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Osteosarcoma, a primary bone tumor, responds poorly to chemotherapy and radiation therapy in children and young adults; hence, as the basis for an alternative treatment, this study investigated the cytotoxic and antiproliferative effects of naringenin on osteosarcoma cell lines, HOS and U2OS, by using cell counting kit-8 and colony formation assays. DNA fragmentation and the increase in the G2/M phase in HOS and U2OS cells upon treatment with various naringenin concentrations were determined by using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and Annexin V/propidium iodide double staining, respectively. Flow cytometry was performed, and 2′,7′-dichlorodihydrofluorescein diacetate, JC-1, and Fluo-4 AM ester probes were examined for reactive oxygen species (ROS) generation, mitochondrial membrane potential, and intracellular calcium levels, respectively. Caspase activation, cell cycle, cytosolic and mitochondrial, and autophagy-related proteins were determined using western blotting. The results indicated that naringenin significantly inhibited viability and proliferation of osteosarcoma cells in a dose-dependent manner. In addition, naringenin induced cell cycle arrest in osteosarcoma cells by inhibiting cyclin B1 and cyclin-dependent kinase 1 expression and upregulating p21 expression. Furthermore, naringenin significantly inhibited the growth of osteosarcoma cells by increasing the intracellular ROS level. Naringenin induced endoplasmic reticulum (ER) stress-mediated apoptosis through the upregulation of ER stress markers, GRP78 and GRP94. Naringenin caused acidic vesicular organelle formation and increased autophagolysosomes, microtubule-associated protein-light chain 3-II protein levels, and autophagy. The findings suggest that the induction of cell apoptosis, cell cycle arrest, and autophagy by naringenin through mitochondrial dysfunction, ROS production, and ER stress signaling pathways contribute to the antiproliferative effect of naringenin on osteosarcoma cells.

Purpose Population ageing is fast becoming a major social concern across the globe. This ageing trend unavoidably fuels elders’ demand for healthcare services. As the main users of health care service, whether the healthcare is geographically approachable in local areas is more imperative to senior residents with restricted mobility. This paper proposes to examine the effect of elders’ healthcare accessibility on property prices of Taipei Metropolis, Taiwan. Design/methodology/approach Luo and Qi’s (2009) enhanced two-step floating catchment area method – taking both healthcare demand and supply into account – was used to measure three types of healthcare services: “physician-to-elder ratio”, “hospital bed-to-elder ratio” and “ambulance-to-elder ratio”. Spatial quantile regression (SQR) model was then used to examine the spatial effect of healthcare accessibility on different property price ranges. Findings The “physician-to-elder ratio” and “hospital bed-to-elder ratio” demonstrated expected consistent positive effects across all quantiles of property prices (p < 0.01) in SQR, and its effects aggravated as the quantiles of property prices rose. The “ambulance-to-elder ratio” demonstrated a non-linear influence on property prices (i.e. a negative effect on lowest quantile prices but a positive on higher quantile prices) possibly due to the semi-obnoxious characteristic of the ambulance. That is, residents living in lower priced neighbourhoods may dislike ambulances’ annoying sound of sirens (i.e. ambulances’ disamenity), while residents living in higher valued neighbourhoods may on the contrary appreciate ambulances’ healthcare services (i.e. amenity). Practical implications These findings are expected to offer some insights for government’s policies in providing elders in their later years with good residential quality and easy access to healthcare resource. Originality/value This paper is one of the few studies that consider the capitalization of the spatial healthcare accessibility to elders into property prices. In this ageing trend across the globe, although all the accessibility to medical resources should be equally critical, the application of spatial quantile regression revealed residents’ inconsistent tendency against semi-obnoxious ambulances. It provides a different perspective in defining the importance of healthcare accessibility in neighbourhoods.

