Search

Abstract Chronic hepatitis C virus (HCV) infection is an important public health issue. However, knowledge on how the virus remodels the metabolic and immune response toward hepatic pathologic environment is limited. The transcriptomic and multiple evidences reveal that the HCV core protein–intestine‐specific homeobox (ISX) axis promotes a spectrum of metabolic, fibrogenic, and immune modulators (e.g., kynurenine, PD‐L1, and B7‐2), regulating HCV‐infection relevant pathogenic phenotype in vitro and in vivo. In a transgenic mice model, the HCV core protein–ISX axis enhance metabolic disturbance (particularly lipid and glucose metabolism) and immune suppression, and finally, chronic liver fibrosis in a high‐fat diet (HFD)‐induced disease model. Mechanistically, cells with HCV JFH‐1 replicons upregulate ISX and, consequently, the expressions of metabolic, fibrosis progenitor, and immune modulators via core protein‐induced nuclear factor‐κB signaling. Conversely, cells with specific ISX shRNAi inhibit HCV core protein‐induced metabolic disturbance and immune suppression. Clinically, the HCV core level is significantly correlated with ISX, IDOs, PD‐L1, and B7‐2 levels in HCC patients with HCV infection. Therefore, it highlights the significance of HCV core protein–ISX axis as an important mechanism in the development of HCV‐induced chronic liver disease and can be a specific therapeutic target clinically.

BackgroundFew studies assess cord blood biomarkers to predict prenatal exposure to di(2-ethylhexyl) phthalate (DEHP) on the development of allergic diseases later in childhood. IL-33 has been indicated to play an important role in allergic diseases. We evaluated the association of prenatal DEHP exposure and IL-33 in cord blood on the development of allergic diseases. We also investigated the mechanism of DEHP in human lung epithelial cells and asthma animal models.Methods66 pregnant women were recruited, and their children followed when they were aged 3 years. Maternal urinary DEHP metabolites were determined using liquid chromatography-electrospray-ionization-tandem mass spectrometry. The effect of DEHP on IL-33 production was investigated in human lung epithelial cells and club cell-specific aryl hydrocarbon receptor (AhR) deficiency mice. ELISA and RT-PCR, respectively, measured the IL-33 cytokine concentration and mRNA expression.ResultsThe concentrations of maternal urinary DEHP metabolites and serum IL-33 in cord blood with childhood allergy were significantly higher than those in the non-childhood allergy group. DEHP and MEHP could induce IL-33 production and reverse by AhR antagonist and flavonoids in vitro. Enhanced ovalbumin-induced IL-4 and IL-33 production in bronchoalveolar lavage fluid (BALF) by DEHP exposure and suppressed in club cell-specific AhR null mice. Kaempferol has significantly reversed the DEHP effect in the asthma animal model.ConclusionsCord blood IL-33 level was correlated to childhood allergy and associated with maternal DEHP exposure. IL-33 might be a potential target to assess the development of DEHP-related childhood allergic disease. Flavonoids might be the natural antidotes for DEHP.

Acute lymphoblastic leukaemia (ALL) is the most prevalent cancer in children, and excessive iron buildup resulting from blood transfusions and chemotherapy potentially has a negative impact on treatment outcomes and prognosis in patients with ALL. Therefore, initiating early iron chelation therapy during ALL treatment is a logical approach. Ideally, the selected iron chelator should also possess anti-leukaemia properties. The aim of the present study was to explore the potential impact and underlying mechanism of deferasirox (DFX) in ALL therapy. This study proved that DFX, an iron chelator, is capable of inducing leukaemia cell death through ferroptosis, which is achievable by increasing the expression of acetylated nuclear factor erythroid 2-related factor 2 (NRF2). More specifically, NRF2 acetylation on Lys599 was facilitated by acetyltransferase-p300/CBP. These findings indicate that DFX could serve as a potent adjunctive medication for patients with ALL. Moreover, DFX may offer dual benefits in ALL treatment, functioning as both an iron chelator and NRF2-modulating agent. Further research and clinical trials are necessary to fully elucidate the therapeutic potential of DFX in patients with ALL and incorporate it into treatment protocols.

