Nanohybrid-Based Redox Homeostasis Perturbators Escaped from Early Lysosomes toward Amplified Sensitization of Tumor Cells and Photothermally Maneuvered Pyroptosis Therapy.

Reactive oxygen species (ROS) hold great potential in tumor pyroptosis therapy, yet they are still limited by short species lifespan and limited diffusion distance. Inducing cells into a metastable state and then applying external energy can effectively trigger pyroptosis, but systemic sensitization still faces challenges, such as limited ROS content, rapid decay, and short treatment windows. Herein, a nanohybrid-based redox homeostasis-perturbator system was designed that synergistically induce early lysosomal escape, autophagy inhibition, and redox perturbation functions to effectively sensitize cells to address these challenges. Specifically, weakly alkaline layered double hydroxide nanosheets (LDH NSs) with pH-responsive degradation properties enabled early lysosomal escape within 4 h, releasing poly(L-dopa) nanoparticles for inducing catechol-quinone redox cycling in the cytoplasm. The intracellular ROS levels were systematically rebounded by 3-4 times in tumor cells and lasted for over 4 h. Subsequently induced lysosomal stress and Ca2+ signaling activation resulted in severe mitochondrial dysfunction, as well as a perilous metastable state. Thereby, sequential near-infrared light was applied to trigger amplified stress through a local photothermal conversion. This led to sufficiently high levels of cleaved caspase-1 and GSDMD activation (2.5-2.8-fold increment) and subsequent pyroptosis response. In addition, OH- released by LDH elevated pH to alleviate the limitation of glutathione depletion by quinones at acidic pH and inhibit protective autophagy. Largely secreted inflammatory factors (2.5-5.6-fold increment), efficient maturation of dendritic cells, and further immune stimulation were boosted for tumor inhibition as a consequence. This study offers a new paradigm and insights into the synergy of internal systematic cellular sensitization and sequential external energy treatment to achieve tumor suppression through pyroptosis.

Maternal Exposure to Ozone and the Risk of Birth Defects: A Time-Stratified Case-Crossover Study in Southwestern China.

A few studies have explored the relationship between air pollution exposure and the risk of birth defects; however, the ozone-related (O3) effects on preconception and first-trimester exposures are still unknown. In this time-stratified case-crossover study, conditional logistic regressions were applied to explore the associations between O3 exposure and the risk of birth defects in Chongqing, China, and stratified analyses were constructed to evaluate the modifiable factors. A total of 6601 cases of birth defects were diagnosed, of which 56.16% were male. O3 exposure was associated with an increased risk of birth defects, and the most significant estimates were observed in the first month before pregnancy: a 10 ug/m3 increase of O3 was related to an elevation of 4.2% [95% confidence interval (CI), 3.4-5.1%]. The associations between O3 exposure and congenital malformations and deformations of the musculoskeletal system were statistically significant during almost all exposure periods. Pregnant women with lower education and income, and from rural areas, were more susceptible to O3 exposure, with the strongest odds ratios (ORs) of 1.066 (95%CI, 1.046-1.087), 1.086 (95%CI, 1.034-1.140), and 1.053 (95%CI, 1.034-1.072), respectively. Our findings highlight the health risks of air pollution exposure and raise awareness of pregnant women's vulnerability and the susceptibility window period.

Indoor Radon Concentrations in Severe Cold Area and Cold Area and Impact of Energy-saving Design on Indoor Radon in China.

ABSTRACT: This study investigated indoor radon concentrations in modern residential buildings in the Cold Area and Severe Cold Area in China. A total of 19 cities covering 16 provinces were selected with 1,610 dwellings measured for indoor radon concentration. The arithmetic mean and geometric mean of indoor radon concentration were 68 Bq m-3 and 57 Bq m-3, respectively. It was found that indoor radon concentrations were much higher in the Severe Cold Area than those in the Cold Area. The indoor radon concentrations showed an increasing trend for newly constructed buildings. It was estimated that the average effective dose from inhalation of indoor radon is 2.15 mSv and 1.60 mSv for the Severe Cold Area and Cold Area, respectively. The more and more rigid energy-saving design for residential buildings in the Severe Cold Area and Cold Area has an obvious impact on the increased trend of indoor radon due to extremely low air exchange rate in China.

