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Background Chronic Obstructive Pulmonary Disease (COPD) remains a significant public health challenge due to its high morbidity and mortality rates. Emerging research has identified eosinophilic inflammation as a crucial factor in the pathogenesis and exacerbation of COPD, warranting a detailed exploration of its underlying mechanisms and therapeutic implications.Objective This review aims to elucidate the role of eosinophils in COPD, focusing on their contribution to airway remodeling, exacerbation frequency, and the inflammatory cascade.Methods We conducted a comprehensive literature review of recent studies that discuss the pathophysiological role of eosinophils in COPD and the clinical outcomes associated with modulating eosinophilic activity.Results Eosinophils contribute to COPD progression by releasing cytotoxic proteins and cytokines that intensify the inflammatory response and airway alterations. Targeting specific eosinophil-related cytokines with monoclonal antibodies or receptor antagonists may potentially reduce eosinophil counts, mitigate exacerbations, and improve patient outcomes.Conclusion Understanding eosinophilic involvement in COPD can facilitate the development of precision medicine approaches, offering more tailored and effective treatment options. Future research should continue to focus on the integration of eosinophil biomarkers in clinical practice to enhance therapeutic decisions and management strategies for COPD patients.

This study aimed to measure personal exposure to sulfuric acid in the electroplating industry to establish a predictive model and test its validation. We collected indoor air parameters and related information from four electroplating plants. Silica gel sorbents were used to collect air samples using high-performance ion chromatography. We collected air samples from three plants (i.e., Plant B, Plant C, and Plant D) and applied multiple linear regressions to build a predictive model. Eight samples collected from the fourth plant (i.e., Plant A) were used to validate the model. A total of 41 samples were collected with a mean of 25.0 ± 9.8 μg/m3 (range 12.1–51.7 μg/m3) in this study, including Plant A (8 samples, 17.5 ± 2.8 μg/m3, 13.0–22.0 μg/m3), Plant B (11 samples, 36.5 ± 9.7 μg/m3, 23.1–51.7 μg/m3), Plant C (11 samples, 16.4 ± 1.7 μg/m3, 12.1–17.8 μg/m3), and Plant D (11 samples, 27.4 ± 1.7 μg/m3, 24.1–29.9 μg/m3). Plant B was significantly higher in sulfuric acid than the other plants. Workers from the electroplating process plants were exposed to sulfuric acid at 29.0 ± 11.5 μg/m3. The predictive model for personal exposure to sulfuric acid fit the data well (r2 = 0.853; adjusted r2 = 0.837) and had an accuracy of 5.52 μg/m3 (bias ± precision; 4.98 ± 2.38 μg/m3), validated by the personal sampling of the fourth plant. This study observed that sulfuric acid exposure was lower than the permissible exposure level of 1000 μg/m3 in Taiwan and the United States, and only two samples were lower than the European Union standard of 50 μg/m3. The developed model can be applied in epidemiological studies to predict personal exposure to sulfuric acid in plants using electroplating.

The Internet of Things (IoT) and low-cost sensor technology have become common tools for environmental exposure monitoring; however, their application in measuring respirable dust (RD) in the workplace remains limited. This study aimed to develop a predictive model for RD using artificial intelligence (AI) algorithms and low-cost sensors and subsequently assess its validity using a standard sampling approach. Various low-cost sensors were combined into an RD sensor module and mounted on a portable aerosol monitor (GRIMM 11-D) for two weeks. AI algorithms were used to capture data per minute over 14 days to establish predictive RD models. The best-fitting model was validated using an aluminum cyclone equipped with an air pump and polytetrafluoroethylene filters to sample the 8-hour RD for 5 days at an aircraft manufacturing company. This module was continuously monitored for two weeks to evaluate its stability. The RD concentration measured by GRIMM 11-D in a general outdoor environment over two weeks was 28.1 ± 16.1 μg/m3 (range: 2.4–85.3 μg/m3). Among the various established models, random forest regression was observed to have the best prediction capacity (R2 = 0.97 and root mean square error = 2.82 μg/m3) in comparison to the other 19 methods. Field-based validation revealed that the predicted RD concentration (35.9 ± 4.1 μg/m3, range: 32.7–42.9 μg/m3) closely approximated the results obtained by the traditional method (38.1 ± 8.9 μg/m3, range: 28.1–52.5 μg/m3), and a strong positive Spearman correlation was observed between the two (rs = 0.70). The average bias was −2.2 μg/m3 and the precision was 5.8 μg/m3, resulting in an accuracy of 6.2 μg/m3 (94.2 %). Data completeness was 99.7 % during the continuous two-week monitoring period. The developed sensor module of RD exhibited excellent predictive performance and good data stability that can be applied to exposure assessments in occupational epidemiological studies.

AbstractThis review article delves into the multifaceted relationship between climate change, air quality, and respiratory health, placing a special focus on the process of particle deposition in the lungs. We discuss the capability of climate change to intensify air pollution and alter particulate matter physicochemical properties such as size, dispersion, and chemical composition. These alterations play a significant role in influencing the deposition of particles in the lungs, leading to consequential respiratory health effects. The review paper provides a broad exploration of climate change’s direct and indirect role in modifying particulate air pollution features and its interaction with other air pollutants, which may change the ability of particle deposition in the lungs. In conclusion, climate change may play an important role in regulating particle deposition in the lungs by changing physicochemistry of particulate air pollution, therefore, increasing the risk of respiratory disease development.

