An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping.

Gastroenteropancreatic (GEP) neuroendocrine neoplasm (NEN) that consists of neuroendocrine tumor and neuroendocrine carcinoma (NEC) is a lethal but under-investigated disease owing to its rarity. To fill the scarcity of clinically relevant models of GEP-NEN, we here established 25 lines of NEN organoids and performed their comprehensive molecular characterization. GEP-NEN organoids recapitulated pathohistological and functional phenotypes of the original tumors. Whole-genome sequencing revealed frequent genetic alterations in TP53 and RB1 in GEP-NECs, and characteristic chromosome-wide loss of heterozygosity in GEP-NENs. Transcriptome analysis identified molecular subtypes that are distinguished by the expression of distinct transcription factors. GEP-NEN organoids gained independence from the stem cell niche irrespective of genetic mutations. Compound knockout of TP53 and RB1, together with overexpression of key transcription factors, conferred on the normal colonic epithelium phenotypes that are compatible with GEP-NEN biology. Altogether, our study not only provides genetic understanding of GEP-NEN, but also connects its genetics and biological phenotypes.

Subcellular progression of mesenchymal transition identified by two discrete synchronous cell lines derived from the same glioblastoma.

Glioblastomas (GBM) exhibit intratumoral heterogeneity of various oncogenic evolutional processes. We have successfully isolated and established two distinct cancer cell lines with different morphological and biological characteristics that were derived from the same tissue sample of a GBM. When we compared their genomic and transcriptomic characteristics, each cell line harbored distinct mutation clusters while sharing core driver mutations. Transcriptomic analysis revealed that one cell line was undergoing a mesenchymal transition process, unlike the other cell line. Furthermore, we could identify four tumor samples containing our cell line-like clusters from the publicly available single-cell RNA-seq data, and in a set of paired longitudinal GBM samples, we could confirm three pairs where the recurrent sample was enriched in the genes specific to our cell line undergoing mesenchymal transition. The present study provides direct evidence and a valuable source for investigating the ongoing process of subcellular mesenchymal transition in GBM, which has prognostic and therapeutic implications.

Hybrid Stomach-Intestinal Chromatin States Underlie Human Barrett's Metaplasia.

BACKGROUND & AIMS: Tissue metaplasia is uncommon in adults because established cis-element programs resist rewiring. In Barrett's esophagus, the distal esophageal mucosa acquires a predominantly intestinal character, with notable gastric features, and is predisposed to developing invasive cancers. We sought to understand the chromatin underpinnings of Barrett's metaplasia and why it commonly displays simultaneous gastric and intestinal properties. METHODS: We profiled cis-regulatory elements with active histone modifications in primary human biopsy materials using chromatin immunoprecipitation followed by DNA sequencing. Mutations in Barrett's esophagus were examined in relation to tissue-specific enhancer landscapes using a random forest machine-learning algorithm. We also profiled open chromatin at single-cell resolution in primary Barrett's biopsy specimens using the assay for transposase-accessible chromatin. We used 1- and 2-color immunohistochemistry to examine protein expression of tissue-restricted genes. RESULTS: Barrett's esophagus bears epigenome fingerprints of human stomach and intestinal columnar, but not esophageal squamous, epithelia. Mutational patterns were best explained as arising on the epigenome background of active gastric cis-elements, supporting the view that adjoining stomach epithelium is a likely tissue source. Individual cells in Barrett's metaplasia coexpress gastric and intestinal genes, reflecting concomitant chromatin access at enhancers ordinarily restricted to one or the other epithelium. Protein expression of stomach-specific mucins; CLDN18; and a novel gastric marker, ANXA10, showed extensive tissue and subclonal heterogeneity of dual stomach-intestinal cell states. CONCLUSIONS: These findings reveal mixed and dynamic tissue-restricted chromatin states and phenotypic heterogeneity in Barrett's esophagus. Pervasive intragland variation argues against stem-cell governance of this phenotype.

Mechanism for Transition of Reverse Cylindrical Micelles to Spherical Micelles Induced by Diverse Alcohols.

