Wastewater-based epidemiology to monitor 68 NPS/conventional drug use in Taipei metropolitan area in Taiwan during and after COVID-19 pandemic.

Amidst far-reaching COVID-19 effects and social constraints, this study leveraged wastewater-based epidemiology to track 38 conventional drugs and 30 new psychoactive substances (NPS) in northern Taiwan. Analyzing daily samples from four Taipei wastewater plants between September 2021 and January 2024-encompassing club reopenings, holidays, Lunar New Year, an outbreak, and regular periods-thirty-one drugs were detected, including 5 NPS. Tramadol, zolpidem tartrate, CMA, and MDPV were newly detected in Taiwanese sewage with frequency of 1.4 %- 89.0 %. Conventional drug use typically increased post-pandemic, aside from benzodiazepines and methadone. Methamphetamine showed 100 % frequency, indicating ongoing daily consumption despite COVID-19 measures. Methamphetamine and morphine's consumption dipped then rose around club reopening, hinting at limited access. The consumption trend of methadone appeared to compensate for the use of morphine. Ketamine and NPS demonstrated similar patterns throughout the entire period. NPS as party drugs seemed influenced by an unstable supply chain and complexities in implementation. Benzodiazepines, commonly abused alongside synthetic cathinones in Taiwan exhibited an opposing trend to NPS while aligned with acetaminophen, suggesting elevated stress and anxiety levels during the pandemic. No significant differences were observed in drug consumption between weekdays and weekends, potentially indicating that COVID-19 measures blurred the traditional distinctions between these timeframes. ENVIRONMENTAL IMPLICATION: New psychoactive substances refer to chemically modified variants of controlled drugs designed to mimic the effects of the original drugs while evading modern detection methods, categorizing them as hazardous materials. The study presents a sewage monitoring project conducted from 2021 to 2024, collecting samples from four WWTPs to analyze NPS and conventional drug trends during and after the COVID-19 pandemic. The findings uncovered connections between drug consumption patterns and pandemic-related policies. In light of the persistent drug abuse and their environmental presence, the results bear critical importance for both environmental and public health. We provide a thorough assessment of these relationships and prioritize areas for future research.

A lesion-selective albumin-CTLA4Ig as a safe and effective treatment for collagen-induced arthritis.

BACKGROUND: CTLA4Ig is a dimeric fusion protein of the extracellular domain of cytotoxic T-lymphocyte protein 4 (CTLA4) and an Fc (Ig) fragment of human IgG1 that is approved for treating rheumatoid arthritis. However, CTLA4Ig may induce adverse effects. Developing a lesion-selective variant of CTLA4Ig may improve safety while maintaining the efficacy of the treatment. METHODS: We linked albumin to the N-terminus of CTLA4Ig (termed Alb-CTLA4Ig) via a substrate sequence of matrix metalloproteinase (MMP). The binding activities and the biological activities of Alb-CTLA4Ig before and after MMP digestion were analyzed by a cell-based ELISA and an in vitro Jurkat T cell activation assay. The efficacy and safety of Alb-CTLA4Ig in treating joint inflammation were tested in mouse collagen-induced arthritis. RESULTS: Alb-CTLA4Ig is stable and inactive under physiological conditions but can be fully activated by MMPs. The binding activity of nondigested Alb-CTLA4Ig was at least 10,000-fold weaker than that of MMP-digested Alb-CTLA4Ig. Nondigested Alb-CTLA4Ig was unable to inhibit Jurkat T cell activation, whereas MMP-digested Alb-CTLA4Ig was as potent as conventional CTLA4Ig in inhibiting the T cells. Alb-CTLA4Ig was converted to CTLA4Ig in the inflamed joints to treat mouse collagen-induced arthritis, showing similar efficacy to that of conventional CTLA4Ig. In contrast to conventional CTLA4Ig, Alb-CTLA4Ig did not inhibit the antimicrobial responses in the spleens of the treated mice. CONCLUSIONS: Our study indicates that Alb-CTLA4Ig can be activated by MMPs to suppress tissue inflammation in situ. Thus, Alb-CTLA4Ig is a safe and effective treatment for collagen-induced arthritis in mice.

