Effects of Hormone Replacement Therapy on Bone Mineral Density in Korean Adults With Turner Syndrome.

BACKGROUND: Turner syndrome (TS) is a common chromosomal abnormality, which is caused by loss of all or part of one X chromosome. Hormone replacement therapy in TS is important in terms of puberty, growth and prevention of osteoporosis however, such a study has never been conducted in Korea. Therefore, the purpose of our study was to determine relationship between the starting age, duration of estrogen replacement therapy (ERT) in TS and develop a hormone replacement protocol suitable for the situation in Korea. METHODS: This is retrospective study analyzed the medical records in TS patients treated at the Severance hospital, Yonsei University College of Medicine, Seoul, Korea from 1997 to 2019. Total of 188 subjects who had received a bone density test at least once were included in the study. Korean National Health and Nutrition Examination Survey (KNHANES) was used for achieving bone mineral density (BMD) of normal control group. Student's t-test, Mann-Whitney U test, ANOVA and correlation analysis were performed using SPSS 18.0. RESULTS: Each BMD measurement was significantly lower in women with TS than in healthy Korean women. Early start and longer duration of ERT is associated with higher lumbar spine BMD but not femur neck BMD. Femur neck BMD, but not lumbar spine BMD was significantly higher in women with mosaicism than 45XO group. CONCLUSION: Early onset and appropriate duration of hormone replacement therapy is important for increasing bone mineral density in patients with Turner syndrome. Also, ERT affects differently to TS patients according to mosaicism.

Effect of catheter-directed ethanol sclerotherapy on ovarian reserve in patients with recurrent endometrioma: comparative analysis with primary endometriosis.

OBJECTIVE: Catheter-directed ethanol sclerotherapy (CDS) is known to less affect the ovarian function, with comparable efficacy. This study aims to investigate the change in ovarian reserve after catheter-directed ethanol sclerotherapy in patients with recurrent endometrioma, as compared to primary endometrioma. MATERIALS AND METHODS: Retrospective, observational study. Electronic medical records and images of patients with endometrioma who underwent CDS from August 2014 to April 2022 at a single institution were obtained. Patients aged > 18 years old and with anti-Müllerian hormone (AMH) level between 0.8 and 10.0 with regular menstruation were enrolled. Cyst diameter, laterality, AMH level, and CA-125 level before and after 1 month, 6 months, 1 year, 2 years, and 3 years of sclerotherapy were obtained. RESULTS: A total of 180 patients were fit for analysis. There was no statistical difference in age and cyst size between the two groups. Mean values of AMH in each group were 3.35 in the primary group and 3.00 in the recurrent group prior to the procedure (p = 0.347). There was no significant difference in delta value of AMH after sclerotherapy in both groups at each follow-up period. Also, this result was consistent when stratified by laterality, preprocedural AMH level, and initial size of endometrioma. No case of recurrence was reported in both groups. CONCLUSIONS: The effect of CDS on ovarian reserve is not inferior in recurrent endometrioma compared to primary endometrioma. Since sclerotherapy is known to less deteriorate the ovarian function than surgical removal of endometrioma, clinician could consider this as the first-line therapy in patients with recurrent endometrioma. CLINICAL RELEVANCE STATEMENT: Catheter-directed ethanol sclerotherapy for patients with recurrent endometrioma has similar effect on ovarian reserve compared to patients with primary endometrioma. KEY POINTS: • Secondary surgery for endometrioma has significant deleterious effect on ovarian function. • Catheter-directed sclerotherapy (CDS) for endometrioma had equally minimal adverse effect on ovarian reserve, represented as anti-Müllerian hormone (AMH), in both primary and recurrent groups. • Physicians should consider CDS for patients with recurrent endometrioma who desire to preserve ovarian function.

Blood eosinophil related to maternal allergic rhinitis is associated with the incidence of allergic rhinitis in offspring: COCOA study.

