Identification and characterization of putative enhancer regions that direct Il6 transcription in murine macrophages.

Interleukin-6 (IL-6) plays a crucial role in various cellular functions, including innate and adaptive immune responses. Dysregulated expression of IL-6 is associated with hyperinflammation and chronic inflammatory diseases. In this study, we aimed to identify the enhancer regions responsible for robust Il6 mRNA expression in murine macrophages. Through comprehensive genome-wide ChIP- and ATAC-seq analyses, we identified two distinct clusters, termed E1 and E2 regions, located at -144 to -163 kb relative to the Il6 transcription start site in lipopolysaccharide (LPS)-activated murine macrophages. These clusters exhibited an accumulation of histone modification marks (H3K27ac and H3K4me1), as well as open chromatin, and were found to contain binding sites for the transcription factors PU.1, NF-κB, C/EBPß, and JunB. Upregulation of non-coding RNA (ncRNA) transcripts from the E1 and E2 regions was observed upon LPS stimulation, and repression of these ncRNAs resulted in abrogation of Il6 expression. Additionally, deletion of either E1 or E2 region significantly impaired Il6 expression, while CRISPR/dCas9 activation-mediated recruitment of the co-activator p300 to the E1 and E2 regions facilitated Il6 expression. Collectively, our findings suggest that the E1 and E2 regions serve as putative enhancers for Il6 expression.

Serum uric acid level as a risk factor for acute kidney injury in hospitalized patients: a retrospective database analysis using the integrated medical information system at Kochi Medical School hospital.

BACKGROUND AND OBJECTIVES: Recent studies have shown that both low and high levels of serum uric acid (SUA) before cardiovascular surgery are independent risk factors for postoperative acute kidney injury (AKI). However, these studies were limited by their small sample sizes. Here, we investigated the association between SUA levels and AKI by performing a retrospective database analysis of almost 30 years of data from 81,770 hospitalized patients. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENT: Hospitalized patients aged ≥18 years were retrospectively enrolled. AKI was diagnosed according to the Kidney Disease: Improving Global Outcomes 2012 Clinical Practice Guideline (KDIGO) criteria. Multivariate logistic regression analyses were performed to investigate the independent association between SUA levels and the incidence of AKI. SUA levels were treated as categorical variables because the relationship between SUA and the incidence of AKI has been suggested to be J-shaped or U-shaped. In addition to stratified SUA levels, we considered kidney function and related comorbidities, medications, and procedures performed prior to AKI onset as possible confounding risk factors. RESULTS: The final study cohort included 59,219 adult patients. Adjusted odds ratios of AKI incidence were higher in both the high- and low-SUA strata. Odds ratios tended to become larger in the higher range of SUA levels in women than in men. Additionally, this study showed that AKI risk was elevated in patients with SUA levels ≤7 mg/dL. An SUA level >7 mg/dL is considered the point of initiation of uric acid crystallization. CONCLUSIONS: SUA level could be an independent risk factor for AKI development in hospitalized patients. Additionally, our results might suggest that intervention to lower SUA levels is necessary, even in cases of moderate elevation that does not warrant hyperuricemia treatment. Results also showed that SUA levels that require attention are lower for women than for men.

[Evaluation of Cellular Effects Caused by Lunar Regolith Simulant Including Fine Particles].

The National Aeronautics and Space Administration has announced a plan to establish a manned colony on the surface of the moon, and our country, Japan, has declared its participation. The surface of the moon is covered with soil called lunar regolith, which includes fine particles. It is possible that humans will inhale lunar regolith if it is brought into the spaceship. Therefore, an evaluation of the pulmonary effects caused by lunar regolith is important for exploration of the moon. In the present study, we examine the cellular effects of lunar regolith simulant, whose components are similar to those of lunar regolith. We focused on the chemical component and particle size in particular. The regolith simulant was fractionated to < 10 µm, < 25 µm and 10-25 µm by gravitational sedimentation in suspensions. We also examined the cellular effects of fine regolith simulant whose primary particle size is 5.10 µm. These regolith simulants were applied to human lung carcinoma A549 cells at concentrations of 0.1 and 1.0 mg/ml. Cytotoxicity, oxidative stress and immune response were examined after 24 h exposure. Cell membrane damage, mitochondrial dysfunction and induction of Interleukin-8 (IL-8) were observed at the concentration of 1.0 mg/ml. The cellular effects of the regolith simulant at the concentration of 0.1 mg/ml were small, as compared with crystalline silica as a positive control. Secretion of IL-1ß and tumor necrosis factor-α (TNF-α) was observed at the concentration of 1.0 mg/ml, but induction of gene expression was not observed at 24 h after exposure. Induction of cellular oxidative stress was small. Although the cellular effects tended to be stronger in the < 10 µm particles, there was no remarkable difference. These results suggest that the chemical components and particle size have little relationship to the cellular effects of lunar regolith simulant such as cell membrane damage, induction of oxidative stress and proinflammatory effect.