A proposed approach to confirm heroin administration - Regional differences in heroin purity is a major factor.

In forensic toxicology, a marker of street heroin use is urgent especially in the absence of urinary 6-monoacetylmorphine. ATM4G, the Glucuronide of Acetylated product of Thebaine compound 4 Metabolite (ATM4), arising from byproducts of street heroin synthesis has been considered as a useful marker in some European studies. However, whether ATM4G is a universal marker particularly in Southeast Asia due to 'street' heroin with high purity, it's still unclear. To investigate putative markers for different regions, ATM4G and other metabolites including the Acetylated product of Thebaine compound 3 Metabolite (ATM3) and thebaol, also originated from thebaine were detected in 552 urine samples from heroin users in Taiwan. Results were compared with that from samples collected in the UK and Germany. Only a sulfo-conjugate of ATM4, ATM4S, was detected in 28 Taiwanese users using a sensitive MS3 method whilst out of 351 samples from the UK and Germany, ATM4G was present in 91. Thebaol-glucuronide was first time detected in 118. No markers were detected in urine following herbal medicine use or poppy seed ingestion. The presence of ATM4S/ATM4G might be affected by ethnicities and heroin supplied in regions. Thebaol-glucuronide is another putative marker with ATM4G and ATM4S for street heroin use.

Lysophosphatidic acid receptor LPA3 prevents oxidative stress and cellular senescence in Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare laminopathy that produces a mutant form of prelamin A, known as Progerin, resulting in premature aging. HGPS cells show morphological abnormalities of the nuclear membrane, reduced cell proliferation rates, accumulation of reactive oxygen species (ROS), and expression of senescence markers. Lysophosphatidic acid (LPA) is a growth factor-like lipid mediator that regulates various physiological functions via activating multiple LPA G protein-coupled receptors. Here, we study the roles of LPA and LPA receptors in premature aging. We report that the protein level of LPA3 was highly downregulated through internalization and the lysosomal degradation pathway in Progerin-transfected HEK293 cells. By treating Progerin HEK293 cells with an LPA3 agonist (OMPT, 1-Oleoyl-2-O-methyl-rac-glycerophosphothionate) and performing shRNA knockdown of the Lpa3r transcript in these cells, we showed that LPA3 activation increased expression levels of antioxidant enzymes, consequently inhibiting ROS accumulation and ameliorating cell senescence. LPA3 was shown to be downregulated in HGPS patient fibroblasts through the lysosomal pathway, and it was shown to be crucial for ameliorating ROS accumulation and cell senescence in fibroblasts. Moreover, in a zebrafish model, LPA3 deficiency was sufficient to cause premature aging phenotypes in multiple organs, as well as a shorter lifespan. Taken together, these findings identify the decline of LPA3 as a key contributor to the premature aging phenotypes of HGPS cells and zebrafish.

Metal composition of ambient PM2.5 influences the pulmonary function of schoolchildren: A case study of school located nearby of an electric arc furnace factory.

The present study combined air sampling with pulmonary function tests (PFTs) to determine both the extent of air pollution proximal to an electric arc furnace (EAF) and its impact on human health. The mass concentrations of particulate matter with aerodynamic diameters less than 2.5 µm (PM2.5) in exposure areas were not significantly higher than the samples taken at a control area. However, the concentrations of five metal elements, Cd, Cr, Cu, Ni, and Zn in PM2.5 were significantly higher in the exposure area than that of the control area. PFTs showed that the average forced vital capacity (FVC) of boys was decreased with decreasing distance from the EAF factory. With normalization of pulmonary function by age, height, and weight, we found that the FVC became more negative with a decrease in distance from the EAF. Lastly, regression analysis was performed to analyze the impact of the concentrations of the five metals in PM2.5 on the performance of pulmonary function. The results showed that the metals can be ranked from the highest to the lowest in terms of impact on the FVC of boys as follows: Cr, Cd, Ni, Cu, and Zn. This finding is consistent with the ranking of metal toxicity reported in the literature for a rat lung epithelial cell line. The results of this study showed that only measuring PM2.5 mass concentrations may not provide a full explanation of its toxicity and health effects. The chemical composition of the PM2.5 can be an important factor that determined the health impact of PM2.5.

