomechanical changes in hind-limb muscles of two distinct muscular dystrophies, emphasizing the potential for this novel multimodal technique to identify important differences between various myopathies.

Multimodal mechano-microscopy reveals mechanical phenotypes of breast cancer spheroids in three dimensions.

Cancer cell invasion relies on an equilibrium between cell deformability and the biophysical constraints imposed by the extracellular matrix (ECM). However, there is little consensus on the nature of the local biomechanical alterations in cancer cell dissemination in the context of three-dimensional (3D) tumor microenvironments (TMEs). While the shortcomings of two-dimensional (2D) models in replicating in situ cell behavior are well known, 3D TME models remain underutilized because contemporary mechanical quantification tools are limited to surface measurements. Here, we overcome this major challenge by quantifying local mechanics of cancer cell spheroids in 3D TMEs. We achieve this using multimodal mechano-microscopy, integrating optical coherence microscopy-based elasticity imaging with confocal fluorescence microscopy. We observe that non-metastatic cancer spheroids show no invasion while showing increased peripheral cell elasticity in both stiff and soft environments. Metastatic cancer spheroids, however, show ECM-mediated softening in a stiff microenvironment and, in a soft environment, initiate cell invasion with peripheral softening associated with early metastatic dissemination. This exemplar of live-cell 3D mechanotyping supports that invasion increases cell deformability in a 3D context, illustrating the power of multimodal mechano-microscopy for quantitative mechanobiology in situ.

Association Between Nonalcoholic Fatty Liver Disease and the Risk of Cardiovascular Disease in the Middle-Age and Elderly Population of Northern China: A Cross-Sectional Study.

Background: Nonalcoholic fatty liver disease (NAFLD) has become a major global health burden, which increases the risk of extra-hepatic complications such as type 2 diabetes mellitus (T2DM), dyslipidemia, metabolic syndrome (MetS), and cardiovascular disease (CVD). However, NAFLD remains underappreciated and underdiagnosed. Our study aimed to explore the prevalence of NAFLD and the association between NAFLD and CVD events among adults aged 40 and older in Northern China. Methods: This study was conducted in the Shijingshan district of Beijing, China from November 2011 to August 2012. A total of 18891 subjects were recruited in the study. The information including demographical information, lifestyle, previous history of diabetes, hypertension, dyslipidemia, CVD, and liver disease were gathered. Data on physical examination, blood lipid profile, fasting blood glucose, and 2-hour blood glucose were recorded. Determination of MetS was according to T2DM guideline of Chinese Diabetes Society (2020 edition). The association between CVD and NAFLD was evaluated by multivariate logistic regression. Results: The prevalence of NAFLD was 15.2%. After adjustment for age, smoking status, alcohol intake, WC, hypertension, dyslipidemia and hyperglycemia, the odds ratios (ORs) of CVD in men were 1.622 (95%CI: 1.345-1.957) and 1.990 (95%CI: 1.709-2.316) in women with NAFLD, compared with the subjects without NAFLD. Conclusions: NAFLD is independently associated with increased risk of CVD development.

Tumor spheroid elasticity estimation using mechano-microscopy combined with a conditional generative adversarial network.

