Enhanced electrophysiological activity and neurotoxicity screening of environmental chemicals using 3D neurons from human neural precursor cells purified with PSA-NCAM.

The assessment of neurotoxicity for environmental chemicals is of utmost importance in ensuring public health and environmental safety. Multielectrode array (MEA) technology has emerged as a powerful tool for assessing disturbances in the electrophysiological activity. Although human embryonic stem cell (hESC)-derived neurons have been used in MEA for neurotoxicity screening, obtaining a substantial and sufficiently active population of neurons from hESCs remains challenging. In this study, we successfully differentiated neurons from a large population of human neuronal precursor cells (hNPC) purified using a polysialylated neural cell adhesion molecule (PSA-NCAM), referred to as hNPCPSA-NCAM+. The functional characterization demonstrated that hNPCPSA-NCAM+-derived neurons improve functionality by enhancing electrophysiological activity compared to total hNPC-derived neurons. Furthermore, three-dimensional (3D) neurons derived from hNPCPSA-NCAM+ exhibited reduced maturation time and enhanced electrophysiological activity on MEA. We employed subdivided population analysis of active mean firing rate (MFR) based on electrophysiological intensity to characterize the electrophysiological properties of hNPCPSA-NCAM+-3D neurons. Based on electrophysiological activity including MFR and burst parameters, we evaluated the sensitivity of hNPCPSA-NCAM+-3D neurons on MEA to screen both inhibitory and excitatory neuroactive environmental chemicals. Intriguingly, electrophysiologically active hNPCPSA-NCAM+-3D neurons demonstrated good sensitivity to evaluate neuroactive chemicals, particularly in discriminating excitatory chemicals. Our findings highlight the effectiveness of MEA approaches using hNPCPSA-NCAM+-3D neurons in the assessment of neurotoxicity associated with environmental chemicals. Furthermore, we emphasize the importance of selecting appropriate signal intensity thresholds to enhance neurotoxicity prediction and screening of environmental chemicals.

Disparities in the Quality of Working Life Among Older Workers: Housing Conditions and Life Satisfaction With Latent Class Analysis.

Little empirical research informs understanding of the disparate active aging experiences among working older adults, especially in terms of the association with living circumstances and life satisfaction. To address this knowledge gap, this study used latent class analysis on data from the 2020 Health and Retirement Study (HRS) core interview and focused on 1,194 employed adults aged 50 and above. The results revealed four subtypes of the quality of working life in older workers. Notably, in contrast to the other identified classes, higher levels of housing satisfaction and feelings of neighborhood safety were significantly associated with an increased likelihood of being a member of the group of older adults with the highest work capacities and the healthy work-life balance. Furthermore, participation in the class characterized by the highest work capacity and a healthy work-life balance was related to the highest levels of overall life satisfaction.

Safety assessment and gastrointestinal retention of orally administered cerium oxide nanoparticles in rats.

Cerium oxide nanoparticles (CeO2 NPs, NM-212) are well-known for their catalytic properties and antioxidant potential, and have many applications in various industries, drug delivery, and cosmetic formulations. CeO2 NPs exhibit strong antimicrobial activity and can be used to efficiently remove pathogens from different environments. However, knowledge of the toxicological evaluation of CeO2 NPs is too limited to support their safe use. In this study, CeO2 NPs were orally administered to Sprague Dawley rats for 13 weeks at the doses of 0, 10, 100, and 1000 mg/kg bw/day, followed by a four week recovery period. The hematology values for the absolute and relative reticulocyte counts in male rats treated with 1000 mg/kg bw/day CeO2 NPs were lower than those in control rats. The clinical chemistry values for sodium and chloride in the treated male rat groups (100 and 1000 mg/kg/day) and total protein and calcium in the treated female rat groups (100 mg/kg/day) were higher than those in the control groups. However, these changes were not consistent in both sexes, and no abnormalities were found in the corresponding pathological findings. The results showed no adverse effects on any of the parameters assessed. CeO2 NPs accumulated in the jejunum, colon, and stomach wall of rats administered 1000 mg/kg CeO2 NPs for 90 days. However, these changes were not abnormal in the corresponding histopathological and immunohistochemical examinations. Therefore, 1000 mg/kg bw/day may be considered the "no observed adverse effect level" of CeO2 NPs (NM-212) in male and female SD rats under the present experimental conditions.

Hepa-ToxMOA: a pathway-screening method for evaluating cellular stress and hepatic metabolic-dependent toxicity of natural products.