OBJECTIVE: The identification of allergic rhinitis (AR) in early life is important for the target of intervention. AR is caused by various environmental factors, including house dust mites. We investigated the relationship between the Dermatophagoides farinae (Der f)-IgE and eosinophil in mothers with AR at delivery and the eosinophil levels and AR incidence in children. METHODS: The study participants were 983 mother-child pairs from the COhort for Childhood Origin of Asthma and Allergic Diseases. AR was diagnosed by a doctor at delivery in mother and at 3 years of age in offspring. The association between eosinophil level and AR was assessed using logistic regression analysis. RESULTS: The Der f-IgE level in mother having AR at delivery was associated with the mother's eosinophil level, and the mother's eosinophil level was associated with the child's eosinophil level both at age 1 and 3. The risk of AR at age 3 in children was increased according to increased eosinophil levels in mothers at delivery and in children both aged 1 and 3 years (adjusted odds ratio [aOR] and 95% confidence interval [CI]: 2.57 [1.14-5.78], 2.28 [1.02-5.13], respectively). The risk of childhood AR at the age of 3 is increased when both mothers and children have high eosiniophils (aOR and 95% CI: 2.62 [1.01-6.79], 1.37 [0.98-1.91]). CONCLUSIONS: Der f-IgE in mothers at delivery was related to eosinophil levels in mothers with AR and higher level of eosinophils in both mother and children was associated with the increased risk of AR incidence at the first 3 years of life of children.

Biofilm and Cancer: Interactions and Future Directions for Cancer Therapy.

There is a growing body of evidence supporting the significant role of bacterial biofilms in the pathogenesis of various human diseases, including cancer. Biofilms are polymicrobial communities enclosed within an extracellular matrix composed of polysaccharides, proteins, extracellular DNA, and lipids. This complex matrix provides protection against antibiotics and host immune responses, enabling the microorganisms to establish persistent infections. Moreover, biofilms induce anti-inflammatory responses and metabolic changes in the host, further facilitating their survival. Many of these changes are comparable to those observed in cancer cells. This review will cover recent research on the role of bacterial biofilms in carcinogenesis, especially in colorectal (CRC) and gastric cancers, emphasizing the shared physical and chemical characteristics of biofilms and cancer. This review will also discuss the interactions between bacteria and the tumor microenvironment, which can facilitate oncogene expression and cancer progression. This information will provide insight into developing new therapies to identify and treat biofilm-associated cancers, such as utilizing bacteria as delivery vectors, using bacteria to upregulate immune function, or more selectively targeting biofilms and cancer for their shared traits.

Dual Function of Secreted APE1/Ref-1 in TNBC Tumorigenesis: An Apoptotic Initiator and a Regulator of Chronic Inflammatory Signaling.

The simultaneous regulation of cancer cells and inflammatory immune cells in the tumor microenvironment (TME) can be an effective strategy in treating aggressive breast cancer types, such as triple-negative breast cancer (TNBC). Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multi-functional nuclear protein that can be stimulated and then secreted. The extracellular APE1/Ref-1 causes a reduction in disulfide bonds in cytokine receptors, resulting in their conformational changes, thereby inhibiting inflammatory signaling. Furthermore, the secreted APE1/Ref-1 in response to acetylation has been shown to bind to a receptor for the advanced glycation end product (RAGE), initiating the apoptotic cell death of TNBC in vitro and in vivo. This study used PPTLS-APE1/Ref-1 in an adenovirus vector (Ad-PPTLS-APE1/Ref-1) for the constant expression of extracellular APE1/Ref-1, and our results demonstrated its dual function as an apoptotic initiator and inflammation regulator. Injecting MDA-MB 231 orthotopic xenografts with the Ad-PPTLS-APE1/Ref-1 inhibited tumor growth and development in response to acetylation. Moreover, Ad-PPTLS-APE1/Ref-1 generated reactive oxygen species (ROS), and tumor tissues derived from these xenografts exhibited apoptotic bodies. Compared to normal mice, a comparable ratio of anti- and pro-inflammatory cytokines was observed in the plasma of Ad-PPTLS-APE1/Ref-1-injected mice. Mechanistically, the disturbed cytokine receptor by reducing activity of PPTLS-APE1/Ref-1 inhibited inflammatory signaling leading to the inactivation of the p21-activated kinase 1-mediated signal transducer and activator of transcription 3/nuclear factor-κB axis in tumor tissues. These results suggest that the regulation of inflammatory signaling with adenoviral-mediated PPTLS-APE1/Ref-1 in tumors modulates the secretion of pro-inflammatory cytokines in TME, thereby inhibiting aggressive cancer cell progression, and could be considered as a promising and safe therapeutic strategy for treating TNBCs.