IntroductionExposure to road traffic noise has been reported to be associated with depression in many epidemiological studies, but the association between noise frequency spectrum and depression remains unclear. This community-based study investigated the associations between road traffic noise exposure and its frequency components with prevalent depression.MethodsA total of 3,191 residents living in Taichung who participated in the Taiwan Biobank between 2010 and 2017, were included as study participants. The land-use regression models were used to evaluate individual annual average values of A-weighted equivalent sound level over 24 h (Leq,24h) and particulate matter with an aerodynamic diameter

Sterol O-acyltransferase 1 (SOAT1, also named ACAT1) is an endoplasmic reticulum resident enzyme which catalyzes the esterification of cholesterol to generate cholesteryl esters. Here, authors report cryo-EM structures of human SOAT1 which reveal the binding site of the competitive inhibitor CI-976.

BackgroundAn association between thyroid disease and tinnitus has been described previously but further longitudinal, population-based studies are limited.ObjectiveTo investigate the incidence of tinnitus in patients with hyperthyroidism in a national sample, and to identify risk level and associated factors for tinnitus in hyperthyroidism patients.DesignRetrospective cohort study. Patient data were collected from the Longitudinal Health Insurance Database (LHID 2000), which includes national claims data of patient expenditures for admissions or ambulatory care from 1996 to 2011.SettingTaiwan hospitals and clinics providing healthcare nationwide.ParticipantsPatients aged 20 years and older with newly diagnosed hyperthyroidism (ICD-9-CM code 242) between 2000-2010 were selected as the study cohort. Hyperthyroidism patient cohort were identified from the LHID2000. Those with tinnitus history (ICD-9-CM code 388.3) before the index date (first hyperthyroidism diagnosis), younger than 20 years, and with incomplete demographic data were excluded. The non-hyperthyroidism cohort included patients with no history of hyperthyroidism and no documented tinnitus.Main Outcomes and MeasuresIncidence of tinnitus was the primary outcome. Baseline demographic factors and comorbidities possibly associated with tinnitus, including age, sex, and comorbidities of hearing loss, vertigo, insomnia and anxiety, were retrieved from the LHID 2000. Patients were followed until end of 2011.ResultsDuring the study period, 780 (4.9%) hyperthyroidism patients and 2007 (3.2%) non-hyperthyroidism controls developed tinnitus. Incidence rate of tinnitus in the hyperthyroidism cohort was significantly higher in hyperthyroidism cohort (7.86 vs. 5.05 per 1000 person-years) than that in non-hyperthyroidism cohort. A higher proportion of patients with hyperthyroidism had comorbid insomnia (45.1% vs. 30.9%) and anxiety (14.0% vs. 5.73%) than those without hyperthyroidism. After adjusting for age, gender and comorbidities (vertigo, insomnia, anxiety, hearing loss), hyperthyroidism patients had 1.38-fold higher risk of tinnitus (95% CI = 1.27-1.50) than those without hyperthyroidism.ConclusionsThis large population-based study suggests patients with diagnosed hyperthyroidism was more prone to develop tinnitus. Our findings suggest evaluation for comorbid vertigo, insomnia, anxiety and/or hearing loss may identify patients who are at high risk of developing tinnitus in patients with hyperthyroidism.

Abstract The aberrant expression of cell adhesion molecules is a hallmark of epithelial‐to‐mesenchymal transition, resulting in the transformation of cancer cells to a more aggressive phenotype. This study investigated the association between genetic variants in cell adhesion pathways and the prognosis of patients with prostate cancer following radical prostatectomy (RP). A total of 18 haplotype‐tagging single‐nucleotide polymorphisms (SNPs) in eight cancer‐related adhesion molecules were genotyped in 458 prostate cancer patients, followed by the replication of the top SNPs in an additional set of 185 patients. Log‐rank test and multivariate Cox regression analysis adjusted for covariates were used to evaluate associations with the risk of biochemical recurrence (BCR) after RP. In the discovery set, four SNPs in CDH2 were marginally associated with BCR. Among these, CDH2 rs643555C > T was found to be associated with BCR in the replication set. Patients with rs643555TT genotype had a significantly shorter BCR‐free survival compared with those with CC/CT genotypes in the combined analysis (adjusted hazard ratio 1.78, 95% confidence interval 1.19‐2.67, P = 0.005). Additional analyses revealed that rs643555T was associated with higher expression of CDH2, and upregulated CDH2 was correlated with tumor aggressiveness and shortened BCR‐free survival. In conclusion, rs643555C > T affects CDH2 expression, and thus influences BCR in localized prostate cancer patients treated with RP. CDH2 rs643555 may be a promising biomarker to identify patients at high risk of poor prostate cancer prognosis.

Abstract Background To determine the association between circadian pathway genetic variants and the risk of prostate cancer progression. Methods We systematically evaluated 79 germline variants in nine circadian pathway genes in a cohort of 458 patients with localized prostate cancer as the discovery phase. We then replicated the significant findings in another cohort of 324 men with more advanced disease. The association of each variant with prostate cancer progression was evaluated by a log-rank test and Cox regression. Results A single nucleotide polymorphism of the neuronal PAS domain protein 2 (NPAS2) gene (rs6542993 A>T) was found to be associated with a significantly higher risk of disease progression in both localized (P = 0.001) and advanced (P = 0.039) prostate cancer cases. In silico analysis revealed decreased expression levels of NPAS2 in carriers of the T allele of rs6542993 compared with those carrying the A allele. Consistently, downregulation of NPAS2 expression was associated with more aggressive prostate cancer and poor progression-free survival (log-rank P = 0.002). Conclusions The NPAS2 rs6542993 polymorphism may be a promising biomarker, and may shed light on the pathways that govern prostate cancer progression.