BACKGROUND AND OBJECTIVES: Techniques for imaging the mechanical properties of cells are needed to study how cell mechanics influence cell function and disease progression. Mechano-microscopy (a high-resolution variant of compression optical coherence elastography) generates elasticity images of a sample undergoing compression from the phase difference between optical coherence microscopy (OCM) B-scans. However, the existing mechano-microscopy signal processing chain (referred to as the algebraic method) assumes the sample stress is uniaxial and axially uniform, such that violation of these assumptions reduces the accuracy and precision of elasticity images. Furthermore, it does not account for prior information regarding the sample geometry or mechanical property distribution. In this study, we investigate the feasibility of training a conditional generative adversarial network (cGAN) to generate elasticity images from phase difference images of samples containing a cell spheroid embedded in a hydrogel. METHODS: To construct the cGAN training and simulated test sets, we generated 30,000 artificial elasticity images using a parametric model and computed the corresponding phase difference images using finite element analysis to simulate compression applied to the artificial samples. We also imaged real MCF7 breast tumor spheroids embedded in hydrogel using mechano-microscopy to construct the experimental test set and evaluated the cGAN using the algebraic elasticity images and co-registered OCM and confocal fluorescence microscopy (CFM) images. RESULTS: Comparison with the simulated test set ground truth elasticity images shows the cGAN produces a lower root mean square error (median: 3.47 kPa, 95 % confidence interval (CI) [3.41, 3.52]) than the algebraic method (median: 4.91 kPa, 95 % CI [4.85, 4.97]). For the experimental test set, the cGAN elasticity images contain features resembling stiff nuclei at locations corresponding to nuclei seen in the algebraic elasticity, OCM, and CFM images. Furthermore, the cGAN elasticity images are higher resolution and more robust to noise than the algebraic elasticity images. CONCLUSIONS: The cGAN elasticity images exhibit better accuracy, spatial resolution, sensitivity, and robustness to noise than the algebraic elasticity images for both simulated and real experimental data.

Quercetin alleviates kidney damage caused by mercury Chloride: The protective effects of quercetin on autophagy and inflammation were studied based on TRIM32/TLR4/LC3 pathway.

OBJECTIVE: Mercury is one of the heavy metal pollutants causing serious harm to human health. Quercetin was observed to repair kidney damage through the TLR4/TRIM32 pathway, and the detoxification effect of quercetin on heavy metal poisoning was observed. METHODS: For the study, the researchers divided 40 male mice from the KM strain into five groups: control, HgCl2, QU30, HgCl2+QU15, and HgCl2+QU30. The biological effects of those mice in each group were detected by the biochemical experiment, histopathology experiment and protein expression experiment respectively. RESULTS: HgCl2 had effects in increasing the level of malondialdehyde (MDA) and decreasing the activity of antioxidant enzymes (P < 0.05). HgCl2 induced inflammation by increasing tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and Toll Like Receptor 4 (TLR-4) (P < 0.05). The expression of creatinine (CRE) and urea nitrogen (BUN) showed that HgCl2 promoted kidney injury. HgCl2 altered renal tissue integrity and TRIM32 expression which resulted in the increased autophagy associated protein levels of LC3. In contrast, quercetin reduced oxidative stress, autophagy, inflammation and histopathological changes (P < 0.05). CONCLUSION: Quercetin has the renal protection effects of anti-inflammation, anti-oxidation and anti-autophagy.

Splittable systems in biomedical applications.

Splittable systems have emerged as a powerful approach for the precise spatiotemporal control of biological processes. This concept relies on splitting a functional molecule into inactive fragments, which can be reassembled under specific conditions or stimuli to regain activity. Several binding pairs and orthogonal split fragments are introduced by fusing with other modalities to develop more complex and robust designs. One of the pillars of these splittable systems is modularity, which involves decoupling targeting, activation, and effector functions. Challenges, such as off-target effects and overactivation, can be addressed through precise control. This review provides an overview of the design principles, strategies, and applications of splittable systems across diverse fields including immunotherapy, gene editing, prodrug activation, biosensing, and synthetic biology.

Enzyme-Powered, Label-Free DNA Walker for Uracil-DNA Glycosylase Detection at Single-Cell Level.

Uracil-DNA glycosylase (UDG) plays a crucial role in the removal of damaged uracil bases, thereby upholding genetic stability and integrity. An enzyme-powered, label-free DNA walker was devised for UDG activity detection. Initially, a label-free DNA track, incorporating a gold nanoparticle (AuNP), multiple hairpin structures, and various swing arms, was engineered for walking mechanism. The hairpin structure was meticulously crafted to include a G-quadruplex sequence, enabling the generation of a label-free fluorescence signal. The swing arm remained inert in the absence of UDG, but became activated upon the introduction of UDG, thereby initiating the enzyme-powered walking process and generating significant dissociative G-quadruplex sequences. By integrating a selective fluorescent dye into the design, an enhanced label-free fluorescence response was achieved. The proposed DNA walker presented a direct and label-free approach for UDG detection, demonstrating exceptional sensitivity with a detection limit of 0.00004 U/mL. Using the uracil glycosylase inhibitor (UGI) as an inhibitory model, inhibitor assay was conducted with satisfactory precision. Furthermore, successful analysis of cellular UDG at the single-cell level was accomplished. Consequently, the developed DNA walker serves as a label-free, selective, and sensitive tool for UDG activity assessment, showing great potential for applications in disease diagnosis, inhibitor screening, and biomedical investigations.