Activation of Lysophosphatidic Acid Receptor 3 Inhibits Megakaryopoiesis in Human Hematopoietic Stem Cells and Zebrafish.

Lysophosphatidic acid (LPA) is a membrane-derived lysophospholipid that exists in the plasma and platelets. It exerts its functions through activation of various LPA receptors (LPARs), which belong to the family of G protein-coupled receptors. Activation of LPARs has important roles in stem cell differentiation. However, how LPA affects human hematopoietic stem cell (HSC) differentiation remains elusive. In our previous studies, we have suggested that LPA receptor 2 (LPA2) and LPA receptor 3 (LPA3) play opposing roles and may act as a molecular switch during megakaryocytic differentiation in K562 cells. In this study, human CD34+ HSCs and zebrafish are adopted to investigate the roles of LPA3 during megakaryopoiesis/thrombopoiesis in vitro and in vivo. Our results show that LPAR3 mRNA expression level is decreased upon induction by thrombopoietin and stem cell factor in human HSCs. Using pharmacological activators and shRNA knockdown experiments, we demonstrate that activation of LPA3 inhibits megakaryopoiesis in human HSCs. In addition, pharmacological activation of LPA3 suppressed thrombopoiesis in zebrafish. Furthermore, blockage of LPA3 translation by morpholino increased the number of CD41-GFP+ cells in Tg(CD41:eGFP) zebrafish. Moreover, the mRNA expression level of zCD41 increased significantly in LPA3-knockout zebrafish. These results clarify the negative role of LPA3 during megakaryopoiesis and provide important information for potential treatments of related diseases, such as megakaryopenia.

trans/cis-Isomerization of fluorene-bridged azo chromophore with significant two-photon absorbability at near-infrared wavelength.

Azo-containing materials have been proven to possess second-order nonlinear optical (NLO) properties, but their third-order NLO properties, which involves two-photon absorption (2PA), has rarely been reported. In this study, we demonstrate a significant 2PA behavior of the novel azo chromophore incorporated with bilateral diphenylaminofluorenes (DPAFs) as a π framework. The electron-donating DPAF moieties cause a redshifted π-π* absorption band centered at 470 nm, thus allowing efficient blue-light-induced trans-to-cis photoisomerization with a rate constant of 2.04 × 10(-1) min(-1) at the photostationary state (PSS). The open-aperture Z-scan technique that adopted a femtosecond (fs) pulse laser as excitation source shows an appreciably higher 2PA cross-section for the fluorene-derived azo chromophore than that for common azobenzene dyes at near-infrared wavelength (λex =800 nm). Furthermore, the fs 2PA response is quite uniform regardless of the molecular geometry. On the basis of the computational modeling, the intramolecular charge-transfer (ICT) process from peripheral diphenylamines to the central azo group through a fluorene π bridge is crucial to this remarkable 2PA behavior.

Analysis of the width of vertical root fracture in endodontically treated teeth by 2 micro-computed tomography systems.

