Development of a Prediction Model for Subjective Physical Symptoms Induced During Systematic Anatomy Practice Among Medical Students.

To prevent unpleasant symptoms in medical students during systematic anatomy practice, we aimed to develop and validate a model that predicts the likelihood of these symptoms occurring during practice based on risk factors prior to the start of practice. A total of 452 medical students enrolled from 2014 to 2018 were surveyed before and during practice, with questions regarding their sex, psychological status, subjective symptoms, and allergies. The sum of the scores concerning three subjective symptoms related to the eyes and three subjective symptoms related to the nose and fatigue were defined as the "eye-score" and "mask-score," respectively, and a total score of 7 or more was considered symptomatic. A prediction model was developed based on a generalized linear mixed model; the outcome variable in the model was symptoms during practice, and the explanatory variables were indoor formaldehyde concentration during practice, sex, and pre-practice status, such as the students' psychological state, eye-score, mask-score, and the presence of allergies. Five-fold cross-validation was used to assess internal validity and the prediction model was applied to 110 medical students enrolled in 2021 to assess external validity. The sensitivity and specificity by five-fold cross-validation were 0.843 and 0.314 for eye symptoms and 0.847 and 0.432 for mask symptoms. In the external validity assessment, the sensitivity and specificity were 0.889 and 0.207 for eye symptoms and 0.879 and 0.532 for mask symptoms. The prediction model developed in this study can be used in future measures aimed at preventing symptoms in students.

Microbial decomposition of biodegradable plastics on the deep-sea floor.

Microbes can decompose biodegradable plastics on land, rivers and seashore. However, it is unclear whether deep-sea microbes can degrade biodegradable plastics in the extreme environmental conditions of the seafloor. Here, we report microbial decomposition of representative biodegradable plastics (polyhydroxyalkanoates, biodegradable polyesters, and polysaccharide esters) at diverse deep-sea floor locations ranging in depth from 757 to 5552 m. The degradation of samples was evaluated in terms of weight loss, reduction in material thickness, and surface morphological changes. Poly(L-lactic acid) did not degrade at either shore or deep-sea sites, while other biodegradable polyesters, polyhydroxyalkanoates, and polysaccharide esters were degraded. The rate of degradation slowed with water depth. We analysed the plastic-associated microbial communities by 16S rRNA gene amplicon sequencing and metagenomics. Several dominant microorganisms carried genes potentially encoding plastic-degrading enzymes such as polyhydroxyalkanoate depolymerases and cutinases/polyesterases. Analysis of available metagenomic datasets indicated that these microorganisms are present in other deep-sea locations. Our results confirm that biodegradable plastics can be degraded by the action of microorganisms on the deep-sea floor, although with much less efficiency than in coastal settings.

Correlation Between Work Motivation and Life Events in Female Physicians.

This study interviewed 39 mother-doctors from two university hospitals in Japan to investigate how certain stages in their lives influenced their working motivation. We conceptualized a Motivational Drive Chart to track changes of work motivation from enrollment in medical courses to the present day, recording changes in motivational values, age, and life events. It was found that the average value of motivation increased from the beginning of medical school enrollment until graduation; however, a sudden drop was noted in the age group 25 to 29 due to childcare and work-life conflicts. Motivational values were found to gradually increase in the 30 to 34 age group, owing to professional accomplishments, such as obtaining a specialist license. In Japanese society, social roles have traditionally been divided between men and women. The present study found that Japanese female doctors faced a decrease in work motivation during childrearing stages. The finding suggests that new avenues should be explored to support mother-doctors.

Effect of geranylated dihydrochalcone from Artocarpus altilis leaves extract on Plasmodium falciparum ultrastructural changes and mitochondrial malate: Quinone oxidoreductase.

Nearly half of the world's population is at risk of being infected by Plasmodium falciparum, the pathogen of malaria. Increasing resistance to common antimalarial drugs has encouraged investigations to find compounds with different scaffolds. Extracts of Artocarpus altilis leaves have previously been reported to exhibit in vitro antimalarial activity against P. falciparum and in vivo activity against P. berghei. Despite these initial promising results, the active compound from A. altilis is yet to be identified. Here, we have identified 2-geranyl-2', 4', 3, 4-tetrahydroxy-dihydrochalcone (1) from A. altilis leaves as the active constituent of its antimalarial activity. Since natural chalcones have been reported to inhibit food vacuole and mitochondrial electron transport chain (ETC), the morphological changes in food vacuole and biochemical inhibition of ETC enzymes of (1) were investigated. In the presence of (1), intraerythrocytic asexual development was impaired, and according to the TEM analysis, this clearly affected the ultrastructure of food vacuoles. Amongst the ETC enzymes, (1) inhibited the mitochondrial malate: quinone oxidoreductase (PfMQO), and no inhibition could be observed on dihydroorotate dehydrogenase (DHODH) as well as bc1 complex activities. Our study suggests that (1) has a dual mechanism of action affecting the food vacuole and inhibition of PfMQO-related pathways in mitochondria.