Herein, the effects of various alcohols on lecithin/CaCl2 organogels are investigated. Mixtures of lecithin and CaCl2 form reverse cylindrical micelles, resulting in optically transparent organogels. The addition of various alcohols to a mixture of lecithin and CaCl2 induces a decrease in viscosity through which reverse cylindrical micelles are transformed into spherical micelles (or short cylindrical micelles). Long-hydrocarbon-chain alcohols decrease the viscosity of lecithin/CaCl2 mixtures more efficiently. Hydrogen bonding and hydrocarbon chain interactions between lecithin and alcohol play important roles in the morphological transition. More importantly, isothermal titration calorimetry was conducted to obtain thermodynamic variables such as the enthalpy, equilibrium constant, Gibbs free energy, entropy, and stoichiometry of the associated molecules observed in the transition. It was found that the transition is an entropically driven process, in which the endothermic and exothermic behaviors were observed depending on the hydrocarbon chain length in the alcohol. In addition, the enthalpy for the association of the alcohol with lecithin showed a linear relationship depending on the hydrocarbon chain length, in which the magnitude of hydrogen bonding and hydrocarbon chain interactions was obtained quantitatively. To the best of our knowledge, this is the first study reporting the thermodynamic properties of the morphological transition observed in a reverse self-assembly process.

Comprehensive methylome map of lineage commitment from haematopoietic progenitors.

Epigenetic modifications must underlie lineage-specific differentiation as terminally differentiated cells express tissue-specific genes, but their DNA sequence is unchanged. Haematopoiesis provides a well-defined model to study epigenetic modifications during cell-fate decisions, as multipotent progenitors (MPPs) differentiate into progressively restricted myeloid or lymphoid progenitors. Although DNA methylation is critical for myeloid versus lymphoid differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs, a comprehensive DNA methylation map of haematopoietic progenitors, or of any multipotent/oligopotent lineage, does not exist. Here we examined 4.6 million CpG sites throughout the genome for MPPs, common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte/macrophage progenitors (GMPs), and thymocyte progenitors (DN1, DN2, DN3). Marked epigenetic plasticity accompanied both lymphoid and myeloid restriction. Myeloid commitment involved less global DNA methylation than lymphoid commitment, supported functionally by myeloid skewing of progenitors following treatment with a DNA methyltransferase inhibitor. Differential DNA methylation correlated with gene expression more strongly at CpG island shores than CpG islands. Many examples of genes and pathways not previously known to be involved in choice between lymphoid/myeloid differentiation have been identified, such as Arl4c and Jdp2. Several transcription factors, including Meis1, were methylated and silenced during differentiation, indicating a role in maintaining an undifferentiated state. Additionally, epigenetic modification of modifiers of the epigenome seems to be important in haematopoietic differentiation. Our results directly demonstrate that modulation of DNA methylation occurs during lineage-specific differentiation and defines a comprehensive map of the methylation and transcriptional changes that accompany myeloid versus lymphoid fate decisions.

Results from a Geographically Focused, Community-Based HCV Screening, Linkage-to-Care and Patient Navigation Program.

BACKGROUND: Many of the five million Americans chronically infected with hepatitis C (HCV) are unaware of their infection and are not in care. OBJECTIVE: We implemented and evaluated HCV screening and linkage-to-care interventions in a community setting. DESIGN: We developed a comprehensive, community-based HCV screening and linkage-to-care program in a medically underserved neighborhood with high rates of HCV infection in Philadelphia, Pennsylvania. We provided patient navigation services to enroll uninsured patients in insurance programs, facilitate referrals from primary care physicians and link patients to an HCV infectious disease specialist with intention to treat and cure. PATIENTS: Philadelphia residents were recruited through street outreach. MAIN MEASURES: We measured anti-HCV seroprevalence and diagnosis, linkage and retention in care outcomes for chronically infected patients. KEY RESULTS: We screened 1,301 participants for HCV; anti-HCV seroprevalence was 3.9 % and 2.8% of all patients were chronically infected. Half of chronically infected patients were newly diagnosed; the remaining patients were aware of infection but not in care. We provided confirmatory RNA testing and results, assisted patients with attaining insurance and linked most chronically infected patients to a primary care provider. The biggest barrier to retaining patients in care was obtaining referrals for subspecialty providers; however, we obtained referrals for 64% of chronically infected participants and have retained most in subspecialty HCV care. Several have commenced treatment. CONCLUSIONS: Non-clinical screening programs with patient navigator services are an effective means to diagnose, link, retain and re-engage patients in HCV care. Eliminating referral requirements for subspecialty care might further enhance retention in care for patients chronically infected with HCV.