The association between houseplants and indoor air quality improvement has been reported in previous studies. However, the effect of houseplant-emitted isoprene on the association between ozone (O3) formation and respiratory health remains unclear. We recruited 60 adult subjects from 60 houses with or without houseplants (1:1) in Taipei; twelve house visits were conducted in each home throughout 2014. The indoor air pollutants that were measured consisted of particulate matter less than or equal to 2.5 μm in diameter (PM2.5), O3 and isoprene. Peak expiratory flow rate (PEFR) was measured in each study subject during each house visit. Household information was collected by a questionnaire. Mixed-effects models were used to explore the association between indoor air pollution levels and PEFR. We found that the concentrations of O3 and isoprene in houses with houseplants were higher than those in houses without houseplants. In contrast, PM2.5 levels and % predicted PEFR were higher in houses without houseplants than in those with houseplants. Moreover, increased levels of O3 and PM2.5 in houses with houseplants were associated with a decreased % predicted PEFR, especially in the summer. We concluded that increased levels of indoor O3 and PM2.5 were associated with decreased PEFR. The presence of houseplants was associated with indoor O3, isoprene and PEFR variations in the summer. Keywords: Houseplant, Indoor air, Ozone, Isoprene, Peak expiratory flow rate

Acyl-CoA:cholestereol acyltransferase 1 (ACAT1) is a two-fold dimer (homotetramer) and has two distinct dimerization domains. One domain is in an alpha-helical rich region near the cytoplasmic N-terminus. The other is proposed to be near the C-terminus where multiple transmembrane domains promote hydrophobic interactions between two ACAT1 subunits. The truncation of the ACAT1 N-terminal dimerization domain, Δ1-65, creates a dimer which is fully enzymatically active. It is currently not known how the C-terminal dimerization domain contributes to ACAT1 enzymatic activity. Here we describe a simple method that dissociates ACAT1 dimers through the addition of the non-ionic detergents Triton X-100 or octyl glucoside which disrupt the C-terminal dimerization domain. We also document the protocols for a method to exchange Triton X-100 with CHAPS to restore C-terminal dimerization of the ACAT1 protein, and an optimized liposomal assay to assess ACAT enzymatic activity. • This method can be applied to dissociate ACAT1 subunits by using Triton X-100 or octyl glucoside. • ACAT1 dimerization can be restored by exchanging Triton X-100 with CHAPS. • The liposomal ACAT activity assay conditions have been optimized. Method name: Dissociation of ACAT1 subunits by non-ionic detergents, Keywords: ACAT1, SOAT1, Two-fold dimer, MBOAT, Quaternary structure, Liposomes, Transmembrane, Cholesterol, Enzyme activity, Detergent

Vascular contributions to cognitive impairment and dementia (VCID) are a common cause of cognitive decline, yet limited therapies exist. This cerebrovascular disease results in neurodegeneration via acute, chronic, local, and systemic mechanisms. The etiology of VCID is complex, with a significant impact from atherosclerosis. Risk factors including hypercholesterolemia and hypertension promote intracranial atherosclerotic disease and carotid artery stenosis (CAS), which disrupt cerebral blood flow and trigger ischemic strokes and VCID. Apolipoprotein E (APOE) is a cholesterol and phospholipid carrier present in plasma and various tissues. APOE is implicated in dyslipidemia and Alzheimer disease (AD); however, its connection with VCID is less understood. Few experimental models for VCID exist, so much of the present information has been drawn from clinical studies. Here, we review the literature with a focus on the clinical aspects of atherosclerotic cerebrovascular disease and build a working model for the pathogenesis of VCID. We describe potential intermediate steps in this model, linking cholesterol, atherosclerosis, and APOE with VCID. APOE4 is a minor isoform of APOE that promotes lipid dyshomeostasis in astrocytes and microglia, leading to chronic neuroinflammation. APOE4 disturbs lipid homeostasis in macrophages and smooth muscle cells, thus exacerbating systemic inflammation and promoting atherosclerotic plaque formation. Additionally, APOE4 may contribute to stromal activation of endothelial cells and pericytes that disturb the blood-brain barrier (BBB). These and other risk factors together lead to chronic inflammation, atherosclerosis, VCID, and neurodegeneration. Finally, we discuss potential cholesterol metabolism based approaches for future VCID treatment.

Nasopharyngeal carcinoma (NPC) is a head and neck cancer involving epithelial squamous-cell carcinoma of the nasopharynx that mainly occurs in individuals from East and Southeast Asia. We investigated whether Chinese herbal medicine (CHM) as a complementary therapy offers benefits to these patients. We retrospectively evaluated the Taiwan Cancer Registry (Long Form) database for patients with advanced NPC, using or not using CHM, between 2007–2013. Cox proportional-hazard model and Kaplan‒Meier survival analyses were applied for patient survival. CHM-users showed a lower overall and cancer-related mortality risk than non-users. For advanced NPC patients, the overall mortality risk was 0.799-fold for CHM-users, after controlling for age, gender, and Charlson comorbidity index (CCI) score (Cancer stages 3 + 4: adjusted hazard ratio [aHR]: 0.799, 95% confidence interval [CI]: 0.676–0.943, p = 0.008). CHM-users also showed a lower cancer-related mortality risk than non-users (aHR: 0.71, 95% CI: 0.53–0.96, p = 0.0273). Association rule analysis showed that CHM pairs were Ban-Zhi-Lian (BZL; Scutellaria barbata D.Don) and For single herbs, Bai-Hua-She-She-Cao (Herba Hedyotis Diffusae; Scleromitrion diffusum (Willd.) R.J.Wang (syn. Hedyotis diffusa Willd.) and Mai-Men-Dong (MMD; Ophiopogon japonicus (Thunb.) Ker Gawl.), and Gan-Lu-Yin (GLY) and BHSSC. Network analysis revealed that BHSSC was the core CHM, and BZL, GLY, and Xin-Yi-Qing-Fei-Tang (XYQFT) were important CHMs in cluster 1. In cluster 2, ShengDH, MMD, Xuan-Shen (XS; Scrophularia ningpoensis Hensl.), and Gua-Lou-Gen (GLG; Trichosanthes kirilowii Maxim.) were important CHMs. Thus, as a complementary therapy, CHM, and particularly the 8 CHMs identified, are important for the treatment of advanced NPC patients.