Biochemical Studies of Mitochondrial Malate: Quinone Oxidoreductase from Toxoplasma gondii.

Toxoplasma gondii is a protozoan parasite that causes toxoplasmosis and infects almost one-third of the global human population. A lack of effective drugs and vaccines and the emergence of drug resistant parasites highlight the need for the development of new drugs. The mitochondrial electron transport chain (ETC) is an essential pathway for energy metabolism and the survival of T. gondii. In apicomplexan parasites, malate:quinone oxidoreductase (MQO) is a monotopic membrane protein belonging to the ETC and a key member of the tricarboxylic acid cycle, and has recently been suggested to play a role in the fumarate cycle, which is required for the cytosolic purine salvage pathway. In T. gondii, a putative MQO (TgMQO) is expressed in tachyzoite and bradyzoite stages and is considered to be a potential drug target since its orthologue is not conserved in mammalian hosts. As a first step towards the evaluation of TgMQO as a drug target candidate, in this study, we developed a new expression system for TgMQO in FN102(DE3)TAO, a strain deficient in respiratory cytochromes and dependent on an alternative oxidase. This system allowed, for the first time, the expression and purification of a mitochondrial MQO family enzyme, which was used for steady-state kinetics and substrate specificity analyses. Ferulenol, the only known MQO inhibitor, also inhibited TgMQO at IC50 of 0.822 µM, and displayed different inhibition kinetics compared to Plasmodium falciparum MQO. Furthermore, our analysis indicated the presence of a third binding site for ferulenol that is distinct from the ubiquinone and malate sites.

Exploring natural microbial resources for the discovery of anti-malarial compounds.

Microorganisms in nature are highly diverse biological resources, which can be explored for drug discovery. Some countries including Brazil, Columbia, Indonesia, China, and Mexico, which are blessed with geographical uniqueness with diverse climates and display remarkable megabiodiversity, potentially provide microorganismal resources for such exploitation. In this review, as an example of drug discovery campaigns against tropical parasitic diseases utilizing microorganisms from such a megabiodiversity country, we summarize our past and on-going activities toward discovery of new antimalarials. The program was held in a bilateral collaboration between multiple Indonesian and Japanese research groups. In order to develop a new platform of drug discovery utilizing Indonesian bioresources under an international collaborative scheme, we aimed at: 1) establishment of an Indonesian microbial depository, 2) development of robust enzyme-based and cell-based screening systems, and 3) technology transfer necessary for screening, purification, and identification of antimalarial compounds from microbial culture broths. We collected, characterized, and deposited Indonesian microbes. We morphologically and genetically characterized fungi and actinomycetes strains isolated from 5 different locations representing 3 Indonesian geographical areas, and validated genetic diversity of microbes. Enzyme-based screening was developed against two validated mitochondrial enzymes from Plasmodium falciparum, dihydroorotate dehydrogenase and malate:quinone oxidoreductase, while cell-based proliferation assay was developed using the erythrocytic stage parasite of 3D7 strain. More than 17 thousands microbial culture extracts were subjected to the enzyme- and cell-based screening. Representative anti-malarial compounds discovered in this campaign are discussed, including a few isolated compounds that have been identified for the first time as anti-malarial compounds. Our antimalarial discovery campaign validated the Indonesian microbial library as a powerful resource for drug discovery. We also discuss critical needs for selection criteria for hits at each stage of screening and hit deconvolution such as preliminary extraction test for the initial profiling of the active compounds and dereplication techniques to minimize repetitive discovery of known compounds.

Identification of 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase.

Plasmodium falciparum's resistance to available antimalarial drugs highlights the need for the development of novel drugs. Pyrimidine de novo biosynthesis is a validated drug target for the prevention and treatment of malaria infection. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the oxidation of dihydroorotate to orotate and utilize ubiquinone as an electron acceptor in the fourth step of pyrimidine de novo biosynthesis. PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue. In this study, we screened 40,400 compounds from the Kyoto University chemical library against recombinant PfDHODH. These studies led to the identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine and its derivatives as a new class of PfDHODH inhibitor. Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development.