[Possibility of exacerbation of allergy by lunar regolith].

Japan, U.S.A. and other foreign space agencies have plans for the construction of a lunar base and long-term stay of astronauts on the moon. The surface of the moon is covered by a thick layer of soil that includes fine particles called "lunar regolith", which is formed by meteorite impact and space weathering. Risk assessment of particulate matter on the moon is important for astronauts working in microgravity on the moon. However, there are few investigations about the biological influences of lunar regolith. Especially, there is no investigation about allergic activity to lunar regolith. The main chemical components of lunar regolith are SiO2, Al2O3, CaO, FeO, etc. Of particular interest, approximately 50% of lunar regolith consists of SiO2. There is a report that the astronauts felt hay fever-like symptoms from the inhalation of the lunar regolith. Yellow sand, whose chemical components are similar to lunar regolith, enhances allergenic reactions, suggesting the possibility that lunar regolith has an adjuvant-like activity. Although intraperitoneal administration of lunar regolith with ovalbumin to mouse did not show enhancement of allergenic reactions, further evaluation of lunar regolith's potential to exacerbate the effects of allergies is essential for development of the moon.

Wine Yeast Cells Acquire Resistance to Severe Ethanol Stress and Suppress Insoluble Protein Accumulation during Alcoholic Fermentation.

Under laboratory conditions, acute 10% (vol/vol) ethanol stress causes protein denaturation and accumulation of insoluble proteins in yeast cells. However, yeast cells can acquire resistance to severe ethanol stress by pretreatment with mild ethanol stress (6% vol/vol) and mitigate insoluble protein accumulation under subsequent exposure to 10% (vol/vol) ethanol. On the other hand, protein quality control (PQC) of yeast cells during winemaking remains poorly understood. Ethanol concentrations in the grape must increase gradually, rather than acutely, to more than 10% (vol/vol) during the winemaking process. Gradual increases in ethanol evoke two possibilities for yeast PQC under high ethanol concentrations in the must: suppression of insoluble protein accumulation through the acquisition of resistance or the accumulation of denatured insoluble proteins. We examined these two possibilities by conducting alcoholic fermentation tests at 15°C that mimic white winemaking using synthetic grape must (SGM). The results obtained revealed the negligible accumulation of insoluble proteins in wine yeast cells throughout the fermentation process. Furthermore, wine yeast cells in fermenting SGM did not accumulate insoluble proteins when transferred to synthetic defined (SD) medium containing 10% (vol/vol) ethanol. Conversely, yeast cells cultured in SD medium accumulated insoluble proteins when transferred to fermented SGM containing 9.8% (vol/vol) ethanol. Thus, wine yeast cells acquire resistance to the cellular impact of severe ethanol stress during fermentation and mitigate the accumulation of insoluble proteins. This study provides novel insights into the PQC and robustness of wine yeast during winemaking. IMPORTANCE Winemaking is a dynamic and complex process in which ethanol concentrations gradually increase to reach >10% (vol/vol) through alcoholic fermentation. However, there is little information on protein damage in wine yeast during winemaking. We investigated the insoluble protein levels of wine yeast under laboratory conditions in SD medium and during fermentation in SGM. Under laboratory conditions, wine yeast cells, as well as laboratory strain cells, accumulated insoluble proteins under acute 10% (vol/vol) ethanol stress, and this accumulation was suppressed by pretreatment with 6% (vol/vol) ethanol. During the fermentation process, insoluble protein levels were maintained at low levels in wine yeast even when the SGM ethanol concentration exceeded 10% (vol/vol). These results indicate that the progression of wine yeast through fermentation in SGM results in stress tolerance, similar to the pretreatment of cells with mild ethanol stress. These findings further the understanding of yeast cell physiology during winemaking.

Vacuolar morphology of Saccharomyces cerevisiae during the process of wine making and Japanese sake brewing.