In the field of drug discovery, natural products have emerged as therapeutic agents for diseases such as cancer. However, their potential toxicity poses significant obstacles in the developing effective drug candidates. To overcome this limitation, we propose a pathway-screening method based on imaging analysis to evaluate cellular stress caused by natural products. We have established a cellular stress sensing system, named Hepa-ToxMOA, which utilizes HepG2 cells expressing green fluorescent protein (GFP) fluorescence under the control of transcription factor response elements (TREs) for transcription factors (AP1, P53, Nrf2, and NF-κB). Additionally, to augment the drug metabolic activity of the HepG2 cell line, we evaluated the cytotoxicity of 40 natural products with and without S9 fraction-based metabolic activity. Our finding revealed different activities of Hepa-ToxMOA depending on metabolic or non-metabolic activity, highlighting the involvement of specific cellular stress pathways. Our results suggest that developing a Hepa-ToxMOA system based on activity of drug metabolizing enzyme provides crucial insights into the molecular mechanisms initiating cellular stress during liver toxicity screening for natural products. The pathway-screening method addresses challenges related to the potential toxicity of natural products, advancing their translation into viable therapeutic agents.

Housing insecurity and employment stability: An investigation of working mothers.

Little evidence informs the relationship between housing insecurity and employment for working mothers. The present study aimed to identify variation in work schedules and supports, as well as the link from housing insecurity to employment experiences in a sample of at-risk mothers. Latent class analysis identified subtypes of employment stability; multinomial logistic regression estimated links from housing insecurity to class membership. Three subtypes of employment stability emerged, "Full-Time and Stable," "Full-Time and Unstable," and "Part-Time Weekend." Housing insecurity increased risk for being in the "Unstable" class relative to the other classes such that these mothers experienced stressful work schedules that offered little support or flexibility for family and child needs. Identifying and intervening on housing insecurity can promote stable employment. Increased workplace supports such as paid leave, flexible schedules, and antidiscrimination training can better enable mothers to juggle the competing demands of motherhood and work.

Aß-induced mitochondrial dysfunction in neural progenitors controls KDM5A to influence neuronal differentiation.

Mitochondria in neural progenitors play a crucial role in adult hippocampal neurogenesis by being involved in fate decisions for differentiation. However, the molecular mechanisms by which mitochondria are related to the genetic regulation of neuronal differentiation in neural progenitors are poorly understood. Here, we show that mitochondrial dysfunction induced by amyloid-beta (Aß) in neural progenitors inhibits neuronal differentiation but has no effect on the neural progenitor stage. In line with the phenotypes shown in Alzheimer's disease (AD) model mice, Aß-induced mitochondrial damage in neural progenitors results in deficits in adult hippocampal neurogenesis and cognitive function. Based on hippocampal proteome changes after mitochondrial damage in neural progenitors identified through proteomic analysis, we found that lysine demethylase 5A (KDM5A) in neural progenitors epigenetically suppresses differentiation in response to mitochondrial damage. Mitochondrial damage characteristically causes KDM5A degradation in neural progenitors. Since KDM5A also binds to and activates neuronal genes involved in the early stage of differentiation, functional inhibition of KDM5A consequently inhibits adult hippocampal neurogenesis. We suggest that mitochondria in neural progenitors serve as the checkpoint for neuronal differentiation via KDM5A. Our findings not only reveal a cell-type-specific role of mitochondria but also suggest a new role of KDM5A in neural progenitors as a mediator of retrograde signaling from mitochondria to the nucleus, reflecting the mitochondrial status.

Investigation of Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney.

Ifosfamide is an alkylating agent, a synthetic analogue of cyclophosphamide, used to treat various solid cancers. In this study, the toxicity of ifosfamide was evaluated using single-and multiple-dose intraperitoneal administration in rats under Good Laboratory Practice guidelines, and an additional microarray experiment was followed to support toxicological findings. A single dose of ifosfamide (50 mg/kg) did not induce any pathological changes. Meanwhile, severe renal toxicity was observed in the 7 and 28 days consecutively administered groups, with significant increases in blood urea nitrogen and creatinine levels. In the tox-list analysis, cholesterol synthesis-related genes were mostly affected in the liver and renal failure-related genes were affected in the kidney after ifosfamide administration. Moreover, interferon regulatory factor 7 was selected as the main upstream regulator that changed in both the liver and kidney, and was found to interact with other target genes, such as ubiquitin specific peptidase 18, radical S-adenosyl methionine domain containing 2, and interferon-stimulated gene 15, which was further confirmed by real-time RT-PCR analysis. In conclusion, we confirmed kidney-biased ifosfamide organ toxicity and identified identically altered genes in both the liver and kidney. Further comprehensive toxicogenomic studies are required to reveal the exact relationship between ifosfamide-induced genes and organ toxicity.