Cold exposure-induced plasma exosomes impair bone mass by inhibiting autophagy.

Recently, environmental temperature has been shown to regulate bone homeostasis. However, the mechanisms by which cold exposure affects bone mass remain unclear. In our present study, we observed that exposure to cold temperature (CT) decreased bone mass and quality in mice. Furthermore, a transplant of exosomes derived from the plasma of mice exposed to cold temperature (CT-EXO) can also impair the osteogenic differentiation of BMSCs and decrease bone mass by inhibiting autophagic activity. Rapamycin, a potent inducer of autophagy, can reverse cold exposure or CT-EXO-induced bone loss. Microarray sequencing revealed that cold exposure increases the miR-25-3p level in CT-EXO. Mechanistic studies showed that miR-25-3p can inhibit the osteogenic differentiation and autophagic activity of BMSCs. It is shown that inhibition of exosomes release or downregulation of miR-25-3p level can suppress CT-induced bone loss. This study identifies that CT-EXO mediates CT-induced osteoporotic effects through miR-25-3p by inhibiting autophagy via targeting SATB2, presenting a novel mechanism underlying the effect of cold temperature on bone mass.

A nomogram-based prediction model for dysphagia in patients with chronic obstructive pulmonary disease: A cross-sectional study.

AIM AND OBJECTIVES: To investigate the prevalence of dysphagia in patients with COPD, identify the risk factors for dysphagia, develop a visual clinical prediction model and quantitatively predict the probability of developing dysphagia. BACKGROUND: Patients with COPD are at high risk of dysphagia, which is strongly linked to the acute exacerbation of their condition. The use of effective tools to predict its risk may contribute to the early identification and treatment of dysphagia in patients with COPD. DESIGN: A cross-sectional design. METHODS: From July 2021 to April 2023, we enrolled 405 patients with COPD for this study. The clinical prediction model was constructed according to the results of a univariate analysis and a logistic regression analysis, evaluated by discrimination, calibration and decision curve analysis and visualized by a nomogram. This study was reported using the TRIPOD checklist. RESULTS: In total, 405 patients with COPD experienced dysphagia with a prevalence of 59.01%. A visual prediction model was constructed based on age, whether combined with cerebrovascular disease, chronic pulmonary heart disease, acute exacerbation of COPD, home noninvasive positive pressure ventilation, dyspnoea level and xerostomia level. The model exhibited excellent discrimination at an AUC of .879. Calibration curve analysis indicated a good agreement between experimental and predicted values, and the decision curve analysis showed a high clinical utility. CONCLUSION: The model we devised may be used in clinical settings to predict the occurrence of dysphagia in patients with COPD at an early stage. RELEVANCE TO CLINICAL PRACTICE: The model can help nursing staff to calculate the risk probability of dysphagia in patients with COPD, formulate personalized preventive care measures for high-risk groups as soon as possible to achieve early prevention or delay of dysphagia and its related complications and improve the prognosis. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Assessment of causal association between the socio-economic status and osteoporosis and fractures: a bidirectional Mendelian randomization study in European population.