INTRODUCTION: Early detection of vertical root fracture (VRF) is important for clinical endodontic practice. The purpose of this study was to measure the fracture width (distance between 2 sides of the fracture) of VRF teeth in vitro by using 2 micro-computed tomography (µ-CT) systems with different spatial resolution and voxel size. METHODS: Thirty-seven endodontically treated teeth with VRF were scanned by 80-µm pixel size µ-CT. Fifteen teeth with no obvious fracture line, blurred image, or fracture space less than 100 µm were scanned by 9-µm pixel size µ-CT. RESULTS: Presence of 2 VRF lines was more common in premolars (82%) than in molars (53%). In 7 premolars (32%) and 9 molars (60%), the VRF lines extended to within the apical 3 mm of the root. All fracture lines were detected by 9-µm pixel size µ-CT, but only 22 of 37 VRF teeth had vertical fracture identified by 80-µm µ-CT. From µ-CT examination, none of the fracture lines showed consistent and uniform fracture space. If 2 fracture lines were present, they were typically in opposite (not linear) directions. There was a significant correlation between 2 fracture lines or fracture lines extending within the 3 mm of the apex and fracture width greater than 100 µm. CONCLUSIONS: Application of 9-µm µ-CT can be accurately used for early detection of VRF. Fracture characteristics (eg, number of fracture lines, extension of fracture line) may affect the fracture width. Appropriate use of µ-CT technology can be helpful for early diagnosis of VRF.

Potentiating the efficacy of molecular targeted therapy for hepatocellular carcinoma by inhibiting the insulin-like growth factor pathway.

Insulin-like growth factor (IGF) signaling pathway is an important regulatory mechanism of tumorigenesis and drug resistance in many cancers. The present study explored the potential synergistic effects between IGF receptor (IGFR) inhibition and other molecular targeted agents (MTA) in HCC cells. HCC cell lines (Hep3B, PLC5, and SK-Hep1) and HUVECs were tested. The MTA tested included sorafenib, sunitinib, and the IGFR kinase inhibitor NVP-AEW541. The potential synergistic antitumor effects were tested by median dose effect analysis and apoptosis assay in vitro and by xenograft models in vivo. The activity and functional significance of pertinent signaling pathways and expression of apoptosis-related proteins were measured by RNA interference and Western blotting. We found that IGF can activate IGFR and downstream AKT signaling activities in all the HCC cells tested, but the growth-stimulating effect of IGF was most prominent in Hep3B cells. NVP-AEW541 can abrogate IGF-induced activation of IGFR and AKT signaling in HCC cells. IGF can increase the resistance of HCC cells to sunitinib. The apoptosis-inducing effects of sunitinib, but not sorafenib, were enhanced when IGFR signaling activity was inhibited by NVP-AEW541 or IGFR knockdown. Chk2 kinase activation was found contributory to the synergistic anti-tumor effects between sunitinib and IGFR inhibition. Our data indicate that the apoptosis-potentiating effects of IGFR inhibition for HCC may be drug-specific. Combination therapy of IGFR inhibitors with other MTA may improve the therapeutic efficacy in HCC.

Evaluation of root and canal systems of mandibular first molars in Taiwanese individuals using cone-beam computed tomography.

BACKGROUND/PURPOSE: Cone-beam computed tomography (CBCT) can provide valuable data for root canal systems of human teeth. This study used CBCT to evaluate the number of roots and canals in mandibular first molars in Taiwanese individuals. METHODS: We screened 151 patients (76 male and 75 female) scheduled for CBCT scan prior to implantation, or orthodontic, endodontic, or periodontic treatment between June 2006 and March 2009 at the Department of Dentistry, Cardinal Tien Hospital, Taipei, Taiwan. A total of 237 image samples of mandibular first molars were obtained and analyzed for their number of roots and canals. RESULTS: We found that 177 (74.7%) mandibular first molars had two roots and 60 (25.3%) had three roots. Of the 237 teeth, 133 (56.1%) had three canals, 96 (40.5%) had four, and eight (3.4%) had two canals. Of the 86 patients (43 male and 43 female) with bilateral mandibular first molars, 22 (25.6%, 15 male and 7 female) had bilateral three-rooted mandibular first molars, and six (7.0%, 4 male and 2 female) had unilateral three-rooted mandibular first molars. The chi(2) test showed a significantly higher incidence of three-rooted mandibular first molars in male (44.2%, 19/43) than in female (20.9%, 9/43, p = 0.038) subjects. CONCLUSION: Our results showed a high overall incidence (32.6%) of three-rooted mandibular first molars in Taiwanese individuals. CBCT could be a valuable tool for identifying an extra distolingual root in mandibular first molars.