African American community leaders' policy recommendations for reducing racial disparities in HIV infection, treatment, and care: results from a community-based participatory research project in Philadelphia, Pennsylvania.

African Americans account for 45% of new HIV infections in the United States. Little empirical research investigates African American community leaders' normative recommendations for addressing these disparities. Philadelphia's HIV infection rate is 5 times the national average, nearly 70% of new infections are among African Americans, and 2% of African Americans in Philadelphia are living with HIV/AIDS. Using a community-based participatory research approach, we convened focus groups among 52 African American community leaders from diverse backgrounds to solicit normative recommendations for reducing Philadelphia's racial disparities in HIV infection. Leaders recommended that (a) Philadelphia's city government should raise awareness about HIV/AIDS with media campaigns featuring local leaders, (b) local HIV-prevention interventions should address social and structural factors influencing HIV risks rather than focus exclusively on mode of HIV transmission, (c) resources should be distributed to the most heavily affected neighborhoods of Philadelphia, and (d) faith institutions should play a critical role in HIV testing, treatment, and prevention efforts. We developed a policy memo highlighting these normative recommendations for how to enhance local HIV prevention policy. This policy memo led to Philadelphia City Council hearings about HIV/AIDS in October 2010 and subsequently informed local HIV/AIDS prevention policy and development of local HIV prevention interventions. This community-based participatory research case study offers important lessons for effectively engaging community leaders in research to promote HIV/AIDS policy change.

The Effects of Nurses' Perception of the Older Adults and Work Stress on Nursing Competency of Nurses Who Care for Older Adult Patients at General Hospital.

The older adult population is rapidly increasing in South Korea, and hospitalization at general hospitals is increasing too. Therefore, nurses working at general hospitals need the nursing competency for older adult patients. The study was conducted to examine the effects of nurses' perception of the older adults and work stress on the nursing competency of nurses at a general hospital, South Korea. A cross-sectional, descriptive correlational design was employed. Participants were a total of 136 nurses working at a general hospital located in Seoul, South Korea. Measures used in the study were the study participants' general characteristics survey, Korean version of the Attitude Toward Old People Scale (KAOPS), the work stress scale, and the nursing competency scale. Data were collected from February to March, 2021. The regression model was statistically significant, and the explanatory power of the regression model was 33%. The significant factors affecting nursing competency were education level, perception of the older adults, and work stress. The greatest affecting factor was education level, followed by perception of the older adults and work stress in order. Nurses caring for older adult patients at general hospitals should pay attention to affecting factors to help improve the nursing competency in clinical practice. Managers should improve relevant policies to ensure that nurses have more opportunities to participate in the practical training of older adult care and explore effective training methods to improve the nurses' perception of older adults.

The Origin and Invasion Pathway of Brown Rats Rattus norvegicus on Dok-Do Island Revealed by Genome-Wide Markers from 3-RADseq Approach.

Biological invasions are known to cause local extinctions on islands. Dok-do, a small, remote volcanic island in the East Sea of Korea in the western Pacific, has recently been invaded by rats, posing ecological problems. To infer their origin and invasion pathway, we collected rats from Dok-do and from the potential introduction source locations, Ulleung-do in the Pacific Ocean, and four east coastal ports. First, we identified that the brown rat (Rattus norvegicus) was the only rat species occurring at collecting sites based on the key morphological characteristics. To determine the population-level genetic diversity pattern, we applied the 3-RADseq approach. After a series of filtrations (minor allele frequency < 0.05, Hardy-Weinberg equilibrium p < 1 × 10-7), 4042 SNPs were retained for the final dataset from the 25,439 SNPs initially isolated. The spatial structure and genetic diversity pattern of brown rats suggested that the rat population on Dok-do was likely introduced from Ulleung-do. Our work provides practical information that will assist in the management of invasive brown rats in vulnerable island ecosystems.