Alzheimer's disease (AD) is the most common form of dementia in older adults. Currently, there is no cure for AD. The hallmark of AD is the accumulation of extracellular amyloid plaques composed of amyloid-β (Aβ) peptides (especially Aβ1-42) and neurofibrillary tangles, composed of hyperphosphorylated tau and accompanied by chronic neuroinflammation. Aβ peptides are derived from the amyloid precursor protein (APP). The oligomeric form of Aβ peptides is probably the most neurotoxic species; its accumulation eventually forms the insoluble and aggregated amyloid plaques. ApoE is the major apolipoprotein of the lipoprotein(s) present in the CNS. ApoE has three alleles, of which the Apoe4 allele constitutes the major risk factor for late-onset AD. Here we describe the complex relationship between ApoE4, oligomeric Aβ peptides, and cholesterol homeostasis. The review consists of four parts: 1) key elements involved in cellular cholesterol metabolism and regulation; 2) key elements involved in intracellular cholesterol trafficking; 3) links between ApoE4, Aβ peptides, and disturbance of cholesterol homeostasis in the CNS; 4) potential lipid-based therapeutic targets to treat AD. At the end, we recommend several research topics that we believe would help in better understanding the connection between cholesterol and AD for further investigations.

Few studies have applied land-use regression to predict road traffic noise exposure, and there are few predictive models for different frequencies. This study aimed to measure 24-h average road traffic noise levels and to analyze the frequency components over one year to establish land-use regression models of noise exposure. Fifty monitoring stations were set up to conduct 3 measurements for A-weighted equivalent sound pressure levels over 24 h (Leq,24h) and night equivalent sound pressure levels (Lnight), as well as octave-band analyses, during the 2013–2014 period. Noise measurements were integrated with land-use types, road and traffic information, meteorological data and geographic information systems to construct land-use regression models. Leave-one-out cross-validation was performed to test the validity of the predictive models. The annual means of Leq,24h and Lnight were 66.4 ± 4.7 A-weighed decibels (dBA) and 62.1 ± 6.0 dBA, respectively. Octave-band frequency analyses revealed that the highest means over 24 h and at night were 61.4 ± 5.3 decibels (dB) and 56.7 ± 6.6 dB (both at 1000 Hz), respectively. The model-explained variance (R2) of the full-frequency noise was 0.83 for Leq,24h and 0.79 for Lnight. The R2 values for octave-band-frequency noise ranged from 0.67 to 0.88 for Leq,24h and 0.65 to 0.85 for Lnight, with the highest R2 at 250 Hz for Leq,24h and at 125 Hz for Lnight. The differences between the model R2 and the leave-one-out cross-validation R2 ranged from 5% to 15% for both Leq,24h and Lnight at all frequencies. In the validation, the root mean squared error was 2.09 dBA and 2.80 dBA for the full-frequency Leq,24 and Lnight, respectively, and ranged from 1.89 to 2.62 dB and from 2.51 to 3.28 dB for the octave-band-frequency Leq,24h and Lnight, respectively. This study observed that the annual means of the measured Leq,24h and Lnight in Taichung were both above 60 dBA and had the highest level at 1000 Hz. The developed land-use regression models of Leq,24 and Lnight both had good predictive capacity for the full frequency spectrum and within octave bands and can therefore be applied for epidemiological studies. Keywords: Land-use regression, Octave-band frequency analysis, Prediction, Road traffic noise, Validity

Vinyl chloride (VC) is classified as a group 1 carcinogen to humans by the International Agency for Research on Cancer, and inhalation is considered to be an important route of occupational exposure. In addition, increasing numbers of studies have observed adverse health effects in people living in the vicinity of petrochemical complexes. The objective of this study was to investigate the adverse in vivo health effects on the lungs and liver caused by pulmonary exposure to low-level VC. BALB/c mice were repeatedly intranasally administrated 50 µL/mouse VC at 0, 1, and 200 ng/mL (5 days/week) for 1, 2, and 3 weeks. We observed that exposure to 1 and 200 ng/mL VC significantly increased the tidal volume (μL). Dynamic compliance (mL/cmH2O) significantly decreased after exposure to 200 ng/mL VC for 3 weeks. Total protein, lactate dehydrogenase (LDH), and interleukin (IL)-6 levels in bronchoalveolar lavage fluid (BALF) significantly increased after exposure to 200 ng/mL VC for 2 and/or 3 weeks. Significant decreases in 8-isoprostane and caspase-3 and an increase in IL-6 in the lungs were found after VC exposure for 2 and/or 3 weeks. We observed that aspartate aminotransferase (AST), alkaline phosphatase (ALKP), albumin (ALB), and globulin (GLOB) had significantly increased after three weeks of VC exposure, whereas the ALB/GLOB ratio had significantly decreased after 3 weeks of exposure to VC. IL-6 in the liver increased after exposure to 1 ng/mL VC, but decreased after exposure to 200 ng/mL. IL-1β in the liver significantly decreased following exposure to 200 ng/mL VC, whereas tumor necrosis factor (TNF)-α and caspase-3 significantly increased. Hepatic inflammatory infiltration was confirmed by histological observations. In conclusion, sub-chronic and repeated exposure to low levels of VC can cause lung and liver toxicity in vivo. Attention should be paid to all situations where humans are frequently exposed to elevated VC levels such as workplaces or residents living in the vicinity of petrochemical complexes.