Although ethanol and osmotic stress affect the vacuolar morphology of Saccharomyces cerevisiae, little information is available about changes in vacuolar morphology during the processes of wine making and Japanese sake (rice wine) brewing. Here, we elucidated changes in the morphology of yeast vacuoles using Zrc1p-GFP, a vacuolar membrane protein, so as to better understand yeast physiology during the brewing process. Wine yeast cells (OC-2 and EC1118) contained highly fragmented vacuoles in the sake mash (moromi) as well as in the grape must. Although sake yeast cells (Kyokai no. 9 and no. 10) also contained highly fragmented vacuoles during the wine-making process, they showed quite a distinct vacuolar morphology during sake brewing. Since the environment surrounding sake yeast cells in the sake mash did not differ much from that surrounding wine yeast cells, the difference in vacuolar morphology during sake brewing between wine yeast and sake yeast was likely caused by innate characters.

[Effect of lunar dust on humans: -lunar dust: regolith-].

We reviewed the effect of lunar dust (regolith) on humans by the combination of the hazard/exposure of regolith and microgravity of the moon. With regard to the physicochemical properties of lunar dust, the hazard-related factors are its components, fibrous materials and nanoparticles. Animal exposure studies have been performed using a simulant of lunar dust, and it was speculated that the harmful effects of the simulant lies between those of crystalline silica and titanium dioxide. Fibrous materials may not have a low solubility judging from their components. The nanoparticles in lunar dust may have harmful potentials from the view of the components. As for exposure to regolith, there is a possibility that particles larger than ones in earth (1 gravity) are respirable. In microgravity, 1) the deposition of particles of less than 1 µm in diameter in the human lung did not decrease, 2) the functions of macrophages including phagocytosis were suppressed, 3) pulmonary inflammation was changed. These data on hazard/exposure and microgravity suggest that fine and ultrafine particles in regolith may have potential hazards and risks for humans.

Factors associated with workers' perceived helpfulness of and need for health consultations given by an occupational physician at a Japanese manufacturing plant.

OBJECTIVE: The aim of this study was to clarify measures for improving the functionality of health consultations by occupational physicians, by examining factors associated with workers' perceived helpfulness of, and need for, these consultations. METHODS: An anonymous self-administered questionnaire survey was conducted at a Japanese manufacturing plant. RESULTS: Multiple regression analyses showed that workers' perceived helpfulness of, and need for, health consultations given by an occupational physician was held in common and significantly associated with the occupational physician's dedication and complete protection of privacy. CONCLUSIONS: For health consultations given by occupational physicians to be effective, it is necessary to help employees realize the physicians' outstanding dedication and to convey to the workers the absolute assurance of their privacy protection.

Formation of cytoplasmic P-bodies in sake yeast during Japanese sake brewing and wine making.

Recent studies have revealed that cytoplasmic processing bodies (P-bodies) play important roles in the control of eukaryotic gene expression in response to stress. Since the formation of P-bodies is in dynamic competition with translation, the status of translation is reflected in the assembly and disassembly of P-bodies in eukaryotic cells. During the brewing of Japanese sake and the making of wine, yeast cells are exposed to stress caused by increases in the concentration of ethanol. Here we found that ethanol stress enhances the formation of P-bodies in yeast cells in SD medium. In the wine-making process, P-body formation was also enhanced as alcoholic fermentation proceeded, but the formation of P-bodies was not simply affected by the ethanol concentration in the sake mash. These findings suggest differences in the rate of translation and the cytoplasmic mRNA flux during the sake brewing and wine making processes.

Survey of the degree of examinees' satisfaction with instructions on how to read results of general health checkups at a workplace.

To clarify measures for making clearer instructions on how to read the results of general health checkups in a workplace by surveying the views of workers on these instructions, an anonymous self-administered questionnaire survey was conducted at a Japanese manufacturing plant. The responses of 984 male workers were analyzed. The average age of the subjects was 32.1 yr (range, 19-60 yr). Regarding the instructions, 4.1% of the subjects answered "definitely sufficient," 58.9% "somewhat sufficient," 28.0% "neither sufficient nor insufficient," 8.1% "somewhat insufficient" and 0.8% "definitely insufficient." Multiple regression analysis showed that the degree of examinees' satisfaction significantly correlated with the health condition (standard partial regression coefficient =0.189, p<0.001), knowledge of health management (standard partial regression coefficient =0.095, p=0.014), and fear of lifestyle-related diseases (standard partial regression coefficient =0.095, p=0.009). The adjusted R square value of the multiple regression analysis was 0.064. It is necessary to provide more detailed information to those with poor health. Because the instructions contain many difficult medical terms, health professionals must give instructions that are easy to understand. Those feeling fear of lifestyle-related diseases may already know how to read checkup results. It is necessary to promote awareness of lifestyle-related diseases targeting people unfamiliar with such diseases.

