Factors and age-related drivers that influence self-rated bad health in police officers: A cross-sectional study.

Objective: Although some previous studies have investigated health in police officers, investigations of related factors have been limited to work-related associations or those affecting certain police officers. To address this gap, this study investigated relationships between sociodemographic factors, work-related factors, health behaviors, health conditions, and self-rated bad health (SRBH) in Korean police officers. Methods: In 2021, we conducted a cross-sectional survey in cooperation with the Korean National Police Agency (KNPA). The respondents were 6,591 police officers aged 21-60 years, all of whom agreed to complete the survey online using the police agency's intranet. After collecting data, we conducted a multiple logistic regression analysis to examine factors that were associated with SRBH, with calculations for adjusted odds ratios (ORs) and 95 % confidence intervals (CIs). The study model included a range of individual socioeconomic characteristics, work-related variables, health behaviors, and health conditions. Results: Although the associated factors varied according to age group, several factors generally related to SRBH, including the lack of exercise, stress, having one or more chronic diseases, and work-related pain. By contrast, neither sex nor sleep duration were associated with SRBH of respondents. Monthly night work, smoking, and alcohol consumption were only associated with SRBH of certain age groups. Conclusions: Several variables clearly related to SRBH of police officers. In this context, health-related associations, especially stress and chronic diseases, tended to differ according to age, including those that should be considered to improve health. These findings have important implications for relevant healthcare programs and interventions.

Molecular mechanism for regulating APOBEC3G DNA editing function by the non-catalytic domain.

APOBEC3G (A3G) belongs to the AID/APOBEC cytidine deaminase family and is essential for antiviral immunity. It contains two zinc-coordinated cytidine-deaminase (CD) domains. The N-terminal CD1 domain is non-catalytic but has a strong affinity for nucleic acids, whereas the C-terminal CD2 domain catalyzes C-to-U editing in single-stranded DNA. The interplay between the two domains in DNA binding and editing is not fully understood. Here, our studies on rhesus macaque A3G (rA3G) show that the DNA editing function in linear and hairpin loop DNA is greatly enhanced by AA or GA dinucleotide motifs present downstream (in the 3'-direction) but not upstream (in the 5'-direction) of the target-C editing sites. The effective distance between AA/GA and the target-C sites depends on the local DNA secondary structure. We present two co-crystal structures of rA3G bound to ssDNA containing AA and GA, revealing the contribution of the non-catalytic CD1 domain in capturing AA/GA DNA and explaining our biochemical observations. Our structural and biochemical findings elucidate the molecular mechanism underlying the cooperative function between the non-catalytic and the catalytic domains of A3G, which is critical for its antiviral role and its contribution to genome mutations in cancer.

Mesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes.

Antiviral DNA cytosine deaminases APOBEC3A and APOBEC3B are major sources of mutations in cancer by catalyzing cytosine-to-uracil deamination. APOBEC3A preferentially targets single-stranded DNAs, with a noted affinity for DNA regions that adopt stem-loop secondary structures. However, the detailed substrate preferences of APOBEC3A and APOBEC3B have not been fully established, and the specific influence of the DNA sequence on APOBEC3A and APOBEC3B deaminase activity remains to be investigated. Here, we find that APOBEC3B also selectively targets DNA stem-loop structures, and they are distinct from those subjected to deamination by APOBEC3A. We develop Oligo-seq, an in vitro sequencing-based method to identify specific sequence contexts promoting APOBEC3A and APOBEC3B activity. Through this approach, we demonstrate that APOBEC3A and APOBEC3B deaminase activity is strongly regulated by specific sequences surrounding the targeted cytosine. Moreover, we identify the structural features of APOBEC3B and APOBEC3A responsible for their substrate preferences. Importantly, we determine that APOBEC3B-induced mutations in hairpin-forming sequences within tumor genomes differ from the DNA stem-loop sequences mutated by APOBEC3A. Together, our study provides evidence that APOBEC3A and APOBEC3B can generate distinct mutation landscapes in cancer genomes, driven by their unique substrate selectivity.

Mesoscale DNA Features Impact APOBEC3A and APOBEC3B Deaminase Activity and Shape Tumor Mutational Landscapes.

