The bipyridyl herbicide paraquat-induced toxicity in human neuroblastoma SH-SY5Y cells: relevance to dopaminergic pathogenesis

Paraquat (PQ) is a cationic non-selective bipyridyl herbicide widely used in agriculture to control weeds and grasses. Epidemiologic studies indicate that exposure to pesticides can be a risk factor in the incidence of Parkinson`s disease (PD). A strong correlation has been reported between exposure to paraquat and PD incidence in Canada, Taiwan, and United States. This correlation is supported by animal studies showing that paraquat produces toxicity in dopaminergic neurons of the rat and mouse brain. However, it is unclear how paraquat triggers toxicity in dopaminergic neurons. Based on the previous reports, it was hypothesized that paraquat may induce oxidative stress and proteasomal dysfunction-mediated toxicity in dopaminergic neurons. To explore this possibility, dopaminergic SH-SY5Y human neuroblastoma cells were treated with paraquat, and several biomarkers of oxidative stress or proteasomal dysfunction were investigated. First, a specific dopamine transporter inhibitor GBR12909 significantly protected SY5Y cells against the toxicity of paraquat, indicating that paraquat exerts its toxicity by a mechanism involving the dopamine transporter (DAT). Second, paraquat increased the levels of reactive oxygen species (ROS) in SY5Y cells, but decreased the levels of glutathione. Third, paraquat inhibited glutathione peroxidase activity, but did not affect glutathione reductase activity. On the other hand, paraquat increased GST activity by 24 hr, after which GST activity returned to the control value at 48 hr. Fourth, paraquat decreased mitochondrial transmembrane potential (MTP). Fifth, paraquat produced the increases in malondialdehyde (MDA) and protein carbonyls, as well as DNA fragmentation, indicating oxidative damage to major cellular components. Sixth, paraquat decreased proteasomal activity, the activities of mitochondrial complex I and V, and intracellular ATP levels, but increased the activities of caspase 3 and 9, indicating that proteasomal inhibition is linked to mitochondrial dysfunction accompanied by the activation of apoptotic signaling pathway. Seventh, paraquat increased the protein levels of heme oxygenase-1 (HO-1), p53, Bax, ñ-synuclein and ubiquitinated proteins. Eighth, paraquat induced nuclear condensation. Taken together, these findings support the hypothesis that paraquat produces oxidative stress and proteasomal dysfunctionmediated toxicity in SY5Y cells. Thus, current findings suggest that paraquat may induce the pathogenesis of dopaminergic neurons through oxidative stress and proteasomal dysfunction

Flexible Acceptance Condition of Generics from a Probabilistic Viewpoint: Towards Formalization of the Semantics of Generics

Formalization of the semantics of generics has been considered extremely challenging for their inherent vagueness and context-dependence that hinder a single fixed truth condition. The present study suggests a way to formalize the semantics of generics by constructing flexible acceptance conditions with comparative probabilities. Findings from our in-depth psycholinguistic experiment show that two comparative probabilities—cue validity and prevalence—indeed construct the flexible acceptance conditions for generics in a systematic manner that can be applied to a diverse types of generics: Acceptability of IS_A relational generics is mostly determined by prevalence without interaction with cue validity; feature-describing generics are endorsed acceptable with high cue validity, albeit mediated by prevalence; and acceptability of feature-describing generics with low cue validity is mostly determined by prevalence irrespective of cue validity. Such systematic patterns indicate a great potential for the formalization of the semantics of generics

Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes. An Individual-Participant Data Meta-Analysis

IMPORTANCE: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. OBJECTIVE: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. DESIGN, SETTING, AND PARTICIPANTS: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. EXPOSURES: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). MAIN OUTCOMES AND MEASURES: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. RESULTS: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). CONCLUSIONS AND RELEVANCE: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations

Pano-AVQA: Grounded Audio-Visual Question Answering on 360◦ Videos

© 2021 IEEE360◦ videos convey holistic views for the surroundings of a scene. It provides audio-visual cues beyond predetermined normal field of views and displays distinctive spatial relations on a sphere. However, previous benchmark tasks for panoramic videos are still limited to evaluate the semantic understanding of audio-visual relationships or spherical spatial property in surroundings. We propose a novel benchmark named Pano-AVQA as a large-scale grounded audio-visual question answering dataset on panoramic videos. Using 5.4K 360◦ video clips harvested online, we collect two types of novel question-answer pairs with bounding-box grounding: spherical spatial relation QAs and audio-visual relation QAs. We train several transformer-based models from Pano-AVQA, where the results suggest that our proposed spherical spatial embeddings and multimodal training objectives fairly contribute to a better semantic understanding of the panoramic surroundings on the dataset.N

Incremental Effect of Aging on Obesity-Related Incident Chronic Kidney Disease in the Korean General Population