Association between intention to stay on the job and job satisfaction among Japanese nurses in small and medium-sized private hospitals.

In order to examine the relationship between the intention to stay on the job and job satisfaction among Japanese nurses, and to obtain clues for preventing turnover, we conducted a questionnaire survey. The subjects involved in the survey included 625 female nurses (registered nurses, licensed practical nurses and assistant nurses) working in 4 small and medium-sized private hospitals, excluding directors of nursing. Of the 625 questionnaires distributed, 556 (89.0%) were returned. After excluding the questionnaires with missing values, 480 questionnaires were analyzed (effective response rate, 76.8%). The average age of the respondents was 32.8 yr (range: 20-65). The content of the questionnaire was nurse attributes, job satisfaction (30 items) and intention to stay on the job. For job satisfaction, factor analysis (principal factor method and promax rotation) was performed, and factors with an eigenvalue of > or =1 were extracted. Six factors were extracted by factor analysis. These factors were interpreted as "Work as specialists" (1st factor), "Relationship with superiors" (2nd factor), "Comfortable life" (3rd factor), "Relationship among nurses" (4th factor), "Communication with physicians" (5th factor) and "Working conditions" (6th factor). The factor scores were calculated and used as a scale for the evaluation of job satisfaction. To investigate the factors associated with intention to stay on the job among nurses, the standard partial regression coefficient was computed by multiple linear regression analysis, with intention to stay on the job as the dependent variable, and nurse attributes and job satisfaction (factor scores) as independent variables. Various factors including the organizational culture of each hospital may affect the relationship between job satisfaction and the intention to stay on the job. In order to adjust for these factors, differences among hospitals were included in the statistical model as independent variables. The result of the multiple regression analysis suggests that the intention to stay on the job was higher among nurses who were older and more satisfied with work as specialists (1st factor) and working conditions (6th factor).

A pilot study testing the dimensions of safety climate among Japanese nurses.

To investigate the dimensions of safety climate among Japanese nurses, an anonymous self-administered questionnaire survey was conducted. The subjects involved in the survey included 293 full-time nurses (registered nurses and licensed practical nurses) working in a public hospital, excluding directors of nursing. A total of 221 of the 293 nurses answered the questionnaires. Among 221 questionnaires, the questionnaires, which had missing values in the question items used in this study, were excluded from the analyses. Consequently, a total of 201 questionnaires were analyzed. The average age of the subjects was 34.7 yr. As a result of exploratory factor analysis, 5 factors were extracted as follows: intellectual development regarding medical safety among nurses, accumulated fatigue, nursing conditions, supervisors' attitudes, and communication with physicians. All the values of Cronback's coefficient alpha among these 5 factors were between 0.804 and 0.892. As a result of the confirmatory factor analysis of the 5 factors, the value of the GFI (Goodness of Fit Index) was 0.868. The value of the CFI (Comparative Fit Index) was 0.943. The value of the RMSEA (Root Mean Square Error of Approximation) was 0.062. The results of this study will contribute to the investigation of the dimensions of a nurses' safety climate scale in the future. The associations between the dimensions of the safety climate and the motivation to work toward improving patients' safety among Japanese nurses will need to be examined, as will those between the dimensions of the safety climate and actual clinical mistakes.

The degree of workers' use of annual health checkup results among Japanese workers.

In Japan, the Industrial Safety and Health Law obliges all workers to undergo annual health checkups in their workplaces. At the plant for this study, workers who have one or more abnormal findings pointed out in their annual health checkups are summoned by occupational health staff and subsequently attend health consultations conducted by occupational health nurses each year. We investigated what kinds of health consultations have improved the workers' use of the results of their annual health checkups by an anonymous self-administered questionnaire survey. In addition, we discussed the associations with the multidimensional health locus of control (MHLC) and the degree of the workers' use of these results. A total of 837 questionnaires were analyzed. The average age of the respondents was 47.9 yr (range: 19-68 yr). The main results suggest that it is necessary for occupational health staff to give workers practical advice to improve their lifestyle habits and convey to them the effectiveness of preventive health behaviors. Workers with high scores in the belief in the "internal health locus of control (IHLC)" and low scores in the "chance health locus of control (CHLC)" use the results of their health checkups to help them manage their own health.