Computed tomography-based contrast features for distinguishing extra-gastrointestinal stromal tumors from intra-abdominal fibromatosis.

PURPOSE: This study aims to define the computed tomography (CT) criteria that distinguish extra-gastrointestinal stromal tumors (eGISTs) from intra-abdominal fibromatosis (IAF). METHODS: Retrospective analysis was conducted on CT images obtained from 31 pathologically confirmed cases, including 17 cases of eGISTs and 14 of IAF. Various parameters [e.g., lesion location, contour characteristics, border delineation, enhancement patterns, presence of intralesional necrosis, vessels, air, fat, and hemorrhage, the long diameter (LD), LD/short diameter (SD) ratio, and volume (LD × SD × height diameter)] were meticulously evaluated. In addition, the degree of enhancement during arterial and portal venous phases and the lesion-to-aorta CT attenuation ratio during both phases were quantified. Statistical analysis was performed using Fisher's exact test, the Student's t-test, and the receiver operating characteristic curve to identify significant CT criteria. Sensitivity and specificity assessments were conducted for single and combined CT criteria. RESULTS: Significant differentiators between eGISTs and IAF include non-mesenteric localization, irregular contour, well-defined borders, heterogeneous enhancement, presence of intralesional necrosis and vessels, and absence of intralesional fat, with LD exceeding 9.6 cm, an LD/SD ratio >1.22, and volume surpassing 603.3 cm3 (P < 0.05). A combination of seven or more of these criteria yielded a specificity of 100%. CONCLUSION: Ten distinct CT criteria have been identified to distinguish eGISTs from IAF, notably encompassing non-mesenteric localization, irregular contour, well-defined borders, heterogeneous enhancement, presence of intralesional necrosis and vessels, absence of intralesional fat, LD >9.6 cm, an LD/SD ratio >1.22, and volume surpassing 603.3 cm3. CLINICAL SIGNIFICANCE: The current findings establish CT criteria to distinguish eGISTs from IAF in a clinical setting.

In situ stress estimation in quantitative micro-elastography.

In quantitative micro-elastography (QME), a pre-characterized compliant layer with a known stress-strain curve is utilized to map stress at the sample surface. However, differences in the boundary conditions of the compliant layer when it is mechanically characterized and when it is used in QME experiments lead to inconsistent stress estimation and consequently, inaccurate elasticity measurements. Here, we propose a novel in situ stress estimation method using an optical coherence tomography (OCT)-based uniaxial compression testing system integrated with the QME experimental setup. By combining OCT-measured axial strain with axial stress determined using a load cell in the QME experiments, we can estimate in situ stress for the compliant layer, more accurately considering its boundary conditions. Our proposed method shows improved accuracy, with an error below 10%, compared to 85% using the existing QME technique with no lubrication. Furthermore, demonstrations on hydrogels and cells indicate the potential of this approach for improving the characterization of the micro-scale mechanical properties of cells and their interactions with the surrounding biomaterial, which has potential for application in cell mechanobiology.

USP14 increases the sensitivity of retinoblastoma to cisplatin by mediating the ferroptosis.