A new type of asymmetric tridentate pyrrolyl-linked pincer ligand and its aluminum dihydride complexes.

The new pyrrolyl-linked pincer-type ligand, [C(4)H(2)NH(2-CH(2)NH(t)Bu)(5-CH(2)NMe(2))] (1), that has been employed conveniently in high yield by treatment of (2-t-butylaminomethyl)pyrrole with 1 equiv of formaldehyde and dimethylamine hydrochloride each in diethylether and its corresponding aluminum derivative, [C(4)H(2)N(2-CH(2)NH(t)Bu)(5-CH(2)NMe(2))]AlH(2) (2), that has been generated from Me(3)N.AlH(3) using diethylether as a solvent are described. Furthermore, reactions of 2 with 2 equiv of either 1,3-diphenylpropane-1,3-dione in diethylether or phenyl thioisocyanate in dichloromethane interestingly formed [C(4)H(2)N(2-CH(2)NH(t)Bu)(5-CH(2)NMe(2))]Al(PhCOCHCOPh)(2) (3) and [C(4)H(2)N(2-CH(2)NH(t)Bu)(5-CH(2)NMe(2))]Al(SCHNPh)(2) (4), respectively, following deprotonation or hydroalumination reaction kinetics under a dry nitrogen environment. All of the compounds have been subjected to the X-ray diffraction technique in the solid state as well as characterized by NMR spectra.

A new approximate solution for chlorine concentration decay in pipes.

Biswas et al. (1993. A model for chlorine concentration decay in pipes. Water Res. 27(12), 1715-1724) presented an analytical solution of a two-dimensional (2-D) steady-state chlorine transport equation in a pipe under the turbulent condition and employed fractional error function and regression technique to develop an approximate solution. However, their approximate solution may not give a good result if the wall decay parameter is large. This paper provides a more accurate approximate solution of the 2-D steady-state chlorine transport equation under the turbulent condition. This new approximate solution has advantages of easy evaluation and good accuracy when compared with the approximate solution given by Biswas et al. (1993). In addition, this paper also develops a methodology that combines simulated annealing (SA) with this new approximate solution to determine the wall decay parameter. Two cases are chosen to demonstrate the application of the present approximate solution and methodology. The first case is to use this new approximate solution in simulating chlorine decay in pipes with the experiment-observed data given by Rossman (2006. The effect of advanced treatment on chlorine decay in metallic pipes. Water Res. 40(13), 2493-2502), while the second case presents the determination of the wall consumption at the end of the pipe network.

A rice gene activation/knockout mutant resource for high throughput functional genomics.

Using transfer DNA (T-DNA) with functions of gene trap and gene knockout and activation tagging, a mutant population containing 55,000 lines was generated. Approximately 81% of this population carries 1-2 T-DNA copies per line, and the retrotransposon Tos17 was mostly inactive in this population during tissue culture. A total of 11,992 flanking sequence tags (FSTs) have been obtained and assigned to the rice genome. T-DNA was preferentially ( approximately 80%) integrated into genic regions. A total of 19,000 FSTs pooled from this and another T-DNA tagged population were analyzed and compared with 18,000 FSTs from a Tos17 tagged population. There was difference in preference for integrations into genic, coding, and flanking regions, as well as repetitive sequences and centromeric regions, between T-DNA and Tos17; however, T-DNA integration was more evenly distributed in the rice genome than Tos17. Our T-DNA contains an enhancer octamer next to the left border, expression of genes within genetics distances of 12.5 kb was enhanced. For example, the normal height of a severe dwarf mutant, with its gibberellin 2-oxidase (GA2ox) gene being activated by T-DNA, was restored upon GA treatment, indicating GA2ox was one of the key enzymes regulating the endogenous level of GA. Our T-DNA also contains a promoterless GUS gene next to the right border. GUS activity screening facilitated identification of genes responsive to various stresses and those regulated temporally and spatially in large scale with high frequency. Our mutant population offers a highly valuable resource for high throughput rice functional analyses using both forward and reverse genetic approaches.