There is growing concern regarding air pollutants (NOx, SOx, and PM) and carbon emissions from ocean-going vessels in harbor areas and the role of high-voltage shore connection (HVSC) systems in mitigating these emissions during vessel berthing. The HVSC operates as a TN grounding system in humid environments, and it needs a proper grounding design to ensure safety when faults occur. This article intends to examine the overvoltage resulting from fault currents and its implications for the safety of operators when a single line-to-ground fault takes place within the design of HVSC grounding systems. The assessment is carried out by employing actual scenarios and parameters from a container berth at Kaohsiung Harbor in Taiwan. Considering site conditions, such as the wet ground surface, human body resistance, and electric shock duration, the tolerable safe voltage level is derived using IEEE Std. 80 and IEC 60479-1. Based on the shore power system grounding architecture specified in IEEE/IEC 80005-1, an equivalent circuit model is constructed to calculate the fault currents using symmetrical component analysis. The actual touch voltages generated in various locations are analyzed under scenarios of connecting or disconnecting the equipotential bonding between the ship and the shore using neutral grounding resistor (NGR) designs. This article delves into the scenarios of electric shock that may occur during the operation of an actual container ship’s shore power system. It evaluates whether various contact voltage values exceed current international standards and verifies the grounding design and safety voltage specifications of IEEE/IEC 80005-1. According to the results of this study, the use of NGR and protective earthed neutral (PEN) conductors in HVSC is crucial. This can limit fault currents, reduce touch voltage, and ensure the safety of personnel and equipment. Therefore, ensuring and monitoring equipment conductors and adopting NGRs of appropriate sizes are crucial elements in maintaining electrical safety in HVSC systems.

This paper addresses the growing concern over air pollutant emissions (NOx, SOx, PM, CO2) from ocean-going vessels in harbor areas and the role of Onshore Power Supply (OPS) systems in mitigating these emissions during vessel berthing. However, the slow progress in global shore power facilities is attributed to safety- and specification-related concerns. Our study conducts a comprehensive analysis, comparing international shore power regulations, with a specific focus on the IEC/IEEE 80005-1 standard and guidelines from various ship classification societies. We introduce checklists, scoring tables, and spider diagrams to evaluate the regulatory content, highlighting the strengths and weaknesses of each approach. Furthermore, this paper emphasizes the significance of a well-defined operational process for high-voltage shore connection (HVSC) to ensure the safety of OPS operations. We present process diagrams for key operational stages, based on IEC/IEEE 80005-1 specifications and evaluation criteria. The ultimate goal of this research is to drive the global adoption of shore power and foster the establishment of shore power facilities worldwide. This aligns with the broader environmental protection objectives of achieving cleaner ports and reducing emissions for a sustainable future.

Abstract Epigenetic regulation is important for cancer tumor metastasis and progression, including lung and liver cancer. However, the mechanism of epigenetic regulation in liver cancer leaves much to be discussed. According to a previous study, p300/CBP‐associated factor (PCAF) mediated epithelial–mesenchymal transition (EMT) and promotes cancer metastasis by recruiting intestine‐specific homeobox (ISX) and bromodomain‐containing protein 4 (BRD4) in lung cancer. To figure out whether the three genes are also expressed in patients with hepatocellular carcinoma (HCC) or not, and their correlation with patients’ outcome, BRD4, PCAF, and ISX messenger RNA (mRNA) expression levels in 377 patients with HCC were investigated using quantitative polymerase chain reaction and confocal fluorescence imaging. The correlation of the gene expression (PCAF, ISX, and BRD4) in liver cancer is also being investigated. Here, we show that the mRNA expression of PCAF, BRD4, and ISX in 377 paired specimens from patients with HCC, and the adjacent normal tissues exhibited a tumor‐specific expression pattern, highly correlated with disease pathogenesis, patient survival time, progression stage, and poor prognosis. The results show that ISX and BRD4 can potentially be a target for improving the survival rate.

Social media has become a vital source of communication for older adults, but its impact is still an ongoing debate. This study investigated the moderating effect of Line and Facebook use on social capital and loneliness in older adults, aged 55 or more, using data obtained from the 2018 Taiwan Communication Survey (TCS). Results from binary logistic regression indicated that older adult users of Line have a lower possibility of being lonely than those who do not use Line. Consistent with past studies, this study found that Line could be a form of social media that has a positive effect on the relationship between social capital and loneliness. Conversely, this article argues that Facebook does not have such a moderation effect. Overall, this study advances understanding of the impact of Facebook and Line on social capital and loneliness. The results are informative for future research on the effects of social media on the elderly.