Mammalian cells synthesize various sterol molecules, including the C30 sterol, lanosterol, as cholesterol precursors in the endoplasmic reticulum. The build-up of precursor sterols, including lanosterol, displays cellular toxicity. Precursor sterols are found in plasma HDL. How these structurally different sterols are released from cells is poorly understood. Here, we show that newly synthesized precursor sterols arriving at the plasma membrane (PM) are removed by extracellular apoA-I in a manner dependent on ABCA1, a key macromolecule for HDL biogenesis. Analysis of sterol molecules by GC-MS and tracing the fate of radiolabeled acetate-derived sterols in normal and mutant Niemann-Pick type C cells reveal that ABCA1 prefers newly synthesized sterols, especially lanosterol, as the substrates before they are internalized from the PM. We also show that ABCA1 resides in a cholesterol-rich membrane domain resistant to the mild detergent, Brij 98. Blocking ACAT activity increases the cholesterol contents of this domain. Newly synthesized C29/C30 sterols are transiently enriched within this domain, but rapidly disappear from this domain with a half-life of less than 1 h. Our work shows that substantial amounts of precursor sterols are transported to a certain PM domain and are removed by the ABCA1-dependent pathway.

Long-term noise exposure often results in noise induced hearing loss (NIHL). Tinnitus, the generation of phantom sounds, can also result from noise exposure, although understanding of its underlying mechanisms are limited. Recent studies, however, are shedding light on the neural processes involved in NIHL and tinnitus, leading to potential new and innovative treatments. This review focuses on the assessment of NIHL, available treatments, and development of new pharmacologic and non-pharmacologic treatments based on recent studies of central auditory plasticity and adaptive changes in hearing. We discuss the mechanisms and maladaptive plasticity of NIHL, neuronal aspects of tinnitus triggers, and mechanisms such as tinnitus-associated neural changes at the cochlear nucleus underlying the generation of tinnitus after noise-induced deafferentation. We include observations from recent studies, including our own studies on associated risks and emerging treatments for tinnitus. Increasing knowledge of neural plasticity and adaptive changes in the central auditory system suggest that NIHL is preventable and transient abnormalities may be reversable, although ongoing research in assessment and early detection of hearing difficulties is still urgently needed. Since no treatment can yet reverse noise-related damage completely, preventative strategies and increased awareness of hearing health are essential.

This cross-sectional study aimed to determine the concentration of indoor volatile organic compounds (VOCs) and to investigate the association between indoor VOCs exposure and the prevalence of hypertension among thin film transistor liquid crystal display (TFT-LCD) workers. A total of 20 canisters were used to collect VOCs samples in the array, cell and module areas over 12 hours and VOCs concentrations were analyzed by the gas chromatography with mass spectrum. Individual information of health examination and lifestyles by self-administrated questionnaire were provided by 155 volunteers. The multivariate regression models were used to evaluate the associations between VOCs exposure, blood pressure and the prevalence of hypertension. The four dominant VOCs were ethanol (1870.8 ± 1754.0 ppb), acetone (689.9 ± 587.4 ppb), isopropyl alcohol (177.1 ± 202.3 ppb) and propylene glycol monomethyl ether acetate (98.2 ± 100.8 ppb), which were identified with the highest level in the module area for ethanol and acetone and in the array area for the others. Subjects exposed to a total level of ethanol, cyclohexanone and toluene ≥ 2500 ppb had an increased systolic blood pressure of 5.95 mmHg (95% confidence interval: 0.20–11.71; p = 0.043) compared with those exposed to

To evaluate the cardiovascular impact of traffic-related pollutant exposure on healthy young adults, the research team has collected the primary data of in-cabin exposure to air pollutants and heart rate variability (HRV). Twenty young healthy college students were recruited in Taipei metropolitan area. In addition to electrocardiogram, personal exposure to air pollutants, i.e., particulate matter (PM) and carbon monoxide (CO), and weather conditions, including temperature and relative humidity (RH), on campus, bus, and mass rapid transit were monitored continuously. The following HRV parameters were evaluated using generalized additive mixed model to adjust for personal and meteorological variables: heart rate (HR), the square root of the mean of the sum of the squares of differences between adjacent normal-to-normal (NN) intervals (r-MSSD), the standard deviation of all NN intervals (SDNN), the percentage of successive NN interval differences greater than 50 ms (pNN50), low-frequency power (LF), high-frequency power (HF), total power (TP), and LF/HF. They were assessed to find out the association between in-cabin exposure and HRV parameters. Compared with the HRV parameters measured on campus, the percent changes in r-MSSD, SDNN, pNN50+1, LF, HF, and TP decreased when the participants were in public transits. After adjusting for all locations, 5 min moving averages of PM2.5−10 and PM1 were significantly associated with the increase in the percent changes in HR and SDNN. Additionally, 5 min moving averages of PM2.5−10 exposure were significantly associated with the decrease in the percent change in HF, while it was significantly associated with the increase of the percent change in LF/HF. The reduction of the percent change in HR was also found to be significantly associated with 5 min CO moving averages. To conclude, current analyses have shown that size-fractionated PMs and CO exposure in public transits might lead to significant changes of HRV parameters for healthy young adults.