Gentisyl alcohol and homogentisic acid: Plasmodium falciparum dihydroorotate dehydrogenase inhibitors isolated from fungi.

Two Indonesian fungi Aspergillus assiutensis BioMCC-f.T.7495 and Penicillium pedernalense BioMCC-f.T.5350 along with a Japanese fungus Hypomyces pseudocorticiicola FKI-9008 have been found to produce gentisyl alcohol (1), which inhibits Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) with an IC50 value of 3.4 µM. Another Indonesian fungus, Penicillium citrinum BioMCC-f.T.6730, produced an analog of 1, homogentisic acid (4), which also inhibits PfDHODH with an IC50 value of 47.6 µM.

Characterization of Plasmodium falciparum Pantothenate Kinase and Identification of Its Inhibitors From Natural Products.

Coenzyme A (CoA) is a well-known cofactor that plays an essential role in many metabolic reactions in all organisms. In Plasmodium falciparum, the most deadly among Plasmodium species that cause malaria, CoA and its biosynthetic pathway have been proven to be indispensable. The first and rate-limiting reaction in the CoA biosynthetic pathway is catalyzed by two putative pantothenate kinases (PfPanK1 and 2) in this parasite. Here we produced, purified, and biochemically characterized recombinant PfPanK1 for the first time. PfPanK1 showed activity using pantetheine besides pantothenate, as the primary substrate, indicating that CoA biosynthesis in the blood stage of P. falciparum can bypass pantothenate. We further developed a robust and reliable screening system to identify inhibitors using recombinant PfPanK1 and identified four PfPanK inhibitors from natural compounds.

Microbial inhibitors active against Plasmodium falciparum dihydroorotate dehydrogenase derived from an Indonesian soil fungus, Talaromyces pinophilus BioMCC-f.T.3979.

An Indonesian soil fungus, Talaromyces pinophilus BioMCC-f.T.3979 was cultured to find novel scaffolds of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. We obtained altenusin (1), which inhibits PfDHODH, with an IC50 value of 5.9 µM, along with other metabolites: mitorubrinol (2) and mitorubrinic acid (3). Compounds 1 and 2 inhibited PfDHODH but displayed no activity against the human orthologue. They also inhibited P. falciparum 3D7 cell growth in vitro. Compound 3 showed little PfDHODH inhibitory activity or cell growth inhibitory activity.

Speed of action and stage specificity of Bencha-loga-wichian, a Thai traditional antipyretic formulation, against Plasmodium falciparum and the chloroquine-potentiating activity of its active compounds, tiliacorinine and yanangcorinine.

ETHNOPHARMACOLOGICAL RELEVANCE: Bencha-loga-wichian (BLW), a Thai traditional antipyretic formulation, has been reported to have promising antiplasmodial activity, and it was previously revealed that tiliacorinine and yanangcorinine, isolated from Tiliacora triandra, were the active compounds. However, the mechanisms of action of BLW have not been investigated. In addition, these active compounds are bisbenzylisoquinoline alkaloids, many compounds of which have been reported to potentiate the efficacy of chloroquine. AIMS OF THE STUDY: To investigate the antiplasmodial mechanisms of action of BLW and evaluate the effects of chloroquine combined with tiliacorinine or yanangcorinine. MATERIALS AND METHODS: Chloroquine-resistant Plasmodium falciparum (PfW2) strains at the ring, trophozoite, and schizont stages were exposed to the extracts or compounds for 2, 4, 6, 8, 10, 12, 24 or 48 h. The percentages of parasitemia were determined by flow cytometry, and their morphologies were examined by Giemsa-stained smear to evaluate the speed of action and stage specificity. For the drug combination assay, a modified fixed-ratio isobologram method was used. RESULTS: The antiplasmodial activity of BLW possessed a slow onset of action and was the most effective against ring-stage parasites. After 48 h of extracts or compounds exposure, most of the treated parasites, at all stages, turned to the pyknotic form and could not recover even after extracts or compounds removal. The results suggested that these extracts and compounds could kill the parasites or possess parasiticidal effects. In addition, the combination of chloroquine with tiliacorinine or yanangcorinine demonstrated a synergistic effect, indicating that these compounds could potentiate chloroquine efficacy against chloroquine-resistant parasites. CONCLUSION: The antiplasmodial mechanisms of action of BLW appeared to differ from that of chloroquine and other current antimalarial drugs. In addition, tiliacorinine and yanangcorinine, the active compounds of BLW, could potentiate the efficacy of chloroquine. Accordingly, BLW was shown to be a good candidate for development as a new antimalarial and useful for drug combination therapy.