This paper describes the non-contact optical detection of debris material that adheres to the substrates of color filters (CFs) and thin-film transistors (TFTs) by area charge-coupled devices (CCDs) and laser sensors. One of the optical detections is a side-view illumination by an area CCD that emits a coherency light to detect debris on the CF. In contrast to the height of the debris material, the image is acquired by transforming the geometric shape from a square to a circle. As a result, the side-view illumination from the area CCD identified the height of the debris adhered to the black matrix (BM) as well as the red, green, and blue of a CF with 95, 97, 98, and 99% accuracy compared to the golden sample. The uncertainty analysis was at 5% for the BM, 3% for the red, 2% for the green, and 1% for the blue. The other optical detection, a laser optical interception with a horizontal alignment, inspected the material foreign to the TFT. At the same time, laser sensors intercepted the debris on the TFT at a voltage of 3.5 V, which the five sets of laser optics make scanning the sample. Consequently, the scanning rate reached over 98% accuracy, and the uncertainty analysis was within 5%. Thus, both non-contact optical methods can detect debris at a 50 μm height or lower. The experiment presents a successful design for the efficient prevention of a valuable component malfunction.

Dengue virus (DENV) infection causes life-threatening diseases such as dengue hemorrhagic fever and dengue shock syndrome. Currently, there is no effective therapeutic agent or vaccine against DENV infection; hence, there is an urgent need to discover anti-DENV agents. The potential therapeutic efficacy of lucidone was first evaluated in vivo using a DENV-infected Institute of Cancer Research (ICR) suckling mouse model by monitoring body weight, clinical score, survival rate, and viral titer. We found that lucidone effectively protected mice from DENV infection by sustaining survival rate and reducing viral titers in DENV-infected ICR suckling mice. Then, the anti-DENV activity of lucidone was confirmed by western blotting and quantitative-reverse-transcription-polymerase chain reaction analysis, with an EC50 value of 25 ± 3 μM. Lucidone significantly induced heme oxygenase-1 (HO-1) production against DENV replication by inhibiting DENV NS2B/3 protease activity to induce the DENV-suppressed antiviral interferon response. The inhibitory effect of lucidone on DENV replication was attenuated by silencing of HO-1 gene expression or blocking HO-1 activity. In addition, lucidone-stimulated nuclear factor erythroid 2-related factor 2 (Nrf2), which is involved in transactivation of HO-1 expression for its anti-DENV activity. Taken together, the mechanistic investigations revealed that lucidone exhibits significant anti-DENV activity in in vivo and in vitro by inducing Nrf2-mediated HO-1 expression, leading to blockage of viral protease activity to induce the anti-viral interferon (IFN) response. These results suggest that lucidone is a promising candidate for drug development.

Multiple sclerosis (MS) is a chronic autoimmune disease mainly caused by autoreactive T cells, followed by neuronal demyelination and disabling paralysis. Hyperbaric oxygen therapy (HBOT) is usually an adjunct to therapy for the treatment of neurological disorders. However, it remains still controversial whether HBOT is an effective option for the treatment of MS. Experimental autoimmune encephalomyelitis (EAE) is a well-studied mouse model investigated for the MS pathogenesis and the efficacy of the therapeutic intervention. Both encephalitogenic Th1 and Th17 are pivotal T cell subsets immunopathogenically producing several disease-initiating/modifying cytokines in the central nervous system (CNS) lesions to further exacerbate/ameliorate the progression of EAE or MS. However, it remains unclear whether HBOT modulates the context of T helper cell subsets in CNS lesions. We employed EAE in the presence of HBOT to assess whether disease amelioration is attributed to alterations of CNS-infiltrating T cell subsets. Our results demonstrated that semi-therapeutic HBOT significantly alleviated the progression of EAE, at least, via the suppression of Th17 response, the downregulation of CD4 T helper cells expressing GM-CSF or TNF-α, and the boosting of immunomodulatory IL-4 or IL-10-expressed CD4 T cells in the CNS lesions. Conclusively, HBOT attenuated EAE through the modulation of T cell responses in an earlier stage.