Microbial Transformation and Biological Activities of the Prenylated Aromatic Compounds from Broussonetia kazinoki.

Broussonetia kazinoki has been used as a traditional medicine for the treatment of burns and acne, and its extracts have been found to show tyrosinase inhibitory and anticancer activities. In this study, the tyrosinase inhibitory and cytotoxic activities of B. kazinoki were explored, leading to the isolation of kazinol C (1), kazinol E (2), kazinol F (3), broussonol N (4), and kazinol X (5), of which the compounds 4 and 5 have not been previously reported. Microbial transformation has been recognized as an efficient tool to generate more active metabolites. Microbial transformation of the major compounds 1 and 3 was conducted with Mucor hiemalis, where four glucosylated metabolites (6-9) were produced from 1, while one hydroxylated (10) and one glucosylated (11) metabolites were obtained from 3. Structures of the isolated metabolites were determined by extensive spectroscopic analyses. All compounds were evaluated for their tyrosinase inhibitory and cytotoxic activities. Compound 3 and its metabolites, kazinol Y (10) and kazinol F-4″-O-ß-d-glucopyranoside (11), exhibited the most potent tyrosinase inhibitory activities with the IC50 values ranging from 0.71 to 3.36 µM. Meanwhile, none of the metabolites, except for kazinol C-2',3″-di-O-ß-d-glucopyranoside (7), showed moderate cytotoxic activities (IC50 17.80 to 24.22 µM) against A375P, B16F10 and B16F1 cell lines.

Metformin usage and the risk of colorectal cancer: a national cohort study.

PURPOSE: This study aimed to investigate the association between metformin usage and the risk of colorectal cancer (CRC) using data from the Korean National Health Insurance Service-National Health Screening Cohort database. METHODS: Data from the NHIS-HEALS cohort between 2002 and 2015 were longitudinally analyzed. Subjects were divided into three groups: metformin non-users with diabetes mellitus (DM), metformin users with DM, and no DM group. CRC was defined using the ICD-10 code (C18.0-C20.0) at the time of admission. Cox proportional hazard regression models were adopted after stepwise adjustment for confounders to investigate the association between metformin usage and colorectal cancer risk. RESULTS: During the follow-up period, of the total 323,430 participants, 2341 (1.33%) of the 175,495 males and 1204 (0.81%) of the 147,935 females were newly diagnosed with CRC. The estimated cumulative incidence of CRC was significantly different among the three groups based on Kaplan-Meier's survival curve (p values < 0.05 in both sexes). Compared with metformin non-users, hazard ratios (95% CIs) of metformin users and the no DM group were 0.66 (0.51-0.85) and 0.72 (0.61-0.85) in males and 0.59 (0.37-0.92) and 0.93 (0.66-1.29) in females, respectively, after being fully adjusted. CONCLUSIONS: Metformin users with diabetes appear to have a significantly lower risk of CRC compared with metformin non-users.

Magnetic Resonance Imaging Texture of Medial Pulvinar in Dementia with Lewy Bodies.

INTRODUCTION: Executive dysfunction is common in dementia with Lewy bodies (DLB). The pulvinar nucleus plays a role in executive control and synchronizes with cortical regions in the salience network that are vulnerable to Lewy pathology. OBJECTIVE: We investigated the pulvinar subregions in patients with mild DLB and their associations with executive function. METHODS: The sample consisted of 38 DLB patients and 38 age- and sex-matched normal controls. We evaluated cognitive function using the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet. We obtained four pulvinar nuclei using preprocessed T1-weighted magnetic resonance images. We compared volumes and textures of the DLB patients and the normal controls for each nucleus. We used a linear regression to determine the association of textures and neuropsychological test scores. RESULTS: The DLB patients showed comparable volumes to the normal controls in all pulvinar nuclei. However, the DLB patients showed different texture of the left medial pulvinar (PuM) from the normal controls. The entropy, contrast, and cluster shade were lower but autocorrelation of left PuM was higher in the DLB patients compared to the normal controls. These texture features of the left PuM were associated with the set-shifting performance measured by the Trail Making Test. CONCLUSIONS: In DLB, the left PuM may be altered from early stage, which may contribute to the development of executive dysfunction.