The correlation between socio-economic status (SES) and bone-related diseases garners increasing attention, prompting a bidirectional Mendelian randomization (MR) analysis in this study. Genetic data on SES indicators (average total household income before tax, years of schooling completed, and Townsend Deprivation Index at recruitment), femoral neck bone mineral density (FN-BMD), heel bone mineral density (eBMD), osteoporosis, and five different sites of fractures (spine, femur, lower leg-ankle, foot, and wrist-hand fractures) were derived from genome-wide association summary statistics of European ancestry. The inverse variance weighted method was employed to obtain the causal estimates, complemented by alternative MR techniques, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO). Furthermore, sensitivity analyses and multivariable MR were performed to enhance the robustness of our findings. Higher educational attainment exhibited associations with increased eBMD (ß: .06, 95% confidence interval [CI]: 0.01-0.10, P = 7.24 × 10-3), and reduced risks of osteoporosis (OR: 0.78, 95% CI: 0.65-0.94, P = 8.49 × 10-3), spine fracture (OR: 0.76, 95% CI: 0.66-0.88, P = 2.94 × 10-4), femur fracture (OR: 0.78, 95% CI: 0.67-0.91, P = 1.33 × 10-3), lower leg-ankle fracture (OR: 0.79, 95% CI: 0.70-0.88, P = 2.05 × 10-5), foot fracture (OR: 0.78, 95% CI: 0.66-0.93, P = 5.92 × 10-3), and wrist-hand fracture (OR: 0.83, 95% CI: 0.73-0.95, P = 7.15 × 10-3). Material deprivation appeared to increase the risk of spine fracture (OR: 2.63, 95% CI: 1.43-4.85, P = 1.91 × 10-3). A higher FN-BMD level positively affected increased household income (ß: .03, 95% CI: 0.01-0.04, P = 6.78 × 10-3). All these estimates were adjusted for body mass index, type 2 diabetes, smoking initiation, and frequency of alcohol intake. The MR analyses show that higher educational levels is associated with higher eBMD, reduced risk of osteoporosis and fractures, while material deprivation is positively related to spine fracture. Enhanced FN-BMD correlates with increased household income. These findings provide valuable insights for health guideline formulation and policy development.

We conducted stratified analyses to explore the causal links between socio-economic status and osteoporosis and various fractures and observed that education significantly reduced the risk of osteoporosis and lower eBMD. It also lowered the risks of fractures of spine, femur, lower leg-ankle, foot, and wrist-hand, while material deprivation exhibited positive associations with spine fracture risk. Bidirectional MR analysis showed that an elevated score of FN-BMD was associated with a higher income level. Our study shows the importance of conducting routine BMD estimations and osteoporosis screening, to enhance knowledge and awareness among individuals to promote bone health and prevent fractures.

Analysis and Monitoring of Indoor Radon Concentrations of 37 Kindergartens - Beijing Municipality, China, 2023.

Introduction: Radon (222Rn or 222radon) is a radioactive gas emitted from building materials, foundations, and soil. Children are especially susceptible to radon exposure, underscoring the need to assess indoor radon levels in kindergartens. This study monitored radon concentrations in 37 Beijing kindergartens from June to October 2023. Methods: A random sample of 37 kindergartens was selected from 18 administrative districts in Beijing. The indoor radon concentration was measured using the solid track accumulation method, with radon detectors continuously monitored over a 3-month period. Results: The mean indoor radon level in 37 kindergartens, observed at 252 monitoring points, was 84.3 Bq/m3, with values varying from 12.9 to 263.5 Bq/m3. About 20.2% of points showed radon levels between 100.0 and 200.0 Bq/m3, while 2.4% exceeded 200.0 Bq/m3. Notably, radon levels were significantly elevated on the ground floor compared to the upper floors. Conclusion: Indoor radon levels in 37 kindergartens remained below the national standard limit of 300.0 Bq/m3 for buildings (GB/T 16146-2015). Nonetheless, 18.9% of the kindergartens exceeded the 100.0 Bq/m3 limit set for new constructions. It is advised to improve radon monitoring in kindergartens and consider developing a national standard for maximum permissible radon levels in such facilities.

An implantable device for wireless monitoring of diverse physio-behavioral characteristics in freely behaving small animals and interacting groups.

Comprehensive, continuous quantitative monitoring of intricately orchestrated physiological processes and behavioral states in living organisms can yield essential data for elucidating the function of neural circuits under healthy and diseased conditions, for defining the effects of potential drugs and treatments, and for tracking disease progression and recovery. Here, we report a wireless, battery-free implantable device and a set of associated algorithms that enable continuous, multiparametric physio-behavioral monitoring in freely behaving small animals and interacting groups. Through advanced analytics approaches applied to mechano-acoustic signals of diverse body processes, the device yields heart rate, respiratory rate, physical activity, temperature, and behavioral states. Demonstrations in pharmacological, locomotor, and acute and social stress tests and in optogenetic studies offer unique insights into the coordination of physio-behavioral characteristics associated with healthy and perturbed states. This technology has broad utility in neuroscience, physiology, behavior, and other areas that rely on studies of freely moving, small animal models.