The aim of this study is to explore the function of USP14 on the sensitivity of retinoblastoma (RB) to cisplatin (DDP) and the underlying mechanism. USP14 was knockdown in Y79 cells by transfecting three siRNAs (si-USP14-1, si-USP14-2, and si-USP14-3), with si-USP14 NC as the negative control. si-USP14-3 was selected by results of Western blotting. The CCK-8 assay was used to detect the IC50 of Y79 cells and the growth curve. The cell cycle, cell apoptosis, and ROS level were measured by flow cytometry. The expression level of P-GP, ERCC1, survivin, GPX4, FTH1, ACSL4, NOX1, COX2, and FASN was determined by the Western blotting assay. CO-IP assay was utilized to evaluate the interaction between USP14 and FASN. The IC50 of DDP in Y79 cells and Y79/DDP cells was 7.83 µM and 24.67 µM, respectively. Compared to control and si-USP14 NC groups, increased apoptotic rate and ROS level, and arrested cell cycle in S phase were observed in USP14-knockdown Y79 cells. Compared to control and si-USP14 NC groups, increased apoptotic rate and arrested cell cycle in G0/G1 phase were observed in USP14-knockdown Y79/DDP cells. Compared to control, increased ROS level was observed in USP14-knockdown Y79/DDP cells. Compared to the si-USP14 NC groups, extremely downregulated P-GP, ERCC1, survivin, GPX4, FTH1, NOX1, COX2, and FASN were observed in USP14-knockdown Y79 cells or Y79/DDP cells, accompanied by the elevated expression of ACSL4. The interaction between USP14 and FASN was identified according to the result of CO-IP assay. By silencing USP14 in Y79 and Y79/DDP cells, levels of resistance-related proteins (P-GP, ERCC1, and survivin), ferroptosis-related proteins (FTH1 and GPX4), and lipid metabolism-related proteins (NOX1, COX2, and FASN) were dramatically reduced, accompanied by enhanced ROS level, increased apoptosis, and restrained DNA content, indicating that USP14 might suppress the DDP resistance in RB by mediating ferroptosis, which is an important target for treating RB.

Ruthenium/η5-Phenoxo-Catalyzed Amination of Phenols with Amines.

Ruthenium(II) complexes are known to form η6-arene complexes with benzene-containing compounds through π-coordination, a property extensively utilized to initiate reactions not typically observed with free arenes. A prime example is nucleophilic aromatic substitution, where ruthenium-complexed aryl halides undergo nucleophilic attack, allowing the direct synthesis of diverse aromatic compounds by displacing halides with nucleophiles. However, this activation relies on the electron-withdrawing effect of the Ru(II) species, as well as is hindered by the resistance of η6-arenes to arene exchange. In the previous pursuit of catalysis, the emphasis of ligand design has centered on promoting arene exchange. In this study, we extended the ruthenium activation strategy to umpolung substitution reactions of phenols. The amination proceeds through a direct condensation between phenols and amines, with a key intermediate identified as [bis(η5-phenoxo)Ru], which is in situ generated from a commercially available ruthenium catalyst. In comparison with the well-studied cyclopentadienyl (Cp) type ligands, we demonstrated that an η5-phenoxo motif, as a superior alternative to Cp, contributes to the amination of phenols in two crucial ways: its less electron-donating nature enhances the withdrawing effect of the ruthenium unit, facilitating substitution on the phenol complex; its distinctive behavior in arene exchange allows for conducting the amination with a catalytic amount of metal. Additionally, hydrogen bonding, wherein the phenoxo serves as the acceptor, was found to be important for the substitution. The versatility of this ruthenium-catalyzed amination was validated by performing reactions with a diverse array of phenols exhibiting various electronic properties, in combination with a wide range of primary amines. This work exemplifies the expansion of the scope of π-coordination activation in catalysis through innovative ligand development.

Stiffness Mediated-Mechanosensation of Airway Smooth Muscle Cells on Linear Stiffness Gradient Hydrogels.