Metformin use reduced the risk of stomach cancer in diabetic patients in Korea: an analysis of Korean NHIS-HEALS database.

BACKGROUND: Diabetes mellitus (DM) increases atherosclerotic cardiovascular complications and cancer risks. Stomach cancer is the most common cancer in Korea. Although the survival rate of stomach cancer has improved, the disease burden is still high. METHODS: This retrospective study investigated the association between metformin use and stomach cancer incidence in a Korean population using the National Health Insurance Service-National Health Screening Cohort database. Participants aged 40-80 years old at the baseline period (2002-2003) were enrolled. The study population was categorized into three groups of metformin non-users with DM, metformin users with DM, and individuals without DM (No DM group). RESULTS: A total of 347,895 participants (14,922 metformin non-users, 9891 metformin users, and 323,082 individuals without DM) were included in the final analysis. The median follow-up duration was 12.70 years. The estimated cumulative incidence of stomach cancer was highest in metformin non-users and lowest in the No DM group (men vs. women: 3.75 vs. 1.97% in metformin non-users, 2.91 vs. 1.53% in metformin users, and 2.54 vs. 0.95% in the No DM group). Compared with metformin non-users, the hazard ratios (95% confidence intervals) for stomach cancer incidence of metformin users and the No DM group were 0.710 (0.579-0.870) and 0.879 (0.767-1.006) in men and 0.700 (0.499-0.981) and 0.701 (0.544-0.903) in women, respectively, after full adjustment. CONCLUSIONS: Metformin users with DM in the Korean population were at lower risk of stomach cancer incidence after controlling for potential confounding factors.

Association between statin use and all-cause mortality in cancer survivors, based on the Korean health insurance service between 2002 and 2015.

BACKGROUND AND AIMS: Cancer is the number one cause of death in Korea. This study aimed to investigate if statin use in cancer survivors was inversely associated with all-cause mortality. METHODS AND RESULTS: Data from the 2002 to 2015 National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) were used. The Kaplan-Meier estimator was used to estimate the survival function according to statin usage. Cox proportional hazards regression models were adopted after stepwise adjustment for potential confounders to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality. The median follow-up duration was 10.0 years. Statin users had a higher percentage of diabetes and hypertension in both sexes. Survival rates of statin users were higher than non-users (p-values <0.001 in men and 0.021 in women). Compared to non-users, the HRs (95% CIs) of statin users for all-cause mortality were 0.327 (0.194-0.553) in men and 0.287 (0.148-0.560) in women after adjustment for potential confounding factors. CONCLUSIONS: Statin users in cancer survivors had higher survival rate than non-users in both sexes.

Metformin use reduced the overall risk of cancer in diabetic patients: A study based on the Korean NHIS-HEALS cohort.

BACKGROUND AND AIM: Several studies have reported the preventive effect of metformin on cancer development. This study aimed to investigate the relationship between use of metformin and risk of cancer in Koreans. METHODS AND RESULTS: This study was designed retrospectively using the National Health Insurance Service-National Health Screening Cohort conducted between 2002 and 2015. 40 to 69-year-old subjects who received a health screening examination from 2002 to 2003 were enrolled. Hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer were estimated in a multivariate Cox proportional regression analysis. A total of 323,430 subjects was enrolled (301,905 individuals without diabetes [No DM], 8643 diabetic patients with metformin treatment [metformin users], and 12,882 diabetic patients without metformin treatment [metformin non-users]). The median follow-up period was 12.7 years. Cumulative incidence of overall cancer was 7.9% (7.7, 10.3, and 11.1% in No DM, metformin users and non-users, respectively). Compared to metformin non-users, the fully adjusted HRs (95% CIs) of metformin users and No DM for overall cancer incidence were 0.73 (0.66-0.81) and 0.75 (0.64-0.88), respectively, in men and 0.83 (0.78-0.89) and 0.81 (0.72-0.92) in women. CONCLUSIONS: Diabetic patients receiving metformin treatment, and individuals without diabetes were at lower risk for cancer incidence than diabetic patients without metformin treatment.