Comparative analyses define differences between BHD-associated renal tumour and sporadic chromophobe renal cell carcinoma.

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome, caused by germline alteration of folliculin (FLCN) gene, develops hybrid oncocytic/chromophobe tumour (HOCT) and chromophobe renal cell carcinoma (ChRCC), whereas sporadic ChRCC does not harbor FLCN alteration. To date, molecular characteristics of these similar histological types of tumours have been incompletely elucidated. METHODS: To elucidate renal tumourigenesis of BHD-associated renal tumours and sporadic renal tumours, we conducted whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) of sixteen BHD-associated renal tumours from nine unrelated BHD patients, twenty-one sporadic ChRCCs and seven sporadic oncocytomas. We then compared somatic mutation profiles with FLCN variants and RNA expression profiles between BHD-associated renal tumours and sporadic renal tumours. FINDINGS: RNA-seq analysis revealed that BHD-associated renal tumours and sporadic renal tumours have totally different expression profiles. Sporadic ChRCCs were clustered into two distinct clusters characterized by L1CAM and FOXI1 expressions, molecular markers for renal tubule subclasses. Increased mitochondrial DNA (mtDNA) copy number with fewer variants was observed in BHD-associated renal tumours compared to sporadic ChRCCs. Cell-of-origin analysis using WGS data demonstrated that BHD-associated renal tumours and sporadic ChRCCs may arise from different cells of origin and second hit FLCN alterations may occur in early third decade of life in BHD patients. INTERPRETATION: These data further our understanding of renal tumourigenesis of these two different types of renal tumours with similar histology. FUNDING: This study was supported by JSPS KAKENHI Grants, RIKEN internal grant, and the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research.

Factors Influencing Male Nursing Students' Adaptation to College Life in Korea.

BACKGROUND: Male nursing students face challenges in the nursing profession because of its female-centered nature. In particular, most male students in South Korea must complete military service while in college. Although these kinds of situations may make it difficult for them to adapt to college life, the number of male nursing students is gradually increasing. Therefore, it is important to identify the influencing factors to promote male nursing students' successful adaptation to college life. PURPOSE: This study was developed to investigate the relationship between self-efficacy, social support, stress coping, and adaptation to college life among male nursing students in Korea. Factors that influence their adaptation to college life were also analyzed. METHODS: A cross-sectional study was conducted on 217 male nursing students from seven colleges in Korea. Participants completed a questionnaire that was designed to measure self-efficacy, social support, stress coping, and adaptation to college life. Data were analyzed using descriptive statistics, independent t test, one-way analysis of variance, Scheffé test, Pearson's correlation coefficient, and multiple regression. RESULTS: Male nursing students' self-efficacy, social support, stress coping, and adaptation to college life were shown to all positively correlate with each other. The main factors influencing adaptation to college life were social support, self-efficacy, satisfaction with major, and problem-solving-centered stress coping. CONCLUSIONS: Strategies to enhance social support, self-efficacy, satisfaction with major, and problem-solving-centered stress coping should be developed to improve male nursing students' adaptation to college life.

Evaluation of the Public Health Emergency Response to the COVID-19 Pandemic in Daegu, Korea During the First Half of 2020.

OBJECTIVES: This study evaluated the response in Daegu, Korea to the first wave of the coronavirus disease 2019 (COVID-19) pandemic according to a public health emergency response model. METHODS: After an examination of the official data reported by the city of Daegu and the Korea Centers for Disease Control and Prevention, as well as a literature review and advisory meetings, we chose a response model. Daegu's responses were organized into 4 phases and evaluated by applying the response model. RESULTS: In phase 1, efforts were made to block further transmission of the virus through preemptive testing of a religious group. In phase 2, efforts were concentrated on responding to mass infections in high-risk facilities. Phase 3 involved a transition from a high-intensity social distancing campaign to a citizen participation-based quarantine system. The evaluation using the response model revealed insufficient systematic preparation for a medical surge. In addition, an incorporated health-related management system and protection measures for responders were absent. Nevertheless, the city encouraged the participation of private hospitals and developed a severity classification system. Citizens also played active roles in the pandemic response by practicing social distancing. CONCLUSIONS: This study employed the response model to evaluate the early response in Daegu to the COVID-19 pandemic and revealed areas in need of improvement or maintenance. Based on the study results, creation of a systematic model is necessary to prepare for and respond to future public health emergencies like the COVID-19 pandemic.