Objectives: Obesity may increase the risk of kidney function decline. However, few studies have addressed how age modifies obesity-associated risk of chronic kidney disease (CKD) in the Asian general population. Design: A community-based prospective cohort study. Setting and Participants: 6538 Korean general population with normal kidney function from the Korean Genome and Epidemiology Study Database. Methods: Participants were stratified according to age (40–49, 50–59, and 60-69 years old) and body mass index [≥18.5–\u3c23 (normal-weight), ≥23–\u3c27.5 (overweight), and ≥27.5 (obese)]. We conducted Kaplan-Meier and multivariable-adjusted Cox regression analyses to investigate the association of aging and obesity with incident CKD. Results: During the 12-year follow-up, an overall incidence rate of CKD was 6.1 cases per 1000 person-years. Obese, but not overweight, people had an increased risk of incident CKD compared with normal-weight people in multivariable models adjusted for metabolic factors. When analyzed by 10-year increments, this association was significant only in 60-69-year-old individuals. Kaplan-Meier analysis showed that the incidence of CKD associated with overweight or obesity showed an accentuated increase with age. With reference to normal-weight individuals aged 40-49 years, the adjusted hazard ratio of CKD increased with age regardless of body mass index, and the positive association between obesity and incident CKD was more prominent with increasing age. Conclusions and Implications: Obesity-associated risk of incident CKD was accentuated in older people, and this association was independent of metabolic abnormalities

High physical activity alleviates the adverse effect of higher sedentary time on the incidence of chronic kidney disease

Background: Low physical activity (PA) increases the prevalence of chronic kidney disease (CKD). This study aimed to investigate the effects of PA and sedentary time (ST) on the changes in renal function and the development of CKD in the middle-aged Korean population. Methods: From the Korean Genome and Epidemiology Study Database, 7988 participants in their 40s and 60s were identified and stratified by (1) PA: high-PA (\u3e24 MET-h/day), moderate-PA (9–24 MET-h/day) and low-PA (\u3c9 MET-h/day); and (2) ST: high-ST (\u3e6 h/day), moderate-ST (3–6 h/day) and low-ST (\u3c3 h/day). Incident CKD was defined as estimated glomerular filtration rate (eGFR) \u3c 60 mL/min/1.73 m2 following the Chronic Kidney Disease Epidemiology Collaboration equation. Results: The mean age of the participants was 52.0 years. The overall incidence of CKD was 16.8 per 1000 person-years over a median of 12 years. The lower the PA and the higher the ST, the lower the baseline eGFR. Relative to the high-PA, the coefficients of the annual eGFR decline were −0.12 (95% confidence interval [CI]: −0.26 to 0.001, P = 0.081) and −0.13 (95% CI: −0.27 to 0.01, P = 0.078) in the moderate- and low-PA groups, respectively. Similarly, relative to the low-ST, the coefficients of annual eGFR decline were −0.07 (59% CI: −0.19 to 0.05, P = 0.236) and −0.14 (95% CI: −0.28 to −0.01, P = 0.039) in the moderate- and high-ST groups, respectively. Incident CKD was higher with lower PA (hazard ratio: high-PA 1.00, moderate-PA 1.13 [1.00, 1.28, P = 0.056] and low-PA 1.25 [1.11, 1.24, P \u3c 0.001]) and higher ST (hazard ratio: low-ST 1.00, moderate-ST 1.04 [0.94, 1.16, P = 0.440] and high-ST 1.19 [1.05, 1.34, P = 0.007]). The high-PA reduced the risk for the CKD development irrespective of the amount of ST. Conclusions: Low-PA and high-ST are risk factors for the development of CKD in the middle-aged Korean population. High-PA recovers high-ST, inducing a harmful effect on the occurrence of CKD

No drug–drug interactions between selective prolyl‐tRNA synthetase inhibitor, bersiporocin, and pirfenidone or nintedanib in healthy participants

Abstract Bersiporocin, a potent and selective prolyl‐tRNA synthetase inhibitor, is expected to show a synergistic effect with pirfenidone or nintedanib in patients with idiopathic pulmonary fibrosis. To validate the combination therapy of bersiporocin with pirfenidone or nintedanib, a randomized, open‐label, two‐part, one‐sequence, three‐period, three‐treatment study was designed to evaluate the effect of drug–drug interactions (DDI) regarding their pharmacokinetics, safety, and tolerability in healthy participants. In addition, the pharmacokinetic profiles of the newly formulated, enteric‐coated bersiporocin tablet were evaluated after single and multiple administrations. The potential effects of cytochrome P450 2D6 (CYP2D6) genotyping on bersiporocin pharmacokinetics and DDI were also explored. In Part 1, participants were sequentially administered a single dose of pirfenidone 600 mg, a single dose of bersiporocin 150 mg followed by multiple doses, and bersiporocin in combination with pirfenidone. In Part 2, participants were sequentially administered a single dose of nintedanib 150 mg, multiple doses of bersiporocin 150 mg, and bersiporocin in combination with nintedanib. Forty‐six participants completed the study. There was no significant pharmacokinetic DDI between bersiporocin, and pirfenidone or nintedanib. All adverse events (AEs) were mild to moderate and did not include serious AEs, suggesting bersiporocin alone or in combination therapy were well‐tolerated. The newly formulated bersiporocin 150 mg tablet showed a moderate accumulation index. There was no significant difference in the pharmacokinetic profiles after administration of bersiporocin alone or in combination therapy between CYP2D6 phenotypes. In conclusion, there are no significant DDI regarding the pharmacokinetics, safety, and tolerability of bersiporocin administration with pirfenidone or nintedanib