Fip1 regulates mRNA alternative polyadenylation to promote stem cell self-renewal.

mRNA alternative polyadenylation (APA) plays a critical role in post-transcriptional gene control and is highly regulated during development and disease. However, the regulatory mechanisms and functional consequences of APA remain poorly understood. Here, we show that an mRNA 3' processing factor, Fip1, is essential for embryonic stem cell (ESC) self-renewal and somatic cell reprogramming. Fip1 promotes stem cell maintenance, in part, by activating the ESC-specific APA profiles to ensure the optimal expression of a specific set of genes, including critical self-renewal factors. Fip1 expression and the Fip1-dependent APA program change during ESC differentiation and are restored to an ESC-like state during somatic reprogramming. Mechanistically, we provide evidence that the specificity of Fip1-mediated APA regulation depends on multiple factors, including Fip1-RNA interactions and the distance between APA sites. Together, our data highlight the role for post-transcriptional control in stem cell self-renewal, provide mechanistic insight on APA regulation in development, and establish an important function for APA in cell fate specification.

Overlapping and distinct functions of CstF64 and CstF64τ in mammalian mRNA 3' processing.

mRNA 3' processing is dynamically regulated spatially and temporally. However, the underlying mechanisms remain poorly understood. CstF64τ is a paralog of the general mRNA 3' processing factor, CstF64, and has been implicated in mediating testis-specific mRNA alternative polyadenylation (APA). However, the functions of CstF64τ in mRNA 3' processing have not been systematically investigated. We carried out a comprehensive characterization of CstF64τ and compared its properties to those of CstF64. In contrast to previous reports, we found that both CstF64 and CstF64τ are widely expressed in mammalian tissues, and their protein levels display tissue-specific variations. We further demonstrated that CstF64 and CstF64τ have highly similar RNA-binding specificities both in vitro and in vivo. CstF64 and CstF64τ modulate one another's expression and play overlapping as well as distinct roles in regulating global APA profiles. Interestingly, protein interactome analyses revealed key differences between CstF64 and CstF64τ, including their interactions with another mRNA 3' processing factor, symplekin. Together, our study of CstF64 and CstF64τ revealed both functional overlap and specificity of these two important mRNA 3' processing factors and provided new insights into the regulatory mechanisms of mRNA 3' processing.

Inflammatory myofibroblastic tumour of the urinary bladder: the role of immunoglobulin G4 and the comparison of two immunohistochemical antibodies and fluorescence in-situ hybridization for the detection of anaplastic lymphoma kinase alterations.

AIMS: We examined gene rearrangement and the expression of anaplastic lymphoma kinase (ALK) in urinary bladder inflammatory myofibroblastic tumour (IMT) using fluorescence in-situ hybridization (FISH) and two immunohistochemical antibodies to ALK. We also investigated whether IMT represents an immunoglobulin (Ig)G4-related disease. METHODS AND RESULTS: The performance of the Dako FLEX ALK monoclonal antibody (CD246) and the Cell Signaling Technology ALK (D5F3) XP monoclonal antibody were compared. Overall, 11 of 16 tumours showed ALK expression by immunohistochemistry (69%). Ten demonstrated ALK expression with both stains and one was positive with D5F3 but not CD246 (91% correlation). The D5F3 antibody yielded a stronger staining intensity and a higher sensitivity. Nine tumours demonstrated ALK rearrangements (56%) by FISH. Three were ALK(+) by immunohistochemistry but negative for rearrangement by FISH, whereas one showed rearrangement by FISH but was negative by immunohistochemistry. In total, 12 tumours were positive for ALK abnormalities (75%). Using current criteria, no cases were classified as an IgG4-related disease. CONCLUSIONS: The ALK D5F3 immunohistochemical stain showed superior staining characteristics compared with ALK CD246. Discrepancies in the results between FISH and immunohistochemistry for ALK abnormalities may have causes that are multifactorial. By current criteria, IMT does not represent an IgG4-related disease.