In obstructive airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), the extracellular matrix (ECM) protein amount and composition of the airway smooth muscle (ASM) is often remodelled, likely altering tissue stiffness. The underlying mechanism of how human ASM cell (hASMC) mechanosenses the aberrant microenvironment is not well understood. Physiological stiffnesses of the ASM were measured by uniaxial compression tester using porcine ASM layers under 0, 5 and 10% longitudinal stretch above in situ length. Linear stiffness gradient hydrogels (230 kPa range) were fabricated and functionalized with ECM proteins, collagen I (ColI), fibronectin (Fn) and laminin (Ln), to recapitulate the above-measured range of stiffnesses. Overall, hASMC mechanosensation exhibited a clear correlation with the underlying hydrogel stiffness. Cell size, nuclear size and contractile marker alpha-smooth muscle actin (αSMA) expression showed a strong correlation to substrate stiffness. Mechanosensation, assessed by Lamin-A intensity and nuc/cyto YAP, exhibited stiffness-mediated behaviour only on ColI and Fn-coated hydrogels. Inhibition studies using blebbistatin or Y27632 attenuated most mechanotransduction-derived cell morphological responses, αSMA and Lamin-A expression and nuc/cyto YAP (blebbistatin only). This study highlights the interplay and complexities between stiffness and ECM protein type on hASMC mechanosensation, relevant to airway remodelling in obstructive airway diseases.

[Clinical and genetic analysis of a Chinese patient with Alström syndrome].

OBJECTIVE: To explore the genetic etiology for a patient with Alström syndrome (ALMS) presenting as dilated cardiomyopathy. METHODS: A 41-year-old male patient who had presented at the Sixth Medical Center of PLA General Hospital on October 20, 2021 was selected as the study subject. Clinical and laboratory examinations were carried out. Whole exome sequencing (WES) was employed for genetic testing, and candidate variants were validated by Sanger sequencing and pathogenicity analysis. RESULTS: The patient had a 14-year medical history characterized by dilated cardiomyopathy, complete atrioventricular block, visual impairment, sensorineural hearing loss, truncal obesity, insulin resistance, type 2 diabetes, hypertension, renal dysfunction, and paranoid delusions. Genetic testing revealed that he has harbored compound heterozygous variants of the ALMS1 gene, namely c.6823C>T (p.Arg2275Ter) and c.9442_9445dup (p.Ser3149LysfsTer2). Sanger sequencing confirmed that they were inherited from his father and mother, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PVS1_VeryStrong+PM2_Supporting+PM3+PP3, PVS1_VeryStrong+PM2_Supporting+PM3). Literature review indicated that the complete atrioventricular block in the patient was a phenotype unreported previously. CONCLUSION: The c.6823C>T (p.Arg2275Ter) and c.9442_9445dup (p.Ser3149LysfsTer2) compound heterozygous variants of the ALMS1 gene probably underlay the pathogenesis in this patient. Above findings have expanded the phenotypic spectrum of ALMS and provided insights for clinicians dealing with similar cases.

The role of sialidases in the pathogenesis of bacterial vaginosis and their use as a promising pharmacological target in bacterial vaginosis.

Bacterial vaginosis (BV) is an infection of the genital tract characterized by disturbance of the normally Lactobacilli-dominated vaginal flora due to the overgrowth of Gardnerella and other anaerobic bacteria. Gardnerella vaginalis, an anaerobic pathogen and the major pathogen of BV, produces sialidases that cleave terminal sialic acid residues off of human glycans. By desialylation, sialidases not only alter the function of sialic acid-containing glycoconjugates but also play a vital role in the attachment, colonization and spread of many other vaginal pathogens. With known pathogenic effects, excellent performance of sialidase-based diagnostic tests, and promising therapeutic potentials of sialidase inhibitors, sialidases could be used as a biomarker of BV. This review explores the sources of sialidases and their role in vaginal dysbiosis, in aims to better understand their participation in the pathogenesis of BV and their value in the diagnosis and treatment of BV.

Prevalence of Reproductive Tract Infections and Association with Human Papillomavirus Infection Among Reproductive-Age Women - Six Tertiary Hospitals, China, June 2021-December 2022.

What is already known about this topic?: Previous studies have indicated a possible association between reproductive tract infections (RTIs) and high-risk human papillomavirus (HPV) infection, but the evidence is still inconclusive. What is added by this report?: This multicenter study found significantly higher positive rates of HPV, including general HPV, high-risk HPV, and HPV 16/18 infections, among women who tested positive for single or multiple RTIs compared to women who tested negative for RTIs in gynecological outpatient clinics. What are the implications for public health practice?: Infection with HPV, especially high-risk types, is linked to RTIs and imbalances in the vaginal microbiota. Implementing standardized protocols for identifying and treating RTIs could support the establishment of a healthy vaginal microenvironment. This, in turn, may offer a novel approach to preventing cervical cancer.