Micromonospora pelagivivens sp. nov., a new species of the genus Micromonospora isolated from deep-sea sediment in Japan.

A novel marine actinomycete, designated strain KJ-029T, was isolated from a marine sediment sample (water depth of 226 m) in Kagoshima, Japan. 16S rRNA gene sequence analysis revealed that the new isolate was most closely related to Micromonospora craniellae LHW 63014T (99.3 % similarity). Phylogenetic analyses of the genus Micromonospora based on 16S rRNA gene sequences showed that strain KJ-029T was clustered with Micromonospora craniellae LHW 63014T and Micromonospora endophytica 202201T. However, digital DNA-DNA hybridization analyses presented low levels of relatedness in the range of 24.8-32.9 % between strain KJ-029T and the above closely related strains. The novel strain contained meso-diaminopimelic acid and 3-OH-diaminopimelic acid, d-glutamic acid, glycine and d-alanine in the cell-wall peptidoglycan. The acyl type of the peptidoglycan was glycolyl and mycolic acids were absent. The major menaquinone was MK-9(H4). The whole-cell sugars consisted of glucose, mannose, xylose and ribose. Phosphatidylethanolamine was detected as the major phospholipid and corresponded to phospholipid type II. The predominant cellular fatty acid was iso-C16 : 0. The DNA G+C content of the genomic DNA was 71.5 mol%. Based on the present polyphasic study, strain KJ-029T represents a novel species of the genus Micromonospora, for which the name Micromonospora pelagivivens sp. nov. is proposed. The type strain is KJ-029T (=NBRC 113519T=TBRC 9233T).

New Antimicrobial Phenyl Alkenoic Acids Isolated from an Oil Palm Rhizosphere-Associated Actinomycete, Streptomyces palmae CMU-AB204T.

Basal stem rot (BSR), or Ganoderma rot disease, is the most serious disease associated with the oil palm plant of Southeast Asian countries. A basidiomycetous fungus, Ganoderma boninense, is the causative microbe of this disease. To control BSR in oil palm plantations, biological control agents are gaining attention as a major alternative to chemical fungicides. In the course of searching for effective actinomycetes as potential biological control agents for BSR, Streptomyces palmae CMU-AB204T was isolated from oil palm rhizosphere soil collected on the campus of Chiang Mai University. The culture broth of this strain showed significant antimicrobial activities against several bacteria and phytopathogenic fungi including G. boninense. Antifungal and antibacterial compounds were isolated by antimicrobial activity-guided purification using chromatographic methods. Their structures were elucidated by spectroscopic techniques, including Nuclear Magnetic Resonance (NMR), Mass Spectrometry (MS), Ultraviolet (UV), and Infrared (IR) analyses. The current study isolated new phenyl alkenoic acids 1-6 and three known compounds, anguinomycin A (7), leptomycin A (8), and actinopyrone A (9) as antimicrobial agents. Compounds 1 and 2 displayed broad antifungal activity, though they did not show antibacterial activity. Compounds 3 and 4 revealed a strong antibacterial activity against both Gram-positive and Gram-negative bacteria including the phytopathogenic strain Xanthomonas campestris pv. oryzae. Compounds 7-9 displayed antifungal activity against Ganoderma. Thus, the antifungal compounds obtained in this study may play a role in protecting oil palm plants from Ganoderma infection with the strain S. palmae CMU-AB204T.

Advantages of the Variable Shift System, and Effective Use of Break Time to Better Support the Work Engagement of Nurses on Extended Day Shifts.

OBJECTIVES: The aim of this study is to clarify factors that support the work engagement of nurses, who bear the burden of extended day shifts, by focusing on the advantages of the variable shift system and workday break activities. METHODS: Nurses who were working under a variable shift system were asked to complete a self-report questionnaire to examine the workload, work engagement, work stressors, stress-coping strategies, and stress-coping break time activities, as well as the advantages and disadvantages of the variable shift system. Nine break activities were classified into the following four categories: social activities, rest/relaxation, entertainment, and cognitive activities. The advantages or disadvantages of the variable shift system were scored by developing composite variables using principal component analysis. These variables were used to perform a multiple regression analysis with work engagement as the dependent variable. RESULTS: The advantage score was the variable most strongly correlated with work engagement. In contrast, "Quantitative workload" was negatively correlated with work engagement. Among break activities, in the social activities category correlations were observed in "Both conversation and Email/SNS" and "Conversation only". Although in fact most nurses chose conversation as one of the break options, more than half of the nurses selected rest/relaxation as their ideal break activity. CONCLUSION: Our study suggested that the variable shift system supported the work engagement of nurses who worked extended day shifts. The results also suggested that it would be useful to arrange the employee lounge environment so that employees could freely choose between "conversation" or "taking a rest" depending on the circumstances.