Oral hormone replacement therapy and uterine volume in Korean adolescents with Turner syndrome: A retrospective case-control study.

STUDY OBJECTIVE: We aimed to identify critical factors for uterine development by comparing uterine volume (UV) among patients with Turner syndrome (TS) who underwent pubertal induction (PI), patients with TS who had natural menarche (NM), and patients in a non-TS control group. METHODS: This retrospective case-control study included patients with TS who had undergone PI with oral estrogen in a PI group(n=31) and a NM group(n=7). The control group included patients without TS with spontaneous puberty who underwent pelvic ultrasound at 16 years of age. For TS patients, both the UV from the first ultrasound performed at age 16 or older (1st-UV) and the UV from the most recent final ultrasound (final-UV) were obtained. RESULTS: The 1st-UV was larger for patients in the NM group than those in the PI group (p<0.001), but did not differ significantly between the NM and control groups (p=0.375). The final-UV of the PI group was larger than their 1st-UV (p<0.001), but still smaller than the NM group (p=0.021). HRT duration and 1st-UV of PI group were positively correlated (p=0.048). There were no variables that were significantly correlated with final-UV of PI group. CONCLUSION: Patients with TS who experienced NM showed normal uterine development, but TS patients who underwent PI showed significantly smaller, undeveloped UV. While HRT duration and UV are positively correlated at the beginning of HRT, it is unclear what determines the final UV; however, late PI initiation and use of oral estrogen probably contributed to the lack of UV development.

Hormone replacement therapy and breast cancer incidence in Korean women.

OBJECTIVES: After the 2002 Women's Health Initiative (WHI) study, the global use of menopausal hormone therapy (MHT) declined, and despite subsequent studies indicating a low risk of breast cancer, concerns about MHT usage persist. We examined the relationship between changes in MHT use and changes in the incidence of breast cancer from 2002 to 2020 in South Korea. STUDY DESIGN: This study used tumor registry information from 2002 to 2020 from the Korean Statistical Information Service and analyzed the incidence rate of invasive breast cancer in women, who were divided into two age groups: <50 and >50 years. The numbers of MHT prescriptions in Korea between 2002 and 2020 was determined from pharmacy data. RESULTS: The incidence of breast cancer per 100,000 women in South Korea increased from 34.3 in 2002 to 96.4 in 2020. Breast cancer incidence rates increased annually in both groups of women (those aged under and over 50 years), with no significant difference between the two (p = 0.614). Prescriptions for estrogen therapy (ET) in 2020 were 52.7 % lower than those in 2002. Prescriptions for estrogen-progesterone therapy (EPT) decreased by 27.9 % over the same period. Conversely, tibolone prescriptions, which had initially decreased by 25.4 % in 2004, subsequently showed a steady increase and were 93.6 % higher in 2020 than in 2002. CONCLUSION: The incidence of breast cancer increased annually in Korean women of all ages; however, the use of ET and EPT for MHT has declined since 2002, particularly the use of EPT after 2010. MHT, especially EPT, did not significantly increase the incidence of breast cancer in Korean women.

Association between Daily Dietary Calcium Intake and the Risk of Cardiovascular Disease (CVD) in Postmenopausal Korean Women.

We aimed to evaluate the association between daily dietary calcium intake and the risk of cardiovascular disease (CVD) in postmenopausal women using data from the Korean National Health and Nutrition Examination Survey (KNHANES). This cross-sectional study included 12,348 women aged 45-70 years who had reached natural menopause. They were classified into three groups according to daily dietary calcium intake: <400 mg, 400-800 mg, and >800 mg. The risks of CVD, stroke, angina, and myocardial infarction were assessed in each group. Further, we performed subgroup analysis according to the post-menopause duration (≤10 vs. >10 postmenopausal years). We performed logistic regression analysis with adjustment for age, menopausal age, income, urban area, education, insulin use, body mass index, hypertension, diabetes mellitus, dyslipidemia, high alcohol intake, smoking, exercise, oral contraceptive use, and hormonal therapy use. Calcium intake level was not significantly associated with the risk of CVD in the total population and the ≤10 postmenopausal years subgroup. However, in the >10 postmenopausal years subgroup, daily calcium intake >800 mg was associated with significantly decreased risks of all CVD (odds ratio [OR], 0.27; 95% confidence interval [CI], 0.11-0.64), stroke (OR, 0.06; 95% CI, 0.01-0.42), and myocardial infarction (OR, 0.27; 95% CI, 0.11-0.64). Our findings suggest that a dietary calcium intake of >800 mg/day decreases the risk of CVD events in women who have been menopausal for >10 years.