Facility and Family Communication during the COVID-19 Visit Restriction: Early Perspectives of Family Members.

During the COVID-19 pandemic, family concerns regarding residents in long-term care facilities (LTCFs) increased due to a high proportion of COVID cases and deaths among residents and restrictions that made it impossible to visit. These changes created numerous challenges for facilities communicating with families, and between families and residents. However, little is known about how these facilities addressed these communication challenges and how those communication strategies were related to family perceptions about the facility. We implemented an online survey of family members or friends of residents in LTCFs from April 28 to June 19, 2020, using convenience sampling. A total of 174 responses nationwide reported the types of communications used, frequency of communication and alternative visits, and whether respondents had peace of mind, would recommend the facility, or were considering removing the resident from the facility. The results of our hierarchical logistic regression showed that respondents felt greater peace of mind when there were multiple communication channels to contact the resident. Also, respondents had more negative perceptions of a facility when they were not informed about confirmed COVID cases. Our findings suggest multiple communication channels and transparency about COVID status were effective in keeping positive family perceptions about the facility.

Impedance Measurement System for Assessing the Barrier Integrity of Three-Dimensional Human Intestinal Organoids.

Human pluripotent stem cell (hPSC)-derived intestinal organoids (HIOs) hold unprecedented promise for basic biology and translational applications. However, developing a quantitative method to evaluate the epithelial cell membrane integrity of HIOs as an in vitro intestinal barrier model is a major challenge because of their complex three-dimensional (3D) structure. In this study, we developed an impedance system to measure the change in electrical resistance of 3D HIOs depending on the integrity of the intestinal epithelial cell membrane, which can reflect functionality and maturity. The expression of intestinal maturation- and tight junction-related markers was significantly higher in HIOs matured in vitro by treatment with IL-2 than in control HIOs. Analysis of gap junction size indicated that mature HIOs have greater integrity, with approximately 30% more compact gaps than immature HIOs. We designed a multi-microchannel system controlled by the inhalation pressure where the HIO is loaded, which enhances the stability and sensitivity of the impedance signal. We demonstrated the applicability of the impedance system by showing the difference in resistance between control and mature HIOs, reflecting the expression of tight junction proteins and their maturation status. We also validated the impedance system by monitoring its resistance in real time during junctional damage to HIOs induced by a digestive agent. In summary, we suggest a quantitative method to directly quantify the physiological changes in complex 3D organoid structures based on impedance spectroscopy, which can be applied to noninvasively monitor live cells and therefore enable their use in subsequent experiments.

Construction of a non-contact community treatment centre for asymptomatic and mildly symptomatic COVID-19 patients during the COVID-19 pandemic.

The explosive outbreak of COVID-19 led to a shortage of medical resources, including isolation rooms in hospitals, healthcare workers (HCWs) and personal protective equipment. Here, we constructed a new model, non-contact community treatment centres to monitor and quarantine asymptomatic and mildly symptomatic COVID-19 patients who recorded their own vital signs using a smartphone application. This new model in Korea is useful to overcome shortages of medical resources and to minimise the risk of infection transmission to HCWs.

TNFα enhances trovafloxacin-induced in vitro hepatotoxicity by inhibiting protective autophagy.

Trovafloxacin (TVX) is associated with idiosyncratic drug-induced liver injury (iDILI) and inflammation-mediated hepatotoxicity. However, the inflammatory stress-regulated mechanisms in iDILI remain unclear. Herein, we elucidated the novel role of tumor-necrosis factor alpha (TNFα), an inflammatory stress factor, in TVX-induced in vitro hepatotoxicity and synergistic toxicity. TVX specifically induced synergistic toxicity in HepG2 cells with TNFα, which inhibits autophagy. TVX-treated HepG2 cells induced protective autophagy by inhibiting the expression of mTOR signaling proteins, while ATG5 knockdown in HepG2 cells, responsible for the impairment of autophagy, enhanced TVX-induced toxicity due to the increase in cytochrome C release and JNK pathway activation. Interestingly, the expression of mTOR signal proteins, which were suppressed by TVX, disrupted the negative feedback of the PI3K/AKT pathway and TNFα rebounded p70S6K phosphorylation. Co-treatment with TVX and TNFα inhibited protective autophagy by maintaining p70S6K activity, which enhanced TVX-induced cytotoxicity. Phosphorylation of p70S6K was inhibited by siRNA knockdown and rapamycin to restore TNFα-inhibited autophagy, which prevented the synergistic effect on TVX-induced cytotoxicity. These results indicate that TVX activates protective autophagy in HepG2 cells exposed to toxicity and an imbalance in negative feedback regulation of autophagy by TNFα synergistically enhanced the toxicity. The finding from this study may contribute to a better understanding of the mechanisms underlying iDILI associated with inflammatory stress.