Background Cardiovascular diseases (CVDs) are related to particulate matter (PM 2.5 ) exposure. Researchers have not clearly determined whether hyperglycemia, a hallmark of diabetes, exacerbates PM 2.5 -induced endothelial damage. Thus, this study aimed to investigate the combined effects of PM 2.5 and high glucose on endothelial damage. Results Here, we treated human umbilical vein endothelial cells (HUVECs) with 30 mM high glucose and 50 μg/mL PM (HG + PM) to simulate endothelial cells exposed to hyperglycemia and air pollution. First, we showed that HUVECs exposed to PM under high glucose conditions exhibited significant increases in cell damage and apoptosis compared with HUVECs exposed to PM or HG alone. In addition, PM significantly increased the production of reactive oxygen species (ROS) in HUVECs and mitochondria treated with HG and decreased the expression of superoxide dismutase 1 (SOD1), a free radical scavenging enzyme. The coexposure group exhibited significantly increased ROS production in cells and mitochondria, a lower mitochondrial membrane potential, and increased levels of the autophagy-related proteins p62, microtubule-associated protein 1 light chain 3β (LC3B), and mitophagy-related protein BCL2 interacting protein 3 (Bnip3). Moreover, autophagosome-like structures were observed in the HG + PM group using transmission electron microscopy. The expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were also increased through the JNK/p38 signaling pathway in the HG + PM group. As a ROS scavenger, vitamin D treatment effectively protected cells under HG and PM conditions by increasing cell viability, reducing mitochondrial ROS production, and suppressing the formation of mitophagy and inflammation. Furthermore, diabetes was induced in mice by administering streptozotocin (STZ). Mice were treated with PM by intratracheal injection. Vitamin D effectively alleviated oxidative stress, mitophagy, and inflammation in the aortas of mice treated with STZ and PM. Conclusion Taken together, simultaneous exposure to PM and high glucose exerts significant harmful effects on endothelial cells by inducing ROS production, mitophagy, and inflammation, while vitamin D reverses these effects.

Staphylococcus aureus (S. aureus) is one of the most common causes of biofilm infections in periprosthetic joint infections (PJIs). Accumulating evidence has shown that the immunosuppressive environment established by S. aureus biofilm infection in PJIs involves the presence of myeloid-derived suppressor cells (MDSCs) and M2-macrophages. Due to the diversity of MDSCs, little is known about whether S. aureus biofilm preferentially expands specific MDSC subsets or whether MDSCs can further differentiate into M2-macrophages during S. aureus biofilm infection. Here, we show that in agreement with the results from an established rat PJI model, S. aureus biofilm cocultured with freshly isolated bone marrow cells (BMCs) in vitro significantly increases the proportions of MDSCs, total macrophages and M2-macrophages. Interestingly, we find that treatment of the BMCs in vitro with S. aureus biofilm preferentially promotes the expansion of monocytic MDSCs but not granulocytic MDSCs. Biofilm treatment also substantially enhances the overall MDSC immunosuppressive activity in addition to the MDSC expansion in vitro. Importantly, we provide evidence that S. aureus biofilm is capable of further stimulating the conversion of monocytic MDSCs into M2-macrophages in vitro and in vivo. Collectively, our studies reveal a direct link between MDSCs and M2-macrophages occurring in S. aureus-associated PJIs.

Necrotizing fasciitis (NF) of the limbs caused by Aeromonas species is an extremely rare and life-threatening skin and soft tissue infection. The purpose of this study was to evaluate the specific characteristics and the independent predictors of mortality in patients with Aeromonas NF. Sixty-eight patients were retrospectively reviewed over an 18-year period. Differences in mortality, demographics data, comorbidities, symptoms and signs, laboratory findings, microbiological analysis, empiric antibiotics treatment and clinical outcomes were compared between the non-survival and the survival groups. Twenty patients died with the mortality rate of 29.4%. The non-survival group revealed significant differences in bacteremia, monomicrobial infection, cephalosporins resistance, initial ineffective empiric antibiotics usage, chronic kidney disease, chronic hepatic dysfunction, tachypnea, shock, hemorrhagic bullae, skin necrosis, leukopenia, band polymorphonuclear neutrophils >10%, anemia, and thrombocytopenia. The multivariate analysis identified four variables predicting mortality: bloodstream infection, shock, skin necrosis, and initial ineffective empirical antimicrobial usage against Aeromonas . NF caused by Aeromonas spp. revealed high mortality rates, even through aggressive surgical debridement and antibacterial therapies. Identifying those independent predictors, such as bacteremia, shock, progressive skin necrosis, monomicrobial infection, and application of the effective antimicrobial agents against Aeromonas under the supervision of infectious doctors, may improve clinical outcomes.