Complex and dynamic landscape of RNA polyadenylation revealed by PAS-Seq.

Alternative polyadenylation (APA) of mRNAs has emerged as an important mechanism for post-transcriptional gene regulation in higher eukaryotes. Although microarrays have recently been used to characterize APA globally, they have a number of serious limitations that prevents comprehensive and highly quantitative analysis. To better characterize APA and its regulation, we have developed a deep sequencing-based method called Poly(A) Site Sequencing (PAS-Seq) for quantitatively profiling RNA polyadenylation at the transcriptome level. PAS-Seq not only accurately and comprehensively identifies poly(A) junctions in mRNAs and noncoding RNAs, but also provides quantitative information on the relative abundance of polyadenylated RNAs. PAS-Seq analyses of human and mouse transcriptomes showed that 40%-50% of all expressed genes produce alternatively polyadenylated mRNAs. Furthermore, our study detected evolutionarily conserved polyadenylation of histone mRNAs and revealed novel features of mitochondrial RNA polyadenylation. Finally, PAS-Seq analyses of mouse embryonic stem (ES) cells, neural stem/progenitor (NSP) cells, and neurons not only identified more poly(A) sites than what was found in the entire mouse EST database, but also detected significant changes in the global APA profile that lead to lengthening of 3' untranslated regions (UTR) in many mRNAs during stem cell differentiation. Together, our PAS-Seq analyses revealed a complex landscape of RNA polyadenylation in mammalian cells and the dynamic regulation of APA during stem cell differentiation.

Efficient internal exon recognition depends on near equal contributions from the 3' and 5' splice sites.

Pre-mRNA splicing is carried out by the spliceosome, which identifies exons and removes intervening introns. In vertebrates, most splice sites are initially recognized by the spliceosome across the exon, because most exons are small and surrounded by large introns. This gene architecture predicts that efficient exon recognition depends largely on the strength of the flanking 3' and 5' splice sites. However, it is unknown if the 3' or the 5' splice site dominates the exon recognition process. Here, we test the 3' and 5' splice site contributions towards efficient exon recognition by systematically replacing the splice sites of an internal exon with sequences of different splice site strengths. We show that the presence of an optimal splice site does not guarantee exon inclusion and that the best predictor for exon recognition is the sum of both splice site scores. Using a genome-wide approach, we demonstrate that the combined 3' and 5' splice site strengths of internal exons provide a much more significant separator between constitutive and alternative exons than either the 3' or the 5' splice site strength alone.

A Case Study on Community Treatment Center for Response to COVID-19 in Korea: Focusing on Surge Capacity 4S Component Analysis and Social Well-Being Perspective.

In March, 2020, during the COVID-19 pandemic in Korea, the first Community Treatment Center (CTC), which is a motel-type Alternate Care Site (ACS) for mild and asymptomatic patients, was opened. This is a case study of the first Community treatment center prepared to respond to COVID-19. One of the researchers worked as a medical doctor in one of the CTCs operated by the Korean government. The CTC's eight medical staff members were interviewed in-depth one-on-one. Then the data obtained from observation, collection, and interview were triangulated. In this study, it was identified based on the 4S factor that evaluates the surge capacity to meet the medical needs of CTC. And how the CTC was operated from a medical and social welfare perspective and what problems appeared to patients during the operation were analyzed. Three dormitories of a national training center were used as the CTC. Each patient used a room equipped with a toilet, a shower, and a washbasin. Medical staff and government officials with various backgrounds were dispatched. Telemedicine was also used to prevent the spread of infection. The CTC made a significant contribution to both medical and social welfare fields. It provided patients psychological stability in a comfortable environment. But some patients had psychological problems and difficulties involving work and family care. Various efforts in conjunction with participation from social workers are required to reduce these problems.