This study aimed to determine indoor and outdoor levels of volatile organic compounds (VOCs) and to assess potential risks among residents living in the vicinity of an optoelectronics industrial park in 2006–2007. We used steel canisters to collect 72 indoor samples and 80 outdoor samples over 24 h. Gas chromatography with a mass-selective detector was used for qualitative and quantitative analyses. The amounts of time residents spent doing activities in different microenvironments were determined by the self-administered questionnaire. The chronic hazard index (HIc) and cancer risk were applied to assess the non-carcinogenic and carcinogenic risks of VOCs among residents. Four VOCs of ethanol (indoor: 77.8 ± 92.8 μg/m3; outdoor: 26.8 ± 49.6 μg/m3), toluene (67.0 ± 36.7 μg/m3; 56.9 ± 19.0 μg/m3), m/p-xylene (50.8 ± 66.1 μg/m3; 21.2 ± 20.3 μg/m3), and acetone (37.7 ± 27.5 μg/m3; 25.8 ± 9.8 μg/m3) were identified as dominant components in both the indoor and outdoor environments. Total VOCs and six VOCs of benzene, toluene, ethylbenzene, m/p-xylene, o-xylene, and ethanol in indoor sites were significantly higher than those in outdoor sites (all p-values < 0.05). All estimated HIc values were less than unity and the cancer risk of benzene exposure was 1.8 × 10−4 (range: 9.3 × 10−5 to 3.4 × 10−4) based on resident time-weighted patterns. Strategies to reduce benzene exposure should be implemented to protect public health.

ACAT1 is normally a resident enzyme in the endoplasmic reticulum (ER). We previously showed that treating macrophages with denatured LDL causes a large increase in ER-derived, ACAT1-positive vesicles. Here, we isolated ER membranes and ER-derived vesicles to examine their ACAT enzyme activity in vitro. The results showed that when macrophages are grown under normal conditions, ACAT1 is located in high density ER membrane; its enzymatic activity is relatively low. Loading macrophages with cholesterol did not increase the total cellular ACAT1 protein content significantly but caused more ACAT1 to appear in ER-derived vesicles. These vesicles exhibit lower density and are associated with markers of both ER and the trans-Golgi network. When normalized with equal ACAT1 protein mass, the enzymatic activities of ACAT1 in ER-derived vesicles were 3-fold higher than those present in ER membrane. Results using reconstituted ACAT enzyme assay showed that the increase in enzyme activity in ER-derived vesicles is not due to an increase in the cholesterol content associated with these vesicles. Overall, our results show that macrophages cope with cholesterol loading by using a novel mechanism: they produce more ER-derived vesicles with elevated ACAT1 enzyme activity without having to produce more ACAT1 protein.

High levels of the inflammatory cytokine tumor necrosis factor-α (TNF-α) are present in atherosclerotic lesions. TNF-α regulates expression of multiple genes involved in various stages of atherosclerosis, and it exhibits proatherosclerotic and antiatherosclerotic properties. ACAT catalyzes the formation of cholesteryl esters (CE) in monocytes/macrophages, and it promotes the foam cell formation at the early stage of atherosclerosis. We hypothesize that TNF-α may be involved in regulating the ACAT gene expression in monocytes/macrophages. In this article, we show that in cultured, differentiating human monocytes, TNF-α enhances the expression of the ACAT1 but not ACAT2 gene, increases the cholesteryl ester accumulation, and promotes the lipid-laden cell formation. Several other proinflammatory cytokines tested do not affect the ACAT1 gene expression. The stimulation effect is consistent with a receptor-dependent process, and is blocked by using nuclear factor-kappa B (NF-kappa B) inhibitors. A functional and unique NF-kappa B element located within the human ACAT1 gene proximal promoter is required to mediate the action of TNF-α. Our data demonstrate that TNF-α, through the NF-kappa B pathway, specifically enhances the expression of human ACAT1 gene to promote the CE-laden cell formation from the differentiating monocytes, and our data support the hypothesis that TNF-α is proatherosclerotic during early phase of lesion development.

Differential regulation has been suggested for cellular cholesterol and phospholipid release mediated by apolipoprotein A-I (apoA-I)/ABCA1. We investigated various factors involved in cholesterol mobilization related to this pathway. ApoA-I induced a rapid decrease of the cellular cholesterol compartment that is in equilibrium with the ACAT-accessible pool in cells that generate cholesterol-rich HDL. Pharmacological and genetic inactivation of ACAT enhanced the apoA-I-mediated cholesterol release through upregulation of ABCA1 and through cholesterol enrichment in the HDL generated. Pharmacological activation of protein kinase C (PKC) also decreased the ACAT-accessible cholesterol pool, not only in the cells that produce cholesterol-rich HDL by apoA-I (i.e., human fibroblast WI-38 cells) but also in the cells that generate cholesterol-poor HDL (mouse fibroblast L929 cells). In L929 cells, the PKC activation caused an increase in apoA-I-mediated cholesterol release without detectable change in phospholipid release and in ABCA1 expression.These results indicate that apoA-I mobilizes intracellular cholesterol for the ABCA1-mediated release from the compartment that is under the control of ACAT. The cholesterol mobilization process is presumably related to PKC activation by apoA-I.