Antiviral DNA cytosine deaminases APOBEC3A and APOBEC3B are major sources of mutations in cancer by catalyzing cytosine-to-uracil deamination. APOBEC3A preferentially targets singlestranded DNAs, with a noted affinity for DNA regions that adopt stem-loop secondary structures. However, the detailed substrate preferences of APOBEC3A and APOBEC3B have been fully established, and the specific influence of the DNA sequence on APOBEC3A APOBEC3B deaminase activity remains to be investigated. Here, we find that APOBEC3B selectively targets DNA stem-loop structures, and they are distinct from those subjected deamination by APOBEC3A. We develop Oligo-seq, a novel in vitro sequencing-based to identify specific sequence contexts promoting APOBEC3A and APOBEC3B activity. Through this approach, we demonstrate that APOBEC3A an APOBEC3B deaminase activity is strongly regulated by specific sequences surrounding the targeted cytosine. Moreover, we identify structural features of APOBEC3B and APOBEC3A responsible for their substrate preferences. Importantly, we determine that APOBEC3B-induced mutations in hairpin-forming sequences within tumor genomes differ from the DNA stem-loop sequences mutated by APOBEC3A. Together, our study provides evidence that APOBEC3A and APOBEC3B can generate mutation landscapes in cancer genomes, driven by their unique substrate selectivity.

Identification of RBM46 as a novel APOBEC1 cofactor for C-to-U RNA-editing activity.

Cytidine (C) to Uridine (U) RNA editing is a post-transcription modification that is involved in diverse biological processes. APOBEC1 (A1) catalyzes the conversion of C-to-U in RNA, which is important in regulating cholesterol metabolism through its editing activity on ApoB mRNA. However, A1 requires a cofactor to form an "editosome" for RNA editing activity. A1CF and RBM47, both RNA-binding proteins, have been identified as cofactors that pair with A1 to form editosomes and edit ApoB mRNA and other cellular RNAs. SYNCRIP is another RNA-binding protein that has been reported as a potential regulator of A1, although it is not directly involved in A1 RNA editing activity. Here, we describe the identification and characterization of a novel cofactor, RBM46 (RNA-Binding-Motif-protein-46), that can facilitate A1 to perform C-to-U editing on ApoB mRNA. Additionally, using the low-error circular RNA sequencing technique, we identified novel cellular RNA targets for the A1/RBM46 editosome. Our findings provide further insight into the complex regulatory network of RNA editing and the potential new function of A1 with its cofactors.

Effect of Cancer-Related Dysfunctional Beliefs About Sleep on Fear of Cancer Progression in the Coronavirus Pandemic.

BACKGROUND: This study aimed to explore clinical correlates of fear of progression (FoP) among patients with cancer during the coronavirus disease 2019 (COVID-19) pandemic and examine the mediation effect of cancer-related dysfunctional beliefs about sleep (C-DBS). METHODS: Medical charts of patients with cancer who visited a psycho-oncology clinic between July and November 2021 were reviewed. Baseline socio-demographic and cancer-related variables were collected. Patients' self-report questionnaires, regarding FoP, depression (Patient Health Questionnaire-9 items; PHQ-9), viral anxiety (Stress and Anxiety to Viral Epidemics-6 items; SAVE-6), C-DBS, and other distress, were investigated. Pearson's correlation and linear regression were performed to examine the risk factors of FoP. Mediation effect analysis with the bootstrap method with 2,000 resamples was implemented. RESULTS: A total of 231 patients were included in the analysis. Linear regression revealed that FoP was predicted by age (ß = -0.14, P = 0.003), PHQ-9 (ß = 0.48, P < 0.001), SAVE-6 (ß = 0.34, P < 0.001), and C-DBS (ß = 0.15, P = 0.005). FoP was directly influenced by SAVE-6 and mediated by C-DBS, while it was directly influenced by PHQ-9 with no mediation effect. CONCLUSION: During the COVID-19 pandemic, the FoP of patients with cancer was associated with younger age, depression, viral anxiety, and C-DBS. Depression and viral anxiety directly influenced FoP, while C-DBS mediated the association between viral anxiety and FoP. Therefore, oncology healthcare professionals are recommended to assess C-DBS of their patients when they are highly distressed from FoP.