Bioresorbable shape-adaptive structures for ultrasonic monitoring of deep-tissue homeostasis.

Monitoring homeostasis is an essential aspect of obtaining pathophysiological insights for treating patients. Accurate, timely assessments of homeostatic dysregulation in deep tissues typically require expensive imaging techniques or invasive biopsies. We introduce a bioresorbable shape-adaptive materials structure that enables real-time monitoring of deep-tissue homeostasis using conventional ultrasound instruments. Collections of small bioresorbable metal disks distributed within thin, pH-responsive hydrogels, deployed by surgical implantation or syringe injection, allow ultrasound-based measurements of spatiotemporal changes in pH for early assessments of anastomotic leaks after gastrointestinal surgeries, and their bioresorption after a recovery period eliminates the need for surgical extraction. Demonstrations in small and large animal models illustrate capabilities in monitoring leakage from the small intestine, the stomach, and the pancreas.

A wireless, implantable bioelectronic system for monitoring urinary bladder function following surgical recovery.

Partial cystectomy procedures for urinary bladder-related dysfunction involve long recovery periods, during which urodynamic studies (UDS) intermittently assess lower urinary tract function. However, UDS are not patient-friendly, they exhibit user-to-user variability, and they amount to snapshots in time, limiting the ability to collect continuous, longitudinal data. These procedures also pose the risk of catheter-associated urinary tract infections, which can progress to ascending pyelonephritis due to prolonged lower tract manipulation in high-risk patients. Here, we introduce a fully bladder-implantable platform that allows for continuous, real-time measurements of changes in mechanical strain associated with bladder filling and emptying via wireless telemetry, including a wireless bioresorbable strain gauge validated in a benchtop partial cystectomy model. We demonstrate that this system can reproducibly measure real-time changes in a rodent model up to 30 d postimplantation with minimal foreign body response. Studies in a nonhuman primate partial cystectomy model demonstrate concordance of pressure measurements up to 8 wk compared with traditional UDS. These results suggest that our system can be used as a suitable alternative to UDS for long-term postoperative bladder recovery monitoring.

Mesoscale size-promoted targeted therapy for acute kidney injury through combined RONS scavenging and inflammation alleviation strategy.

Acute kidney injury (AKI) is a heterogeneous, high-mortality clinical syndrome with diverse pathogenesis and prognosis, but it lacks the effective therapy clinically. Its pathogenesis is associated with production of reactive oxygen/nitrogen species and infiltration of inflammatory cells. To overcome these pathogenic factors and improve the therapeutic efficiency, we synthesized triptolide-loaded mesoscale polydopamine melanin-mimetic nanoparticles (MeNP4TP) as the antioxidant plus anti-inflammatory therapeutic platform to synergistically scavenge reactive oxygen/nitrogen species (RONS), inhibit the activity of macrophages and dendritic cells, and generate Treg cells for AKI therapy. It was demonstrated that mesoscale size was beneficial for MeNP4TP to specifically accumulate at renal tubule cells, and MeNP4TP could significantly attenuate oxidative stress, reduce proinflammatory immune cells in renal, and repair renal function in cisplatin-induced AKI mouse model. MeNP4TP might be a potential candidate to inhibit oxidative damages and inflammatory events in AKI.

FAP deficiency enhances thermogenesis and attenuates metabolic inflammation in diet-induced obesity.

OBJECTIVE: Fibroblast activation protein α (FAP) is expressed in normal adipose tissue and related to some pleiotropic metabolic regulators. However, the exact role and mechanism of FAP in obesity and related metabolic disorders are not well understood. METHODS: FAP knockout mice were fed a normal diet or a high-fat diet (HFD) for 12 weeks. FAP knockout mice or wild-type mice treated with an FAP inhibitor were subjected to cold stress for 5 days. RESULTS: FAP deficiency protected mice against HFD-induced obesity and obesity-associated metabolic dysfunction, including glucose intolerance, insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. Notably, FAP deficiency largely reversed obesity-induced adipose tissue macrophage accumulation and M1-M2 imbalance in white adipose tissue (WAT). Moreover, energy expenditure was significantly higher in FAP-deficient mice fed an HFD. Both FAP deficiency and inhibition increased cold tolerance through enhancing WAT beiging. CONCLUSIONS: This study demonstrated that FAP deficiency protects mice against diet-induced obesity and related metabolic dysfunction. Furthermore, the protective effects are probably mediated via the promotion of WAT beiging and suppression of inflammation.