Due to the multiple influences of unique physicochemical properties of helium, petrographic characteristics and temperature and pressure conditions, little is known about the helium adsorption behaviors in minerals and rocks at geological conditions. Based on the grand canonical Monte Carlo simulations, this study revealed the adsorption characteristics of pure helium and the competitive adsorption of binary mixtures with different proportions of methane and helium under geological temperature and pressure conditions in quartz slit model. Molecular simulation of pure helium shows that physical adsorption of helium exists in mineral surfaces, which indicates a preservation mechanism of helium in helium source rocks. Binary mixtures simulations indicate that the adsorption capacity of methane in quartz is stronger than that of helium, and the competitive adsorption of methane increases with decreasing burial depth. This means that during the upwards migration processes of natural gas, the adsorbed helium that distributed in the migration pathway will be gradually displaced by methane, then concentrate in the hydrocarbon gases and subsequently accumulate together in favorable traps to form helium-rich natural gas reservoirs. Our results provide a molecular-scale insight into the preservation and accumulation of helium in helium source rocks and are significant for assessing the helium resource potential.

The aim of this study is to reveal the clinical and histopathological features of HBsAg-positive and HBeAg-positive chronic hepatitis B infected patients with high level of HBV DNA, from 17 hospitals and medical centres in China, with alanine aminotransferase levels within the lower region of normal range versus those with levels within the upper region of normal range and to investigate the clinical risk factors for the requirement of treatment through the examination of liver biopsy. Liver biopsy was performed on high level of HBV DNA of 455 patients with HBsAg-positive and HBeAg-positive chronic hepatitis B infection and persistently normal alanine aminotransferase level. Liver necroinflammation and fibrosis were graded per the Knodell histological activity index and Ishak's fibrosis score, respectively. Univariate analysis of the clinical parameters versus necroinflammation and fibrosis was carried out. Of the subjects in this multicentre-based study, 5.49% and 10.11% had significant necroinflammation with Knodell histological activity index ≥ 9 and hepatic fibrosis stages with Ishak scores ≥ 3, respectively. The subjects were stratified into three age groups (30-39, 40-49 and ≥ 50 years), and our data clearly suggested that age, particularly in the age group over 50, was an independent predictor of liver necroinflammation and fibrosis. Lower HBV-DNA viral levels were found in patients with Knodell histological activity index ≥ 9 or advanced fibrosis (Ishak scores ≥ 3). Our results showed that histological changes in liver tissues were observed in a significant proportion of patients with persistently normal alanine aminotransferase level. According to the data evaluation results, liver biopsy is advisable for HBeAg-positive chronic hepatitis B infected patients aged older than 40 and high HBV-DNA viral load in China.

The proximal humerus fracture (PHF) is the third most common fragility fracture. Diabetes mellitus (DM) and chronic kidney disease (CKD) are both risks for fragility fractures; however, the interplay of DM and CKD makes treatment outcomes unpredictable. This study aimed to investigate and compare early and late outcomes following proximal humerus fracture fixation surgery in diabetic patients with different renal function conditions. DM patients receiving PHF fixation surgery during 1998-2013 were recruited from Taiwan's National Health Insurance Research Database. According to their renal function, patients were divided into three study groups: non-chronic kidney disease (CKD), non-dialysis CKD, and dialysis. Outcomes of interest were early and late perioperative outcomes. Early outcomes included in-hospital newly-onset morbidities. Late outcomes included infection, revision, readmission, and all-cause mortality. This study included a total of 10,850 diabetic patients: 2152 had CKD (non-dialysis CKD group), 196 underwent permanent dialysis (dialysis group), and the remaining 8502 did not have CKD (non-CKD group). During a mean follow-up of 5.56 years, the dialysis group showed the highest risk of overall infection, all-cause revision, readmission, and mortality compared to the non-dialysis CKD group and non-CKD group. Furthermore, subgroup analysis showed that CKD patients had a higher risk of surgical infection following PHF surgery than non-CKD patients in cases with a traffic accident or fewer comorbidities (Charlson Comorbidity Index, CCI <3) (P for interaction: 0.086 and 0.096, respectively). Also, CKD patients had an even higher mortality risk after PHF surgery than non-CKD patients, in females, those living in higher urbanization areas, or with more comorbidities (CCI ≥3) (P for interaction: 0.011, 0.057, and 0.069, respectively). CKD was associated with elevated risks for infection, revision, readmission, and mortality after PHF fixation surgery in diabetic patients. These findings should be taken into consideration when caring for diabetic patients.