Fetuin as a potential serum biomarker to detect subclinical shedder of bovine paratuberculosis.

Paratuberculosis (PTB) is a chronic contagious granulomatous enteritis of wild and domestic ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). PTB causes considerable economic losses to the dairy industry through decreased milk production and premature culling. PTB-affected cattle undergo a subclinical stage without clinical signs and initiate fecal shedding of MAP into the environment. Current diagnostic tools have low sensitivity for the detection of subclinical PTB infection. Therefore, alternative diagnostic tools are required to improve the diagnostic sensitivity of subclinical PTB infection. In this study, we performed ELISA for three previously identified host biomarkers (fetuin, alpha-1-acid glycoprotein, and apolipoprotein) and analyzed their diagnostic performance with conventional PTB diagnostic methods. We observed that serum fetuin levels were significantly lowered in the subclinical shedder and clinical shedder groups than in the healthy control group, indicating its potential utility as a diagnostic biomarker for bovine PTB. Also, fetuin showed an excellent discriminatory power with an AUC = 0.949, a sensitivity of 92.6%, and a specificity of 94.4% for the detection of subclinical MAP infection. In conclusion, our results demonstrated that fetuin could be used as a diagnostic biomarker for enhancing the diagnostic sensitivity for the detection of subclinical MAP infections that are difficult to detect based on current diagnostic methods.

Assessing the Sleep-wake Pattern in Cancer Patients for Predicting a Short Sleep Onset Latency.

Objective: We investigated the sleep parameters and clinical factors related to short sleep onset latency (SL) in cancer patients. Methods: We retrospectively reviewed the medical records of 235 cancer patients. Patient Health Questionnaire-9, State and Trait Anxiety Inventory (State subcategory), Insomnia Severity Index (ISI), Cancer-related Dysfunctional Beliefs about Sleep, and Fear of Progression scale scores and sleep related parameters including sleeping pill ingestion time, bedtime, sleep onset time, and wake-up time were collected. We also calculated the duration from sleeping pill ingestion to bedtime, sleep onset time, and wake-up time; duration from wake-up time to bedtime and sleep onset time; and time spent in bed over a 24 hours period. Results: Among patients not taking sleeping pills (n = 145), early wake-up time (adjusted odds ratio [OR]: 0.39, 95% confidence interval [CI] 0.19-0.78), early sleep onset time (OR: 0.50, 95% CI 0.27-0.93), and low ISI score (OR: 0.82, 95% CI 0.71-0.93) were identified as expecting variables for SL ≤ 30 minutes. Longer duration from wake-up time to bedtime (OR: 2.49, 95% CI 1.48-4.18) predicted SL ≤ 30 minutes. Among those taking sleeping pills (n = 90), early sleep onset time (OR: 0.54, 95% CI 0.39-0.76) and short duration from pill ingestion to sleep onset time (OR: 0.05, 95% CI 0.02-0.16) predicted SL ≤ 30 minutes. Conclusion: Cancer patients who fell asleep quickly spent less time in bed during the day. Thus, before cancer patients with insomnia are prescribed sleeping pills, their sleep parameters should be examined to improve their SL.

Functional Impairments in the Mental Health, Depression and Anxiety Related to the Viral Epidemic, and Disruption in Healthcare Service Utilization among Cancer Patients in the COVID-19 Pandemic Era.