COOBoostR: An Extreme Gradient Boosting-Based Tool for Robust Tissue or Cell-of-Origin Prediction of Tumors.

We present here COOBoostR, a computational method designed for the putative prediction of the tissue- or cell-of-origin of various cancer types. COOBoostR leverages regional somatic mutation density information and chromatin mark features to be applied to an extreme gradient boosting-based machine-learning algorithm. COOBoostR ranks chromatin marks from various tissue and cell types, which best explain the somatic mutation density landscape of any sample of interest. A specific tissue or cell type matching the chromatin mark feature with highest explanatory power is designated as a potential tissue- or cell-of-origin. Through integrating either ChIP-seq based chromatin data, along with regional somatic mutation density data derived from normal cells/tissue, precancerous lesions, and cancer types, we show that COOBoostR outperforms existing random forest-based methods in prediction speed, with comparable or better tissue or cell-of-origin prediction performance (prediction accuracy-normal cells/tissue: 76.99%, precancerous lesions: 95.65%, cancer cells: 89.39%). In addition, our results suggest a dynamic somatic mutation accumulation at the normal tissue or cell stage which could be intertwined with the changes in open chromatin marks and enhancer sites. These results further represent chromatin marks shaping the somatic mutation landscape at the early stage of mutation accumulation, possibly even before the initiation of precancerous lesions or neoplasia.

Cellular direct conversion by cell penetrable OCT4-30Kc19 protein and BMP4 growth factor.

BACKGROUND: The number of patients suffering from osteoporosis is increasing as the elderly population increases. The demand for investigating bone regeneration strategies naturally arises. One of the approaches to induce bone regeneration is somatic cell transdifferentiation. Among the transcriptional regulators for transdifferentiation, octamer-binding transcription factor 4 (OCT4) is famous for its role in the regulation of pluripotency of stem cells. Bone morphogenetic protein 4 (BMP4) is another factor that is known to have a significant role in osteogenic differentiation. Previous studies have achieved transdifferentiation of cells into osteoblasts using viral and plasmid deliveries of these factors. Although these methods are efficient, viral and plasmid transfection have safety issues such as permanent gene incorporations and bacterial DNA insertions. Herein, we developed a cell penetrating protein-based strategy to induce transdifferentiation of endothelial cells into osteoblasts via nuclear delivery of OCT4 recombinant protein combined with the BMP4 treatment. For the nuclear delivery of OCT4 protein, we fused the protein with 30Kc19, a cell-penetrating and protein stabilizing protein derived from a silkworm hemolymph of Bombyx mori with low cytotoxic properties. This study proposes a promising cell-based therapy without any safety issues that existing transdifferentiation approaches had. METHODS: OCT4-30Kc19 protein with high penetrating activities and stability was synthesized for a protein-based osteogenic transdifferentiation system. Cells were treated with OCT4-30Kc19 and BMP4 to evaluate their cellular penetrating activity, cytotoxicity, osteogenic and angiogenic potentials in vitro. The osteogenic potential of 3D cell spheroids was also analyzed. In addition, in vivo cell delivery into subcutaneous tissue and cranial defect model was performed. RESULTS: OCT4-30Kc19 protein was produced in a soluble and stable form. OCT4-30Kc19 efficiently penetrated cells and were localized in intracellular compartments and the nucleus. Cells delivered with OCT4-30Kc19 protein combined with BMP4 showed increased osteogenesis, both in 2D and 3D culture, and showed increased angiogenesis capacity in vitro. Results from in vivo subcutaneous tissue delivery of cell-seeded scaffolds confirmed enhanced osteogenic properties of transdifferentiated HUVECs via treatment with both OCT4-30Kc19 and BMP4. In addition, in vivo mouse cranial defect experiment demonstrated successful bone regeneration of HUVECs pretreated with both OCT4-30Kc19 and BMP4. CONCLUSIONS: Using a protein-based transdifferentiation method allows an alternative approach without utilizing any genetic modification strategies, thus providing a possibility for safer use of cell-based therapies in clinical applications.