The increasing popularity of small drones has stressed the urgent need for an effective drone‐oriented surveillance system that can work day and night. Herein, an acoustic and optical sensor‐fusion‐based system‐termed multimodal unmanned aerial vehicle 3D trajectory exposure system (MUTES) is presented to detect and track drone targets. MUTES combines multiple sensor modules including microphone array, camera, and lidar. The 64‐channel microphone array provides semispherical surveillance with high signal‐to‐noise ratio of sound source estimation, while the long‐range lidar and the telephoto camera are capable of subsequent precise target localization in a narrower but higher definition field of view. MUTES employs a coarse‐to‐fine, passive‐to‐active localization strategy for wide‐range detection (semispherical) and high‐precision 3D tracking. To further increase the fidelity, an environmental denoising model is trained, which helps to select valid acoustic features from a drone target, thus overcomes the drawbacks of the traditional sound source localization approaches when facing noise interference. The effectiveness of the proposed sensor‐fusion approach is validated through field experiments. To the best of the knowledge, MUTES provides the farthest detection range, highest 3D position accuracy, strong anti‐interference capability, and acceptable cost for unverified drone intruders. Noncooperative micro unmanned aerial vehicles (UAVs) bring potential threats to public security and citizens’ privacy. A system‐termed multimodal UAV 3D trajectory exposure system integrating a 64‐channel microphone array, a camera, and a lidar is devised to provide a wide range detection (90° × 360°) and high‐precision (<0.8° at 180 m) 3D tracking for UAVs.

Although ubiquitin-conjugating enzymes are critical regulators of cellular function and fate, their roles in tumorigenesis remain incompletely defined. Here, we provide genetic and molecular evidence that the Ubiquitin-Conjugating Enzyme E2 D3 (UBE2D3) is specifically overexpressed in cancerous pancreatic ductal cells, including early-stage pancreatic intraepithelial neoplasia and advanced pancreatic ductal adenocarcinoma (PDAC). This overexpression is independent of oncogenic KRAS status and is driven by the inflammatory tumor microenvironment, particularly interferon-γ (IFN-γ). Mechanistically, UBE2D3 binds the ubiquitin ligase Kelch Like Family Member 13 (KLHL13) to mediate K63-linked polyubiquitination at lysine 245 of transporter 2 (TAP2), resulting in steric hindrance that blocks the transporter. Genetic or pharmacologic inhibition of UBE2D3 enhances antigen presentation in cancer cells and restores CD8 + T-cell-mediated tumor surveillance in pancreatic cancer models in male mice. Furthermore, combining an UBE2D3 small-molecule inhibitor with KRAS G12D -specific TCR-T-cell therapy yields synergistic antitumor effects. Our findings reveal a negative feedback mechanism in which cancer cells, “camouflaging” themselves, evade IFN-γ-induced antigen presentation via UBE2D3 upregulation, highlighting a potential therapeutic target for enhancing antitumor immunity. Ubiquitin-conjugating enzymes (E2s), including UBE2D3, are important regulator of cellular function and fate. Here the authors report that IFN-y driven upregulation of UBE2D3 is associated with impaired antigen presentation in pancreatic cancer, also showing that its targeting enhances antitumor immunity.