Plant-based dietary patterns and risk of esophageal cancer: A prospective cohort study spanning 17 years.

Objective: Plant-based diets have multiple health benefits for cancers; however, little is known about the association between plant-based dietary patterns and esophageal cancer (EC).This study presents an investigation of the prospective associations among three predefined indices of plant-based dietary patterns and the risk of EC. Methods: We performed endoscopic screening for 15,709 participants aged 40-69 years from two high-risk areas of China from January 2005 to December 2009 and followed the cohort until December 31, 2022. The overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI), were calculated using survey responses to assess dietary patterns. We applied Cox proportional hazard regression to estimate the multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) of EC across 3 plant-based diet indices and further stratified the analysis by subgroups. Results: The final study sample included 15,184 participants in the cohort. During a follow-up of 219,365 person-years, 176 patients with EC were identified. When the highest quartile was compared with the lowest quartile, the pooled multivariable-adjusted HR of EC was 0.50 (95% CI, 0.32-0.77) for hPDI. In addition, the HR per 10-point increase in the hPDI score was 0.42 (95% CI, 0.27-0.66) for ECs. Conversely, uPDI was positively associated with the risk of EC, and the HR was 1.80 (95% CI, 1.16-2.82). The HR per 10-point increase in the uPDI score was 1.90 (95% CI, 1.26-2.88) for ECs. The associations between these scores and the risk of EC were consistent in most subgroups. These results remained robust in sensitivity analyses. Conclusions: A healthy plant-based dietary pattern was associated with a reduced risk of EC. Emphasizing the healthiness and quality of plant-based diets may be important for preventing the development of EC.

Mechanical overload-induced release of extracellular mitochondrial particles from tendon cells leads to inflammation in tendinopathy.

Tendinopathy is one of the most common musculoskeletal diseases, and mechanical overload is considered its primary cause. However, the underlying mechanism through which mechanical overload induces tendinopathy has not been determined. In this study, we identified for the first time that tendon cells can release extracellular mitochondria (ExtraMito) particles, a subtype of medium extracellular particles (mEPs), into the environment through a process regulated by mechanical loading. RNA sequencing systematically revealed that oxygen-related reactions, extracellular particles, and inflammation were present in diseased human tendons, suggesting that these factors play a role in the pathogenesis of tendinopathy. We simulated the disease condition by imposing a 9% strain overload on three-dimensional mouse tendon constructs in our cyclic uniaxial stretching bioreactor. The three-dimensional mouse tendon constructs under normal loading with 6% strain exhibited an extended mitochondrial network, as observed through live-cell confocal laser scanning microscopy. In contrast, mechanical overload led to a fragmented mitochondrial network. Our microscopic and immunoblot results demonstrated that mechanical loading induced tendon cells to release ExtraMito particles. Furthermore, we showed that mEPs released from tendon cells overloaded with a 9% strain (mEP9%) induced macrophage chemotaxis and increased the production of proinflammatory cytokines, including IL-6, CXCL1, and IL-18, from macrophages compared to mEP0%, mEP3%, and mEP6%. Partial depletion of the ExtraMito particles from mEP9% by magnetic-activated cell sorting significantly reduced macrophage chemotaxis. N-acetyl-L-cysteine treatment preserved the mitochondrial network in overloaded tendon cells, diminishing overload-induced macrophage chemotaxis toward mEP9%. These findings revealed a novel mechanism of tendinopathy; in an overloaded environment, ExtraMito particles convey mechanical response signals from tendon cells to the immune microenvironment, culminating in tendinopathy.

Detection and discrimination of glutathione among biological thiols based on oxalyl dihydrazide decorated sulfur nanodots.

The quantitative detection and discrimination of glutathione (GSH) were achieved based on oxalyl dihydrazide (ODH) decorated sulfur nanodots. ODH resulted in the aggregation and fluorescence quenching of the sulfur nanodots, and GSH selectively triggered fluorescence recovery through forming stronger hydrogen bonds with ODH than other biological thiols.