Niemann-Pick type C (NPC) is a neurodegenerative disorder characterized by progressive accumulation of cholesterol, gangliosides, and other lipids in the central nervous system and visceral organs. In the NPC1 mouse model, neurodegeneration and neuronal cell loss occur before postnatal day 21. Whether neuronal cholesterol accumulation occurs in vivo before the first signs of neuronal cell loss has not been demonstrated. In this report, we used the NPC1 mouse model and employed a novel cholesterol binding reagent, BCθ, that enabled us to visualize cellular cholesterol accumulation at a level previously unattainable.The results demonstrate the superiority of BCθ staining over conventional filipin staining in confocal microscopy and highlight several new findings. We show that at postnatal day 9, although only mild signs of neurodegeneration are detectable, significant neuronal cholesterol accumulation has already occurred throughout the NPC1 brain. In addition, although NPC1 Purkinje neurons exhibit a normal morphology at day 9, significant cholesterol accumulation within their extensive dendritic trees has occurred. We also show that in the thalamus and cortex of NPC1 mice, activated glial cells first appear at postnatal day 9 and heavily populate by day 22, suggesting that in NPC1 mice, neuronal cholesterol accumulation precedes neuronal injury and neuronal cell loss.

Niemann-Pick type C1 disease (NPC1) is an inherited neurovisceral lipid storage disorder, hallmarked by the intracellular accumulation of unesterified cholesterol and glycolipids in endocytic organelles. Cells acquire cholesterol through exogenous uptake and endogenous biosynthesis. NPC1 participation in the trafficking of LDL-derived cholesterol has been well studied; however, its role in the trafficking of endogenously synthesized cholesterol (endoCHOL) has received much less attention. Previously, using mutant Chinese hamster ovary cells, we showed that endoCHOL moves from the endoplasmic reticulum (ER) to the plasma membrane (PM) independent of NPC1. After arriving at the PM, it moves between the PM and internal compartments. The movement of endoCHOL from internal membranes back to the PM and the ER for esterification was shown to be defective in NPC1 cells. To test the generality of these findings, we have examined the trafficking of endoCHOL in four different physiologically relevant cell types isolated from wild-type, heterozygous, and homozygous BALB/c NPC1NIH mice. The results show that all NPC1 homozygous cell types (embryonic fibroblasts, peritoneal macrophages, hepatocytes, and cerebellar glial cells) exhibit partial trafficking defects, with macrophages and glial cells most prominently affected.Our findings suggest that endoCHOL may contribute significantly to the overall cholesterol accumulation observed in selective tissues affected by Niemann-Pick type C disease.

BCθ is a proteolytically nicked and biotinylated derivative of a cholesterol binding protein perfringolysin O (θ-toxin), and has been used to detect cholesterol-rich domains at the plasma membrane (PM). Here we show that by modifying the cell fixation condition, BCθ can also be used to detect cholesterol-rich domains intracellularly. When cells were processed for PM cholesterol staining, the difference in BCθ signals between the CT43 (CT) cell, a mutant Chinese hamster ovary cell line lacking the Niemann-Pick type C1 (NPC1) protein, and its parental cell 25RA (RA) was minimal. However, when cells were fixed with 4% paraformaldehyde, they became permeable to BCθ. Under this condition, BCθ mainly stained cholesterol-rich domains inside the cells, with the signal being much stronger in CT cells than in RA cells. The sensitivity of BCθ staining was superior to that of filipin staining. The staining of cholesterol-rich domain(s) inside RA cells was sensitive to β-cyclodextrin treatment, while most of the staining inside CT cells was relatively resistant to cyclodextrin treatment. Clear differences in intracellular BCθ staining were also seen between the normal and mutant NPC1 fibroblasts of human or mouse origin.Thus, BCθ is a powerful tool for visually monitoring cholesterol-rich domains inside normal and NPC cells.

We report the chemical synthesis of a new photoactivatable cholesterol analog 7,7-azocholestanol (AC) and its linoleate ester (ACL). We also examined the biochemical properties of the sterol and its ester by employing several different mutant Chinese hamster ovary (CHO) cell lines with defined abnormalities in cholesterol metabolism as tools. AC mimics cholesterol in supporting the growth of a mutant cell line (M19) that requires cholesterol for growth. In normal cells, tritiated ACL present in low-density lipoprotein (LDL) was hydrolyzed and reesterified in a manner similar to tritiated cholesteryl linoleate (CL) in LDL. Also, in the mutant cell line (AC29) lacking the enzyme acyl-coenzyme A:cholesterol acyltransferase or in the mutant cell line (CT60) defective in the Niemann-Pick type C1 protein, the hydrolysis of ACL in LDL was normal, but the reesterification of the liberated AC was defective. Therefore, the metabolism of ACL in LDL is very similar to that of CL in LDL. Tritium-labeled AC delivered to intact CHO cells as a cyclodextrin complex was shown to photoaffinity label several discrete polypeptides, including caveolin-1.These results demonstrate AC as an effective reagent for studying cholesterol-protein interactions involved in intracellular cholesterol trafficking.