The telomere maintenance mechanism spectrum and its dynamics in gliomas.

BACKGROUND: The activation of the telomere maintenance mechanism (TMM) is one of the critical drivers of cancer cell immortality. In gliomas, TERT expression and TERT promoter mutation are considered to reliably indicate telomerase activation, while ATRX mutation and/or loss indicates an alternative lengthening of telomeres (ALT). However, these relationships have not been extensively validated in tumor tissues. METHODS: Telomerase repeated amplification protocol (TRAP) and C-circle assays were used to profile and characterize the TMM cross-sectionally (n = 412) and temporally (n = 133) across glioma samples. WES, RNA-seq, and NanoString analyses were performed to identify and validate the genetic characteristics of the TMM groups. RESULTS: We show through the direct measurement of telomerase activity and ALT in a large set of glioma samples that the TMM in glioma cannot be defined solely by the combination of telomerase activity and ALT, regardless of TERT expression, TERT promoter mutation, and ATRX loss. Moreover, we observed that a considerable proportion of gliomas lacked both telomerase activity and ALT. This telomerase activation-negative and ALT negative group exhibited evidence of slow growth potential. By analyzing a set of longitudinal samples from a separate cohort of glioma patients, we discovered that the TMM is not fixed and can change with glioma progression. CONCLUSIONS: This study suggests that the TMM is dynamic and reflects the plasticity and oncogenicity of tumor cells. Direct measurement of telomerase enzyme activity and evidence of ALT should be considered when defining TMM. An accurate understanding of the TMM in glioma is expected to provide important information for establishing cancer management strategies.

Epidemiological characteristics of a COVID-19 outbreak caused by religious activities in Daegu, Korea.

OBJECTIVES: A coronavirus disease 2019 (COVID-19) outbreak triggered by religious activities occurred in Daegu, Korea in February 2020. This outbreak spread rapidly to the community through high-risk groups. This study describes the characteristics of COVID-19 cases based on S religious group membership and summarizes the Daegu municipal government's processes and responses to control the outbreak. METHODS: The epidemiological characteristics of confirmed cases were obtained through basic and in-depth epidemiological surveys. General characteristics, the proportion of asymptomatic cases, the case-fatality rate, and the time-to-event within each group were presented after stratifying confirmed cases according to S religious group membership. RESULTS: Overall, 7,008 COVID-19 cases were confirmed in Daegu from February 18, 2020 to June 30, 2020, and 61.5% (n= 4,309) were S religious group members. Compared with non-members, members had a higher proportion of female (p< 0.001) and younger age (p< 0.001), as well as lower disease prevalence. At the time of the investigation, 38.4% of cases in members were asymptomatic versus 23.7% of cases in non-members (p< 0.001). The case-fatality rate of non-members aged ≥ 60 years was significantly higher than that of members (p< 0.001). Compared with non-members, members had longer intervals from symptom onset to diagnosis (p< 0.001) and from diagnosis to admission (p< 0.001), and a shorter interval from admission to discharge (p< 0.001). CONCLUSIONS: The epidemiological features of S religious group members, including the proportion of asymptomatic cases, case-fatality rate, and time-to-event, differed from non-members. The Daegu authorities prevented further COVID-19 spread through immediate isolation and active screening tests of all S religious group members.

Psycho-Electrophysiological Benefits of Forest Therapies Focused on Qigong and Walking with Elderly Individuals.