Global, regional, and national lifetime risks of developing and dying from gastrointestinal cancers in 185 countries: a population-based systematic analysis of GLOBOCAN.

BACKGROUND: Gastrointestinal cancers account for a quarter of the global cancer incidence and a third of cancer-related deaths. We sought to estimate the lifetime risks of developing and dying from gastrointestinal cancers at the country, world region, and global levels in 2020. METHODS: For this population-based systematic analysis, we obtained estimates of gastrointestinal cancer incidence and mortality rates from GLOBOCAN for 185 countries, alongside all-cause mortality and population data from the UN. Countries were categorised into quartiles of the Human Development Index (HDI). The lifetime risk of gastrointestinal cancers was estimated with a standard method that adjusts for multiple primaries, taking into account competing risks of death from causes other than cancer and life expectancy. FINDINGS: The global lifetime risks of developing and dying from gastrointestinal cancers from birth to death was 8·20% (95% CI 8·18-8·21) and 6·17% (6·16-6·18) in 2020. For men, the risk of developing gastrointestinal cancers was 9·53% (95% CI 9·51-9·55) and of dying from them 7·23% (7·22-7·25); for women, the risk of developing gastrointestinal cancers was 6·84% (6·82-6·85) and of dying from them 5·09% (5·08-5·10). Colorectal cancer presented the highest risk, accounting for 38·5% of the total lifetime risk of developing, and 28·2% of dying from, gastrointestinal cancers, followed by cancers of the stomach, liver, oesophagus, pancreas, and gallbladder. Eastern Asia has the highest lifetime risks for cancers of the stomach, liver, oesophagus, and gallbladder, Australia and New Zealand for colorectal cancer, and Western Europe for pancreatic cancer. The lifetime risk of gastrointestinal cancers increased consistently with increasing level of HDI; however, high HDI countries (the third HDI quartile) had the highest death risk. INTERPRETATION: The global lifetime risk of gastrointestinal cancers translates to one in 12 people developing, and one in 16 people dying from, gastrointestinal cancers. The identified high risk and observed disparities across countries warrants context-specific targeted gastrointestinal cancer control and health systems planning. FUNDING: Beijing Nova Program, CAMS Innovation Fund for Medical Sciences, and Talent Incentive Program of Cancer Hospital, CAMS (Hope Star).

Utilizing a novel model of PANoptosis-related genes for enhanced prognosis and immune status prediction in kidney renal clear cell carcinoma.

Kidney renal clear cell carcinoma (KIRC) is the most common histopathologic type of renal cell carcinoma. PANoptosis, a cell death pathway that involves an interplay between pyroptosis, apoptosis and necroptosis, is associated with cancer immunity and development. However, the prognostic significance of PANoptosis in KIRC remains unclear. RNA-sequencing expression and mutational profiles from 532 KIRC samples and 72 normal samples with sufficient clinical data were retrieved from the Cancer Genome Atlas (TCGA) database. A prognostic model was constructed using differentially expressed genes (DEGs) related to PANoptosis in the TCGA cohort and was validated in a Gene Expression Omnibus (GEO) cohorts. Incorporating various clinical features, the risk model remained an independent prognostic factor in multivariate analysis, and it demonstrated superior performance compared to unsupervised clustering of the 21 PANoptosis-related genes alone. Further mutational analysis showed fewer VHL and more BAP1 alterations in the high-risk group, with alterations in both genes also associated with patient prognosis. The high-risk group was characterized by an unfavorable immune microenvironment, marked by reduced levels of CD4 + T cells and natural killer cells, but increased M2 macrophages and regulatory T cells. Finally, the risk model was predictive of response to immune checkpoint blockade, as well as sensitivity to sunitinib and paclitaxel. The PANoptosis-related risk model developed in this study enables accurate prognostic prediction in KIRC patients. Its associations with the tumor immune microenvironment and drug efficacy may offer potential therapeutic targets and inform clinical decisions.