FAP expression in adipose tissue macrophages promotes obesity and metabolic inflammation.

Adipose tissue macrophages (ATM) are key players in the development of obesity and associated metabolic inflammation which contributes to systemic metabolic dysfunction. We here found that fibroblast activation protein α (FAP), a well-known marker of cancer-associated fibroblast, is selectively expressed in murine and human ATM among adipose tissue-infiltrating leukocytes. Macrophage FAP deficiency protects mice against diet-induced obesity and proinflammatory macrophage infiltration in obese adipose tissues, thereby alleviating hepatic steatosis and insulin resistance. Mechanistically, FAP specifically mediates monocyte chemokine protein CCL8 expression by ATM, which is further upregulated upon high-fat-diet (HFD) feeding, contributing to the recruitment of monocyte-derived proinflammatory macrophages with no effect on their classical inflammatory activation. CCL8 overexpression restores HFD-induced metabolic phenotypes in the absence of FAP. Moreover, macrophage FAP deficiency enhances energy expenditure and oxygen consumption preceding differential body weight after HFD feeding. Such enhanced energy expenditure is associated with increased levels of norepinephrine (NE) and lipolysis in white adipose tissues, likely due to decreased expression of monoamine oxidase, a NE degradation enzyme, by Fap-/- ATM. Collectively, our study identifies FAP as a previously unrecognized regulator of ATM function contributing to diet-induced obesity and metabolic inflammation and suggests FAP as a potential immunotherapeutic target against metabolic disorders.

DNA methylome profiling in occupational radon exposure miners using an Illumina Infinium Methylation EPIC BeadChip.

Background: A causal relationship between occupational radon exposure in underground miners and lung cancer risk has been demonstrated through large cohort epidemiological studies. However, the mechanisms by which radon exposure causes adverse effects on lung tissue remain unclear. Epigenetic alterations such as DNA methylation may provide new insights into interactions at molecular levels induced by prolonged radon exposure. Methods: We used the Illumina Infinium Human Methylation 850 K BeadChip to detect and compare genome-wide DNA methylation profiles in peripheral blood samples from underground miners (n = 14) and aboveground workers (n = 9). Results: The average concentration of radon in underground workplaces was significantly higher than that of aboveground places (1,198 Bq·m-3 vs 58 Bq·m-3, p < 0.001). A total of 191 differentially methylated positions (DMPs) corresponding to 104 hub genes were identified when |Δß| ≥ 0.1 and p < 0.05, with 107 hypermethylated sites and 84 hypomethylated sites. GO and KEGG analysis revealed that differentially methylated genes between underground miners and aboveground workers were prominently enriched in pathways/networks involved in neurotransmitter regulation, immunomodulatory effects and cell adhesion ability. Furthermore, methylation changes of selected genes FERMT1, ALCAM, HLA-DPA1, PON1 and OR2L13 were validated by pyrosequencing, which may play vital roles in these biological processes induced by radon. Conclusion: In summary, the DNA methylation pattern of the underground miners exposed to radon was distinct from that of the aboveground workers. Such abnormalities in the genomic DNA methylation profile associated with prolonged radon exposure are worth studying in terms of neuro- and immune-system regulation, as well as cell adhesion ability in the future.

Wireless broadband acousto-mechanical sensing system for continuous physiological monitoring.