Competition Among Mental Health Organizations: Environmental Drivers and Strategic Responses.

While mental health system reforms have sought to leverage competition in the private sector to improve service quality and costs, competition among mental health organizations is poorly understood. To inform future studies about the impact of policy and system reforms on mental health organizations and service delivery, this qualitative study explores (1) resources for which organizations compete most intensively, (2) drivers of competition, and (3) leaders' strategic organizational responses. Semi-structured phone interviews were conducted with 15 organizational leaders (CEO's, executive directors) representing about 22% of organizations in the regional mental health market. Interviews covered leaders' perceptions about competition, and their strategic responses. Porter's seminal framework on competition was used to interpret codes and themes. Intensive competition for personnel was driven by workforce shortages, new for-profit organizations, and alternative employment opportunities. In response, organizations have attended to wages/benefits, recruitment, and retention. However, strong community need, expanded insurance coverage, and a history of local strategic responses that created service niches appeared to have minimized competition for financial resources in the region. Competition for funding and clients was expected to intensify under systems reform, and in anticipation, organizations were expanding services. Leaders also feared for the viability of smaller organizations in highly competitive environments. Consistent with theory on competition, mental health organizations compete and respond in ways that might improve services. However, the goals of privatization may have been unrealized because of minimal competition for funding and clients, and intense competition may undermine quality.

Does Self-Efficacy and Team Leader Equity Matter for Older Workers' Mental Health?

BACKGROUND AND OBJECTIVES: Prolonged working life is not necessarily associated with good mental health. Despite the importance of healthy working life in later years, little research has been conducted on predictors of mental health in the workplace among older workers. This study aimed to investigate how personal (self-efficacy) and team (leader equity) factors are associated with older workers' mental health through work engagement. RESEARCH DESIGN AND METHODS: We analyzed responses of 508 U.S. workers aged 50 years and older from the Age and Generations Study data using structural equation modeling. RESULTS: Results showed that perceived self-efficacy was a strong predictor of mental health. Also, work engagement was a powerful mechanism for promoting older adults' mental health; engagement partially mediated the relationship between perceived self-efficacy and mental health, and fully mediated the relationship between team leader equity and mental health. DISCUSSION AND IMPLICATIONS: The findings highlight how important it is for employers to invest in human capital development, suggesting human resource programs should focus on strategies that target older adults' engagement through tailored self-efficacy programs and inclusive leadership training programs. Such attempts would contribute to enhancing the mental health of older workers.

Age-friendly communities and perceived disconnectedness: the role of built environment and social engagement.

Objective: To examine the effect of access to outdoor space and buildings and social or community events on elders' perceived disconnectedness. Method: Data were from a representative survey conducted as part of an age-friendly community initiative in a large midwestern city in the United States. Hierarchical logistic regression was employed to examine the relationships between environment, engagement, and connection. Results: Having access to ramps to enter buildings reduced the odds of perceived disconnectedness by 79%, participation in social or community events reduced the odds of perceived disconnectedness by 83%. The odds of perceived disconnectedness for elders "not sure" of their access to public buildings were around 6 times that of those without access, holding all else constant. Discussion: Ensuring access to ramps to enter buildings, disseminating information about the accessibility of parks and buildings, and social or community events may reduce elders' perceived disconnectedness.

Access to Employment, Volunteer Activities, and Community Events and Perceptions of Age-Friendliness: The Role of Social Connectedness.

The aim of this study was to investigate the direct and indirect effects of access to employment, volunteer opportunities, and community events on older adults' perception of age-friendliness and feelings of connectedness. Data were from an age-friendly community survey conducted in a Midwestern city in the United States. We analyzed the responses of 264 older adult residents (50 years and older) using path analysis. Results showed that access to community events, job resources, and connectedness were predictors of older adults' perceptions of age-friendliness of their community, and that connectedness mediated the relationship between access to community events and perceived age-friendliness. The findings help to refine the concept of an age-friendly community from older adults' perspectives and emphasize the importance of fostering interactions through community events to enhance older adults' feelings of connectedness.