In this study, we developed a high-resolution, more accurate, non-destructive apparatus for refining the detection of electrode pixels in a thin-film-transistor liquid-crystal display (TFT-LCD). The hybrid optoelectronic apparatus simultaneously uses an array tester linked with the automatic optical inspection of panel defects. Unfortunately, due to a tiny air gap in the electro-optical inspector, the situation repeatedly causes numerous scratches and damages to the modulator; therefore, developing alternative equipment is necessary. Typically, in TFT-LCDs, there are open, short, and cross short electrical defects. The experiment utilized a multiple-line scan with the time delay integration (TDI) of a charge-coupled device (CCD) to capture a sharp image, even under low light, various speeds, or extreme conditions. In addition, we explored the experimental efficacy of detecting the electrode pixel of the samples and evaluated the effectiveness of a 7-inch opaque quartz mask. The results show that an array tester and AOI can detect a TFT-LCD electrode pixel sufficiently; therefore, we recommend adopting the hybrid apparatus in the TFT-LCD industry.

This paper explores the effectiveness of the white, red, green, and blue light emitted diodes (LEDs) light sources to detect the third layer of the electrode pixel and the fourth layer of the via-hole passivation on thin-film transistors. The time-delay-integration charge-coupled device and a reflective spectrometer were implemented in this experiment. The optical conditions are the same, as each light source and the digital image’s binary method also recognize the sharpness and contrast in the task. Consequently, the white and the blue LED light sources can be candidates for the light source for the optical inspection, especially for monochromic blue LED’s outperformance among the light sources. The blue LED demonstrates the high spatial resolution and short wavelength’s greater energy to trigger the photosensor. Additionally, the metal material has shown a tremendous responsibility in the photosensor with 150 Dn/nj/cm2 over the sensibility. The mercury 198Hg-pencil discharge lamp emits the stable spectral wavelength to significantly calibrate the spectrometer’s measurement.

Resistance to chemotherapeutic drugs is one of the major challenges in the treatment of cancer. A better understanding of how resistance arises and what molecular alterations correlate with resistance is the key to developing novel effective therapeutic strategies. To investigate the underlying mechanisms of gemcitabine (Gem) resistance and provide possible therapeutic options, three Gem-resistant urothelial carcinoma sublines were established (NG0.6, NG0.8, and NG1.0). These cells were cross-resistant to arabinofuranosyl cytidine and cisplatin, but sensitive to 5-fluorouracil. The resistant cells expressed lower values of [hENT1 × dCK/RRM1 × RRM2] mRNA ratio. Two adenosine triphosphate-binding cassette proteins ABCD1 as well as multidrug resistance protein 1 were elevated. Moreover, cyclin D1, cyclin-dependent kinases 2 and 4 were upregulated, whereas extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase (MAPK) activity were repressed significantly. Administration of p38 MAPK inhibitor significantly reduced the Gem sensitivity in NTUB1 cells, whereas that of an extracellular signal-regulated kinase MAPK inhibitor did not. Furthermore, the Gem-resistant sublines also exhibited higher migration ability. Forced expression of p38 MAPK impaired the cell migration activity and augmented Gem sensitivity in NG1.0 cells. Taken together, these results demonstrate that complex mechanisms were merged in acquiring Gem resistance and provide information that can be important for developing therapeutic targets for treating Gem-resistant tumors.

Spinal muscular atrophy (SMA) is a lethal hereditary disease caused by homozygous absence of the survival of the motor neuron (SMN) 1 gene (SMN1), and it is the leading genetic cause of infant mortality. The severity of SMA is directly correlated with SMN protein levels in affected patients; however, the cellular regulatory mechanisms for SMN protein expression are not completely understood. In this study, we investigated the regulatory effects between SMN expression and miR-9a, a downstream noncoding small RNA. Using an inducible SMN short hairpin RNA interference (shRNAi) system in NSC 34 and human skin fibroblast cells, cellular miR-9 levels and SMN protein repression were time-dependently upregulated. Conversely, cellular miR-9 levels decreased when HeLa cells were transfected with SMN protein fused with green fluorescent protein. In SMA-like mice spinal cords and human primary skin fibroblasts isolated from patients with different degrees of SMA, human SMN exhibited a disease severity-dependent decrease, whereas cellular miR-9 levels increased. These results clearly suggested that cellular SMN proteins regulated miR-9 expression and that miR-9 expression was related to SMA severity. Thus, miR-9 may be a marker for SMA prognosis.

