Search

(1) Background: Antifolate methotrexate (MTX) is the most common disease-modifying antirheumatic drug (DMARD) for treating human rheumatoid arthritis (RA). The mitochondrial-produced formate is essential for folate-mediated one carbon (1C) metabolism. The impacts of MTX on formate homeostasis in unknown, and rigorously controlled kinetic studies can greatly help in this regard. (2) Methods: Combining animal model (8-week old female C57BL/6JNarl mice, n = 18), cell models, stable isotopic tracer studies with gas chromatography/mass spectrometry (GC/MS) platforms, we systematically investigated how MTX interferes with the partitioning of mitochondrial and cytosolic formate metabolism. (3) Results: MTX significantly reduced de novo deoxythymidylate (dTMP) and methionine biosyntheses from mitochondrial-derived formate in cells, mouse liver, and bone marrow, supporting our postulation that MTX depletes mitochondrial 1C supply. Furthermore, MTX inhibited formate generation from mitochondria glycine cleavage system (GCS) both in vitro and in vivo. Folinate selectively rescued 1C metabolic pathways in a tissue-, cellular compartment-, and pathway-specific manner: folinate effectively reversed the inhibition of mitochondrial formate-dependent 1C metabolism in mouse bone marrow (dTMP, methionine, and GCS) and cells (dTMP and GCS) but not methionine synthesis in liver/liver-derived cells. Folinate failed to fully recover hepatic mitochondrial-formate utilization for methionine synthesis, suggesting that the efficacy of clinical folinate rescue in MTX therapy on hepatic methionine metabolism is poor. (4) Conclusion: Conducting studies in mouse and cell models, we demonstrate novel findings that MTX specifically depletes mitochondrial 1C supply that can be ameliorated by folinate supplementation except for hepatic transmethylation. These results imply that clinical use of low-dose MTX may particularly impede 1C metabolism via depletion of mitochondrial formate. The MTX induced systematic and tissue-specific formate depletion needs to be addressed more carefully, and the efficacy of folinate with respect to protecting against such depletion deserves to be evaluated in medical practice.

Amphetamines elevate extracellular dopamine, but the underlying mechanisms remain uncertain. Here we show in rodents that acute pharmacological inhibition of the vesicular monoamine transporter (VMAT) blocks amphetamine-induced locomotion and self-administration without impacting cocaine-induced behaviours. To study VMAT's role in mediating amphetamine action in dopamine neurons, we have used novel genetic, pharmacological and optical approaches in Drosophila melanogaster. In an ex vivo whole-brain preparation, fluorescent reporters of vesicular cargo and of vesicular pH reveal that amphetamine redistributes vesicle contents and diminishes the vesicle pH-gradient responsible for dopamine uptake and retention. This amphetamine-induced deacidification requires VMAT function and results from net H(+) antiport by VMAT out of the vesicle lumen coupled to inward amphetamine transport. Amphetamine-induced vesicle deacidification also requires functional dopamine transporter (DAT) at the plasma membrane. Thus, we find that at pharmacologically relevant concentrations, amphetamines must be actively transported by DAT and VMAT in tandem to produce psychostimulant effects.

Eye fundus diseases, such as retinal degenerative diseases, which lead to blindness in ≈12% of individuals aged >65 years, cause permanent damage to retinal cells. The antioxidant quercetin (QC) is promising for the effective treatment of eye fundus diseases; however, its poor solubility and low retention rate often limit its clinical application. Herein, an in situ ophthalmic tethered gold yarnball (GY) that doubles as an ocular retention agent and QC reservoir to overcome low fundus drug retention is developed. After intravitreal injection, QC@GYs enhance retinal cell leakage and internal limiting membrane permeability, facilitating the partial penetration of QC@GYs into the intraretinal tissue. The combination of retina‐tethered QC@GY and first‐level sustained release reduces macular degeneration in vivo by effectively regulating oxidative stress. Furthermore, the sustained release of QC preserves the viability of retinal pigment epithelium cells, reduces apoptosis, and suppresses drusen formation. This preservation of retinal morphology and function maximizes the therapeutic impact while minimizing the need for frequent intraocular administration. Overall, the ophthalmic tethered GY platform is a versatile tool for retinal drug delivery for the treatment of eye fundus diseases. [ABSTRACT FROM AUTHOR]

Stigma remains a significant barrier preventing individuals from seeking the support they need, particularly for individuals with East Asian heritages. To explore potential mechanisms, this study examined links from East Asian ideologies to mental health help‐seeking attitudes and peace of mind across five cultural groups: 322 respondents in China, 400 in Japan, 362 in Taiwan, 319 Asian Americans, and 688 white Americans. The three teachings of East Asia accounted for 31%–85% of the cross‐cultural differences in mental health attitudes and peace of mind. Empowering Confucian tenets (self‐cultivation, leading by example, and human heartedness), Taoism, and Buddhism all uniquely predicted greater peace of mind across most of the groups. Empowering Confucianism also predicted lower mental health stigma whereas Buddhism predicted greater stigma. Finally, Restrictive Confucian tenets (e.g., interpersonal harmony, propriety, and relational hierarchy) predicted greater stigma and lower peace of mind. Implications for addressing stigma/resistance within treatment and for promoting mental health across cultures are discussed. [ABSTRACT FROM AUTHOR]

Purpose: This study constructs an efficiency evaluation framework for assessing the human, structural and relational capital in the semiconductor industry of Taiwan. Furthermore, we analyze whether there are significant differences in efficiency across different levels concerning the industry supply chain (upstream, midstream and downstream), employee service tenure, capital scale and company establishment years. Design/methodology/approach: This study focuses on Taiwanese semiconductor companies, utilizing data sourced from the Taiwan Economic Journal (TEJ) Database for the period spanning 2017 to 2021, encompassing a total of five years. Due to the nondisclosure of intangible asset values by all companies, an effort was made to ensure a comparable baseline by excluding companies with incomplete or missing data. Finally, empirical analysis was conducted on a sample of 64 companies using the dynamic network data envelopment analysis method. Findings: (1) Overall efficiency demonstrates structural capital as the most prominent, followed by relational capital, while human capital shows relatively poorer efficiency. (2) To enhance the efficiency of intellectual capital, priority should be given to improving the efficiency of outputs related to intellectual property rights such as patents. (3) The midstream segment exhibits the best efficiency in both structural and relational capital. (4) Companies with longer employee service tenures exhibit superior efficiency in human capital in the long run. (5) Companies with extended establishment years and larger capital scales demonstrate superior efficiency in both human and structural capital. Originality/value: Reflecting on past literature, scholars have primarily focused on the relationship between intellectual capital and firm efficiency, often emphasizing the overall efficiency of intellectual capital. However, within organizations, human capital, structural capital, and relational capital are interrelated. This study, for the first time, assesses the efficiency of these three components within an organization. The research addresses the challenges in analyzing the efficiency of intellectual capital and introduces a highly contemporary approach – dynamic network data envelopment analysis (DNDEA). Using the semiconductor industry in Taiwan as a case study, this paper conducts empirical analysis in a captivating and worthy industry. Therefore, the ideas presented in this paper are original. [ABSTRACT FROM AUTHOR]

This article presents a novel approach for detecting the folding angle (Of) of foldahle OLED TDDI panels using mutual capacitance driving. It offers the potential to reduce the number of module components, conserve space, and provide additional folding angle (Of) reference data for a wide range of applications. This method can be applied in self‐capacitive and mutual‐capacitive touch sensors, eliminating the need for additional sensors or design modifications. [ABSTRACT FROM AUTHOR]