Intimate Partner Violence in India: Abuse in India's Empowered Action Group States.

Married women in India experience intimate partner violence (IPV) at alarming rates. This study explores regional differences in Indian women's physical IPV experiences by looking at the effect of living in eight Empowered Action Group (EAG) states. It is hypothesized that women in EAG states will be more likely to have experienced physical IPV than women living outside EAG states. A sample of 65,587 women was selected from the 2005-2006 India National Family Health Survey (NFHS-3). Counter to our hypothesis, logistic regression results show that living in an EAG state decreases likelihood of physical IPV in the past 12 months.

Chronic encapsulated expanding hematoma after stereotactic radiosurgery of cerebral arteriovenous malformation.

Stereotactic radiosurgery has become excellent alternative treatment for cerebral arteriovenous malformations (AVM). This technique has expanded to treatment of larger AVM which is not amenable to surgical management. However, its variable adverse effects should be also taken into considerations sincerely because of radiobiological characteristics such as delayed onset and progressive neurological deteriorations. Herein, we report a case in which progressively expanding hemorrhagic cyst with repeated bleedings so called chronic encapsulated expanding hematoma was developed on several years after radiosurgery treatment. Neurological and radiological findings were improved by surgical removal.

Dysregulation of the miRNA biogenesis components DICER1, DROSHA, DGCR8 and AGO2 in clear cell renal cell carcinoma in both a Korean cohort and the cancer genome atlas kidney clear cell carcinoma cohort.

Impairment of microRNA (miRNA) biogenesis may be involved in clear cell renal cell carcinoma (ccRCC). The objective of the present study was to investigate the mRNA levels of important miRNA machinery components, DICER1, DROSHA, DiGeroge syndrome critical region gene 8 (DGCR8), and Argonaute 2 (AGO2), and their correlations with clinicopathological characteristics of ccRCC using mRNA expression data from The Cancer Genome Atlas kidney clear cell carcinoma (TCGA KIRC) cohort and a Korean ccRCC cohort. mRNA levels of DICER1, DROSHA, and DGCR8 were significantly decreased in both cohorts. However, AGO2 was significantly downregulated only in the Korean ccRCC cohort. Additionally, positive correlations were observed between the altered mRNA levels of DICER1 and DROSHA as well as DROSHA and DGCR8 in both cohorts. In the TCGA KIRC cohort, alterations in the mRNA levels of DICER1 were significantly correlated with histological grade. Furthermore, the altered mRNA levels of DGCR8 showed significant associations with sex and histologic grades. However, in the Korean ccRCC cohort, no factors were significantly associated with any clinicopathological parameters, including sex, age, T stage, Fuhrman grade/The International Society of Urological Pathology grade, lymphovascular invasion, and peri-renal fat invasion. Taken together, these findings indicate that DICER1, DROSHA, DGCR8 and AGO2 are significantly dysregulated in ccRCC, suggesting that they are important in the pathophysiology of this malignancy.

Identification of clinical characteristics and factors predicting favorable treatment outcomes in elderly patients with traumatic brain injury.

Age is an important prognostic factor for patients with traumatic brain injury (TBI), and worse treatment outcomes have been reported in elderly patients. Therefore, proper treatment is needed for the increasing number of elderly patients with TBI. We aimed to analyze predictive factors of favorable treatment outcomes (FTO) in elderly patients. Clinical and radiological data from 493 patients with TBI who visited a single institute were retrospectively collected from January 2014 to December 2015. We compared the characteristics of the elderly group (individuals above 65 years) and younger group (16-65 years). We analyzed the characteristics and outcomes in both groups and the factors related to the Glasgow outcome scale-extended score at 6 months after injury in 170 elderly patients. The treatment outcomes were dichotomized into favorable and unfavorable groups. In the elderly group, the proportion of female patients and the incidence of subdural hemorrhage (SDH) were higher than in the younger group. Among the 170 elderly patients, 62 had pure SDH, and 21 of the 62 with pure SDH had undergone surgical treatment. Compared with other types of intracranial hemorrhage, FTO was as high as 85.5%, and mortality was as low as 11.3% in patients with pure SDH. High initial Glasgow coma scale score, low injury severity score, and normal pupillary reflex were significantly related to FTO in multivariate analysis. Therefore, active therapeutic strategies, including surgery should be considered for elderly patients with pure SDH without intra-parenchymal injury.