We developed two distinct forest therapy programs (FTPs) and compared their effects on dementia prevention and related health problems for older adults. One was focused on Qigong practice in the forest (QP) and the other involved active walking in the forest (WP). Both FTPs consisted of twelve 2-h sessions over six weeks and were conducted in an urban forest. We obtained data from 25, 18, and 26 participants aged 65 years or above for the QP, WP, and control groups, respectively. Neuropsychological scores via cognition (MoCA), geriatric depression (GDS) and quality of life (EQ-5D), and electrophysiological variables (electroencephalography, bioimpedance, and heart rate variability) were measured. We analyzed the intervention effects with a generalized linear model. Compared to the control group, the WP group showed benefits in terms of neurocognition (increases in the MoCA score, and alpha and beta band power values in the electroencephalogram), sympathetic nervous activity, and bioimpedance in the lower body. On the other hand, the QP group showed alleviated depression and an increased bioimpedance phase angle in the upper body. In conclusion, both active walking and Qigong in the forest were shown to have distinctive neuropsychological and electrophysiological benefits, and both had beneficial effects in terms of preventing dementia and relieving related health problems for elderly individuals.

Optimization of the enzymatic one pot reaction for the synthesis of uridine 5'-diphosphogalactose.

Five recombinant Escherichia coli extracts harboring overexpressed galactokinase, galactose-1-phosphate uridyltransferase, UDP-glucose pyrophophorylase, UMP kinase, and acetate kinase (AK) were utilized for the production of UDP-galactose (UDP-Gal). We analyzed the parameters which limit the yield of UDP-Gal in the reaction, and the reaction was optimized by increasing the concentration of AK. AK was used for the ATP regeneration as well as the conversion of UDP to UTP. The activities of four overexpressed enzymes were identically fixed, and then we increased the activity of AK to 20 times higher than others. The extracts catalyzed the production of UDP-Gal from UMP (10 mM), galactose (12 mM), ATP (1 mM), and acetyl phosphate (40 mM). As the result of the reaction, the conversion yield of UDP-Gal reached to 95% from 10 mMUMP.

Role of Commensal Microbes in the γ-Ray Irradiation-Induced Physiological Changes in Drosophila melanogaster.

Ionizing radiation induces biological/physiological changes and affects commensal microbes, but few studies have examined the relationship between the physiological changes induced by irradiation and commensal microbes. This study investigated the role of commensal microbes in the γ-ray irradiation-induced physiological changes in Drosophila melanogaster. The bacterial load was increased in 5 Gy irradiated flies, but irradiation decreased the number of operational taxonomic units. The mean lifespan of conventional flies showed no significant change by irradiation, whereas that of axenic flies was negatively correlated with the radiation dose. γ-Ray irradiation did not change the average number of eggs in both conventional and axenic flies. Locomotion of conventional flies was decreased after 5 Gy radiation exposure, whereas no significant change in locomotion activity was detected in axenic flies after irradiation. γ-Ray irradiation increased the generation of reactive oxygen species in both conventional and axenic flies, but the increase was higher in axenic flies. Similarly, the amounts of mitochondria were increased in irradiated axenic flies but not in conventional flies. These results suggest that axenic flies are more sensitive in their mitochondrial responses to radiation than conventional flies, and increased sensitivity leads to a reduced lifespan and other physiological changes in axenic flies.

Somatic mutation landscape reveals differential variability of cell-of-origin for primary liver cancer.

Primary liver tissue cancer types are renowned to display a consistent increase in global disease burden and mortality, thus needing more effective diagnostics and treatments. Yet, integrative research efforts to identify cell-of-origin for these cancers by utilizing human specimen data were poorly established. To this end, we analyzed previously published whole-genome sequencing data for 384 tumor and progenitor tissues along with 423 publicly available normal tissue epigenomic features and single cell RNA-seq data from human livers to assess correlation patterns and extended this information to conduct in-silico prediction of the cell-of-origin for primary liver cancer subtypes. Despite mixed histological features, the cell-of-origin for mixed hepatocellular carcinoma/intrahepatic cholangiocarcinoma subtype was predominantly predicted to be hepatocytic origin. Individual sample-level predictions also revealed hepatocytes as one of the major predicted cell-of-origin for intrahepatic cholangiocarcinoma, thus implying trans-differentiation process during cancer progression. Additional analyses on the whole genome sequencing data of hepatic progenitor cells suggest these cells may not be a direct cell-of-origin for liver cancers. These results provide novel insights on the nature and potential contributors of cell-of-origins for primary liver cancers.