Characterisation of Two Polyketides from Streptomyces sp. SKH1-2 Isolated from Roots of Musa (ABB) cv. 'Kluai Sao Kratuep Ho'

An endophytic actinomycete strain SKH1-2 isolated from Musa (ABB) cv. 'Kluai Sao Kratuep Ho' collected in Suphan Buri province (14° 54′ 22.5″ N/100° 04′ 50″ E), Thailand, was identified as Streptomyces pseudovenezuelae based on phenotypic and chemotaxonomic characteristics, and 16S rRNA sequence analyses. A chemical investigation led to the isolation of two polyketide molecules from the n-butanol crude extract of the strain SKH1-2 culture broth. The compounds were purified using various chromatographic techniques and identified using spectroscopic methods compared with earlier published data. Compound 1, chartreusin, is known as an anti-Gram (+) bacterial compound and was active against Bacillus subtilis ATCC 6633, Kocuria rhizophila ATCC 9341 and Staphylococcus aureus ATCC 6538p with MIC values of 3.1, 1.6 and 12.5 μg/mL, respectively. Compound 2, lumichrome, did not show activity against all tested microbes. To our knowledge, this is the first report of chartreusin and lumichrome isolated from S. pseudovenezuelae. Taken together, it could be proved that Thai plant species are valuable reservoirs of interesting endophytic actinomycetes producing several interesting biologically active compounds

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[Relationship between pregnancy factors and low birth weight infants, miscarriages, and stillbirths: A follow-up survey on birth conditions of pregnant women who received the maternal and child health handbook from public health nurses and midwives].

Objectives　The final evaluation of the Japanese government's Healthy Parents and Children 21 project in 2014 noted an increase in low birth weight infants as an aspect that worsened. In order to reduce the number of low birth weight infants, miscarriages, and stillbirths in Kurume City, we conducted a survey aimed at researching new measures, including the search for new risk factors of birth complications.Methods　The participants of this study were 2,986 pregnant women who submitted a pregnancy notification form in 2014. We excluded women who moved away from Kurume city or for whom birth weight records could not be obtained. Information from the pregnancy notification form was linked to birth weight records to examine the relationships between low birth weight infants, miscarriages, stillbirths, and pregnancy attributes. Variables that were shown to be related in an initial univariate analysis were analyzed further in a multiple logistic regression analysis with low birth weight, miscarriage, or stillbirth as the response variables.Results　A multiple logistic regression analysis showed that being 35 years or older (odds ratio [OR]: 1.41), height less than 158 cm (OR: 1.45), non-pregnant body mass index (BMI) less than 18.5 (OR: 1.48), and detection of physical abnormalities by a physician during the pregnancy (OR: 2.20) were independent maternal factors that were significantly associated with low birth weight. Being aged 35 years or older (OR: 2.05) and smoking (OR: 3.42) were independent factors that were significantly associated with miscarriage and stillbirth. In addition, the cessation of alcohol use (OR: 0.51) significantly reduced this risk.Conclusion　Because some biological factors such as "age" and "non-pregnant BMI" are invariable, we encourage pregnant women to get checkups to detect abnormalities early or to attend birthing classes that offer mental support, especially for pregnant women over 35 years. We want to tell young generations that pregnant women over 35 are at an increased risk of having low birth weight infants, miscarriages, and stillbirths, and those pregnant women with a lower BMI have an increased risk of low birth weight infants. "Maintenance of appropriate body weight," "smoking," "alcohol," socioeconomic issues such as "lack of systems for seeking advice and support staff," and "financial concerns" can be improved with health education from public health nurses and multidisciplinary support interventions. At the Children Care Support Center in Kurume city, professionals work together to provide continuous support to families during pregnancy, childbirth, and parenting. As a result, we may be able to contribute to reducing the number of low birth weight infants, miscarriages, and stillbirths.