The human body generates various forms of subtle, broadband acousto-mechanical signals that contain information on cardiorespiratory and gastrointestinal health with potential application for continuous physiological monitoring. Existing device options, ranging from digital stethoscopes to inertial measurement units, offer useful capabilities but have disadvantages such as restricted measurement locations that prevent continuous, longitudinal tracking and that constrain their use to controlled environments. Here we present a wireless, broadband acousto-mechanical sensing network that circumvents these limitations and provides information on processes including slow movements within the body, digestive activity, respiratory sounds and cardiac cycles, all with clinical grade accuracy and independent of artifacts from ambient sounds. This system can also perform spatiotemporal mapping of the dynamics of gastrointestinal processes and airflow into and out of the lungs. To demonstrate the capabilities of this system we used it to monitor constrained respiratory airflow and intestinal motility in neonates in the neonatal intensive care unit (n = 15), and to assess regional lung function in patients undergoing thoracic surgery (n = 55). This broadband acousto-mechanical sensing system holds the potential to help mitigate cardiorespiratory instability and manage disease progression in patients through continuous monitoring of physiological signals, in both the clinical and nonclinical setting.

Vascular wall microenvironment: exosomes secreted by adventitial fibroblasts induced vascular calcification.

Vascular calcification often occurs in patients with chronic renal failure (CRF), which significantly increases the incidence of cardiovascular events in CRF patients. Our previous studies identified the crosstalk between the endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and the paracrine effect of VSMCs, which regulate the calcification of VSMCs. Herein, we aim to investigate the effects of exosomes secreted by high phosphorus (HPi) -induced adventitial fibroblasts (AFs) on the calcification of VSMCs and the underlying mechanism, which will further elucidate the important role of AFs in high phosphorus vascular wall microenvironment. The conditioned medium of HPi-induced AFs promotes the calcification of VSMCs, which is partially abrogated by GW4869, a blocker of exosomes biogenesis or release. Exosomes secreted by high phosphorus-induced AFs (AFsHPi-Exos) show similar effects on VSMCs. miR-21-5p is enriched in AFsHPi-Exos, and miR-21-5p enhances osteoblast-like differentiation of VSMCs by downregulating cysteine-rich motor neuron 1 (Crim1) expression. AFsHPi-Exos and exosomes secreted by AFs with overexpression of miR-21-5p (AFsmiR21M-Exos) significantly accelerate vascular calcification in CRF mice. In general, AFsHPi-Exos promote the calcification of VSMCs and vascular calcification by delivering miR-21-5p to VSMCs and subsequently inhibiting the expression of Crim1. Combined with our previous studies, the present experiment supports the theory of vascular wall microenvironment.

Alteration of genome-wide DNA methylation in non-uranium miners induced by high level radon exposure.

In China, according to statistics about underground non-uranium mine radon levels, 15% exceed the national standard intervention level of 1000 Bq/m3, and some mines may exceed 10,000 Bq/m3. The relationship between radon exposure in underground miners and lung cancer has already been established, but the mechanisms and biological processes underlying it are poorly understood. In order to identify the genome-wide DNA methylation profile associated with long-term radon exposure, we performed the Infinium Human Methylation 850 K BeadChip measurement in whole blood samples obtained from 15 underground non-uranium miners and 10 matched aboveground control workers. Radon concentrations in the air of workplaces and living environments were measured by CR-39 radon detectors, and annual effective doses were calculated using the detection data. Under the high radon concentration with an average value of 12,700 Bq·m-3, a total of 165 significant differentially methylated positions (127 hypermethylated sites and 38 hypomethylated sites) annotated to 71 genes were identified in underground miners (|Δß| ≥ 0.10, p < 0.05), and the average DNA methylation level of 165 DMPs was significantly higher than that of the control workers. Most DMPs were found on chromosome 1, and approximately one-quarter of them were located in genomic promoter regions. Through bioinformatics analysis and pyrosequencing validation, five candidate genes differentially methylated by radon, including TIMP2, EMP2, CPT1B, AMD1 and SLC43A2 were identified. GO and KEGG analysis implicated that long term radon exposure could induce the lung cancer related biological processes such as cell adhesion and cellular polarity maintenance. Our study provides evidence for the alterations of genome-wide DNA methylation profiles induced by long-term high level radon exposure, and new insights into searching for carcinogenic biomarkers of high radon exposure in future studies.