Classification of patients complaining of sick house syndrome and/or multiple chemical sensitivity.

Sick house syndrome (SHS) is a Japanese concept derived from sick building syndrome (SBS), however SHS includes a broader scope of sickness than does SBS. Symptoms of SHS/SBS disappear after leaving the sick house/building, while symptoms of multiple chemical sensitivity (MCS) are elicited by the chance of chemical exposure after leaving the sick house/building. To establish the concept of SHS, we propose to introduce a new classification for SHS. A total of 214 patients complaining of SHS and/or MCS were independently classified using a new classification by clinical ecologists who are experienced physicians with expert knowledge of clinical ecology and general physicians according to disease pathogenesis from clinical records. The classification is as follows: type 1 (symptoms of chemical intoxication), type 2 (symptoms developed possibly due to chemical exposure), type 3 (symptoms developed not because of chemical exposure but rather because of psychological or mental factors), and type 4 (symptoms developed due to allergies or other diseases). The agreements on the classification made by clinical ecologists and general physicians reached 77.1% (Cohen's kappa=0.631), suggesting that this new classification was both apt and accurate. Relations between SHS and allergy/MCS were also studied. The cases classified as SHS type 4 more frequently had allergic past histories than did other types. The proportion of possible MCS cases was higher in the chemical induced SHS group (types 1 and 2) than in other types among male patients. For the universal use in clinical practice, it is necessary to prepare helpful diagnostic criteria of this SHS classification based on pathogenesis and carry our study forward all over the country.

Factors associated with turnover interntion among nurses in small and medium-sized medical institutions.

OBJECTIVES: The objective of this study was to evaluate factors associated with turnover intention among nurses in small and medium-sized medical institutions. METHODS: A self-administered questionaire survey was performed in 293 registered nurses, licensed practical nurses, and assistant nurses working full-time in various medical institutions. Multiple linear regression analysis was conducted, with turnover intention as the dependent variable, and nurses' basic attributes and job satisfaction as independent variables. RESULTS: As for nurses' basic attributes, turnover intention was significantly associated with registered nurses, younger nurses and those with low satisfaction with sleep. As for nurses' job satisfaction, the number of nurses with turnover intention was significantly higher for those with low satisfaction with salary, low satisfaction with welfare, poor implementation of fair salary raise and poor cooperation among nurses. CONCLUSION: Turnover intention may be reduced by the enhancement of trust in the organization, giving appropriate advice to young nurses and registered nurses, and developing measures for addressing sleep disorders.

Characterization of the export of bulk poly(A)+ mRNA in Saccharomyces cerevisiae during the wine-making process.

Ethanol stress affects the nuclear export of mRNA similarly to heat shock in Saccharomyces cerevisiae. However, we have little information about mRNA transport in actual alcoholic fermentation. Here we characterized the transport of mRNA during wine making and found that bulk poly(A)+ mRNA accumulated in the nucleus as fermentation progressed.

Behavior of new type of rock wool (HT wool) in lungs after exposure by nasal inhalation in rats.

OBJECTIVES: Previous types of rock wool has been recently replaced with high-temperature wool (HT wool). HT wool is characterized by a chemical composition with a higher concentration of Al(2)O(3) and a lower concentration of SiO(2), lower biopersistence, and a higher melting point than previous types of rock wool. To evaluate the safety of HT wool, an asbestos substitute, we examined the biopersistence of HT wool in the lungs, based on changes in fiber count according to the length and fiber size (length and width), by performing a nose-only inhalation exposure study in rats. METHODS: Male Fischer 344 rats were exposed to fibers at the target exposure concentration of 30 mg/m(3) continuously for 3 hours daily for 5 consecutive days. Rats were sacrificed shortly after exposure, and 1, 2, and 4 weeks after exposure, and their lung tissues were incinerated at a low temperature. Then, fiber counts and sizes in the lungs were analyzed using a phase contrast microscope. RESULTS: The fiber count in the lungs 4 weeks after exposure significantly decreased from the baseline value (shortly after exposure). The half-life of fibers calculated from the approximation curve was 34 days for all fibers and 11 days for fibers longer than 20 µm. CONCLUSIONS: Both the length and width significantly decreased 4 weeks after exposure, probably because fibers were ingested by alveolar macrophages, discharged to outside of the body by mucociliary movement, or lysed by body fluid. In future studies, it is necessary to examine the long-term persistence of fibers in the lungs.