Wntless (GPR177) protein is a newly identified regulator of Wnt signals in Drosophila, but its cellular function in mammals is still unclear. In this study, we explored the expression pattern and potential cellular function of Wntless in mammalian cells. Wntless mRNA was expressed in many mouse tissues, including the spleen, lung, kidney, thymus, and stomach, and lower levels of expression were detected in the mouse brain and testis. Expression of Wntless protein analyzed by Western blot and immunohistochemical staining was only detected in the submucosa, muscle, ganglia, and nerve cells of murine large intestines. Both immunofluorescence staining and subcellular fraction extraction analysis revealed that endogenous Wntless protein was expressed predominantly in the cytoplasmic organelles with a morphologically dot-shaped distribution. Furthermore, overexpression of Wntless could be corrected by and may activate the nuclear factor-κB (NF-κB) signaling pathway in cancer (HeLa) cells. These results suggest that Wntless plays a role in signaling regulation during the formation of cancer in addition to its role as a retromer protein in mammalian systems.

Chronic hepatitis C virus (HCV) infection leads to intrahepatic inflammation and liver cell injury, which are considered a risk factor for virus-associated hepatitis, cirrhosis, and hepatocellular carcinoma worldwide. Inflammatory cytokines are critical components of the immune system and influence cellular signaling, and genetic imbalances. In this study, we found that cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) were significantly induced by HCV infection and HCV NS5A expression, and induction of COX-2 correlated with HCV-induced IL-8 production. We also found that the ERK and JNK signaling pathways were involved in the regulation of IL-8-mediated COX-2 induction in response to HCV infection. Using a promoter-linked reporter assay, we identified that the C/EBP regulatory element within the COX-2 promoter was the dominant factor responsible for the induction of COX-2 by HCV. Silencing C/EBP attenuated HCV-induced COX-2 expression. Our results revealed that HCV-induced inflammation promotes viral replication, providing new insights into the involvement of IL-8-mediated COX-2 induction in HCV replication.

BACKGROUND: Ambient particulate matter with an aerodynamic diameter of ≤ 2.5 μm (PM2.5) is suggested to act as an adjuvant for allergen-mediated sensitization and recent evidence suggests the importance of T follicular helper (Tfh) cells in allergic diseases. However, the impact of PM2.5 exposure and its absorbed polycyclic aromatic hydrocarbon (PAHs) on Tfh cells and humoral immunity remains unknown. OBJECTIVES: We aimed to explore the impact of environmental PM2.5 and indeno[1,2,3-cd]pyrene (IP), a prominent PAH, as a model, on Tfh cells and the subsequent pulmonary allergic responses. METHODS: PM2.5- or IP-mediated remodeling of cellular composition in lung lymph nodes (LNs) was determined by mass cytometry in a house dust mite (HDM)-induced mouse allergic lung inflammation model. The differentiation and function of Tfh cells in vitro were analyzed by flow cytometry, quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, chromatin immunoprecipitation, immunoprecipitation, and western blot analyses. RESULTS: Mice exposed to PM2.5 during the HDM sensitization period demonstrated immune cell population shifts in lung LNs as compared with those sensitized with HDM alone, with a greater number of differentiated Tfh2 cells, enhanced allergen-induced immunoglobulin E (IgE) response and pulmonary inflammation. Similarly enhanced phenotypes were also found in mice exposed to IP and sensitized with HDM. Further, IP administration was found to induce interleukin-21 (Il21) and Il4 expression and enhance Tfh2 cell differentiation in vitro, a finding which was abrogated in aryl hydrocarbon receptor (AhR)-deficient CD4+ T cells. Moreover, we showed that IP exposure increased the interaction of AhR and cellular musculoaponeurotic fibrosarcoma (c-Maf) and its occupancy on the Il21 and Il4 promoters in differentiated Tfh2 cells. DISCUSSION: These findings suggest that the PM2.5 (IP)–AhR–c-Maf axis in Tfh2 cells was important in allergen sensitization and lung inflammation, thus adding a new dimension in the understanding of Tfh2 cell differentiation and function and providing a basis for establishing the environment–disease causal relationship. [ABSTRACT FROM AUTHOR]

Chronic inflammation drives initiation of hepatocellular carcinoma (HCC), but the underlying mechanisms linking inflammation and tumor formation remain obscure. In this study, Xenograft tumor assay was used to determine the tumorigenic activity of hepatoma cells with ISX over expression on nude mice in vivo.

Chronic inflammation drives initiation of hepatocellular carcinoma (HCC), but the underlying mechanisms linking inflammation and tumor formation remain obscure. In this study, soft agar anchorage-independent assay were used to determine tumor transform activity of hepatoma cells with ISX over expression or knockdown in vitro.