We have previously shown that acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) protein content increases significantly during the human monocyte-macrophage differentiation process. To gain further insight, we used undifferentiated human monocytic THP-1 cells as a model system with which to examine whether ACAT-1 mRNA and protein content can be increased by treating cells with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] or with 9-cis-retinoic acid (9-cis-RA), two agents known to upregulate the expression of various genes during the monocyte-macrophage differentiation process. Immunoblot analysis with anti-human ACAT-1 antibodies revealed that ACAT-1 protein was increased by 2.6-fold, using 1,25-(OH)2D3 at a physiological concentration (100 pM). ACAT-1 protein was also increased when using 9-cis-RA, but only at relatively high concentrations (0.1–1 μM). Northern blot analysis revealed that among the four ACAT-1 mRNA transcripts (2.8, 3.6, 4.2, and 7.0 kb) examined, only the 2.8- and 3.6-kb transcripts were selectively increased. On the basis of enzyme assays in vitro, ACAT activity was increased 3.0-fold by using 100 nM 1,25-(OH)2D3, and 1.8-fold by using 1 μM 9-cis-RA. Together, our results suggest that 1,25-(OH)3 participates in ACAT-1 gene expression during the monocyte-macrophage differentiation process. —Maung, K. K., A. Miyazaki, H. Nomiyama, C. C. Y. Chang, T-Y. Chang, and S. Horiuchi. Induction of acyl-coenzyme A:cholesterol acyltransferase-1 by 1,25-dihydroxyvitamin D3 or 9-cis-retinoic acid in undifferentiated THP-1 cells.

The first acyl-coenzyme A:cholesterol acyltransferase (ACAT) cDNA cloned and expressed in 1993 is designated as ACAT-1. In various human tissue homogenates, ACAT-1 protein is effectively solubilized with retention of enzymatic activity by the detergent CHAPS along with high salt. After using anti-ACAT-1 antibodies to quantitatively remove ACAT-1 protein from the solubilized enzyme, measuring the residual ACAT activity remaining in the immunodepleted supernatants allows us to assess the functional significance of ACAT-1 protein in various human tissues. The results showed that ACAT activity was immunodepleted 90% in liver (83% in hepatocytes), 98% in adrenal gland, 91% in macrophages, 80% in kidney, and 19% in intestines, suggesting that ACAT-1 protein plays a major catalytic role in all of the human tissue/cell homogenates examined except intestines. Intestinal ACAT activity is largely resistant to immunodepletion and is much more sensitive to inhibition by the ACAT inhibitor Dup 128 than liver ACAT activity.—Lee, O., C. C. Y. Chang, W. Lee, and T-Y. Chang. Immunodepletion experiments suggest that acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) protein plays a major catalytic role in adult human liver, adrenal gland, macrophages, and kidney, but not in intestines.

Compelling evidence has implicated the Wnt signaling pathway in the pathogenesis of colorectal cancer. We assessed the use of tag single nucleotide polymorphisms (tSNPs) in adenomatous polyposis coli (APC)/β-catenin (CTNNB1) genes to predict outcomes in patients with colorectal cancer. We selected and genotyped 10 tSNP to predict common variants across entire APC and CTNNB1 genes in 282 colorectal cancer patients. The associations of these tSNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis, Cox regression model, and survival tree analysis. The 5-year overall survival rate was 68.3%. Survival tree analysis identified a higher-order genetic interaction profile consisting of the APC rs565453, CTNNB1 2293303, and APC rs1816769 that was significantly associated with overall survival. The 5-year survival overall rates were 89.2%, 66.1%, and 58.8% for the low-, medium-, and high-risk genetic profiles, respectively (log-rank P = 0.001). After adjusting for possible confounders, including age, gender, carcinoembryonic antigen levels, tumor differentiation, stage, lymphovascular invasion, perineural invasion, and lymph node involvement, the genetic interaction profile remained significant. None of the studied SNPs were individually associated with distant metastasis-free survival and overall survival. Our results suggest that the genetic interaction profile among Wnt pathway SNPs might potentially increase the prognostic value in outcome prediction for colorectal cancer.

Although most advanced prostate cancer patients respond to androgen-deprivation therapy (ADT), the efficacy is widely variable. We investigated whether the host genetic variations in sex hormone pathway genes are associated with the efficacy of ADT. A cohort of 645 patients with advanced prostate cancer treated with ADT was genotyped for 18 polymorphisms across 12 key genes involved in androgen and estrogen metabolism. We found that after adjusting for known risk factors in multivariate Cox regression models, AKR1C3 rs12529 and AR-CAG repeat length remained significantly associated with prostate cancer-specific mortality (PCSM) after ADT (P ≤ 0.041). Furthermore, individuals carrying two unfavorable genotypes at these loci presented a 13.7-fold increased risk of PCSM compared with individuals carrying zero (P

This study describes the performance evaluation of an energy management system, based on electricity consumption, for a Gen 6 Thin Film Transistor Liquid Crystal Display (TFT-LCD) panel plant. Of the various production lines and facility systems, the array system and the compressed dry air consumed the most electricity of 21.8% and 19.8%, respectively, while the public utility used only 1.6% of the total electricity. The baseline electricity consumptions were correlated well (R2 ≥ 0.77) to the monthly average wet-bulb temperatures of ambient air and the panel yield rates, which were determined by the product yield over the equipment available time index. After implementing the energy saving projects, the energy conservation performance was determined using a three-parameter change-point regression model incorporated with the panel yield rates. The post-retrofit monthly savings of the total electricity consumption for the panel manufacture were 5.35%–10.36%, with the efficiency of the electricity performance revealing an upswing trend following the implementation of the energy management system.