PURPOSE: Literature is scarce regarding cancer care utilization during the massive outbreak of coronavirus disease 2019 (COVID-19) in the Republic of Korea. We investigated functional impairments in mental health and their relationships with depression, anxiety regarding the viral epidemic, and disruptions in healthcare service utilization among cancer patients in the COVID-19 pandemic era. MATERIALS AND METHODS: We used an online survey with questions related to the disturbances faced by patients with cancer in utilizing healthcare services in the pandemic era. Current mental health status was assessed using the Work and Social Adjustment Scale (WSAS), Stress and Anxiety to Viral Epidemics-6 (SAVE-6) scale, Patient Health Questionnaire-9 (PHQ-9), Insomnia Severity Index (ISI), Brief Resilience Scale (BRS), Cancer-Related Dysfunctional Beliefs about Sleep Scale (C-DBS), and Fear of COVID-19 over Cancer (FCC). RESULTS: Among the 221 responders, 95 (43.0%) reported disruptions in healthcare service utilization during the COVID-19 pandemic. Logistic regression analysis revealed that functional impairment in the mental health of these patients was expected due to disruptions in healthcare service utilization, high levels of depression, anxiety regarding the viral epidemic, fear of COVID over cancer, and low resilience. Mediation analysis showed that patient resilience and cancer-related dysfunctional beliefs about sleep partially mediated the effects of viral anxiety on functional impairment. CONCLUSION: In this pandemic era, patients with cancer experience depression, anxiety regarding the viral epidemic, and disruptions in healthcare service utilization, which may influence their functional impairments in mental health.

A protein interaction landscape of breast cancer.

Cancers have been associated with a diverse array of genomic alterations. To help mechanistically understand such alterations in breast-invasive carcinoma, we applied affinity purification­mass spectrometry to delineate comprehensive biophysical interaction networks for 40 frequently altered breast cancer (BC) proteins, with and without relevant mutations, across three human breast cell lines. These networks identify cancer-specific protein-protein interactions (PPIs), interconnected and enriched for common and rare cancer mutations, that are substantially rewired by the introduction of key BC mutations. Our analysis identified BPIFA1 and SCGB2A1 as PIK3CA-interacting proteins, which repress PI3K-AKT signaling, and uncovered USP28 and UBE2N as functionally relevant interactors of BRCA1. We also show that the protein phosphatase 1 regulatory subunit spinophilin interacts with and regulates dephosphorylation of BRCA1 to promote DNA double-strand break repair. Thus, PPI landscapes provide a powerful framework for mechanistically interpreting disease genomic data and can identify valuable therapeutic targets.

A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity.

We outline a framework for elucidating tumor genetic complexity through multidimensional protein-protein interaction maps and apply it to enhancing our understanding of head and neck squamous cell carcinoma. This network uncovers 771 interactions from cancer and noncancerous cell states, including WT and mutant protein isoforms. Prioritization of cancer-enriched interactions reveals a previously unidentified association of the fibroblast growth factor receptor tyrosine kinase 3 with Daple, a guanine-nucleotide exchange factor, resulting in activation of Gαi- and p21-activated protein kinase 1/2 to promote cancer cell migration. Additionally, we observe mutation-enriched interactions between the human epidermal growth factor receptor 3 (HER3) receptor tyrosine kinase and PIK3CA (the alpha catalytic subunit of phosphatidylinositol 3-kinase) that can inform the response to HER3 inhibition in vivo. We anticipate that the application of this framework will be valuable for translating genetic alterations into a molecular and clinical understanding of the underlying biology of many disease areas.

Increased Risk of Severe Gastric Symptoms by Virulence Factors vacAs1c, alpA, babA2, and hopZ in Helicobacter pylori Infection.

Two virulence factors of Helicobacter pylori, cagA and vacA, have been known to play a role in the development of severe gastric symptoms. However, they are not always associated with peptic ulcer or gastric cancer. To predict the disease outcome more accurately, it is necessary to understand the risk of severe symptoms linked to other virulence factors. Several other virulence factors of H. pylori have also been reported to be associated with disease outcomes, although there are many controversial descriptions. H. pylori isolates from Koreans may be useful in evaluating the relevance of other virulence factors to clinical symptoms of gastric diseases because the majority of Koreans are infected by toxigenic strains of H. pylori bearing cagA and vacA. In this study, a total of 116 H. pylori strains from Korean patients with chronic gastritis, peptic ulcers, and gastric cancers were genotyped. The presence of virulence factors vacAs1c, alpA, babA2, hopZ, and the extremely strong vacuolating toxin was found to contribute significantly to the development of severe gastric symptoms. The genotype combination vacAs1c/alpA/babA2 was the most predictable determinant for the development of severe symptoms, and the presence of babA2 was found to be the most critical factor. This study provides important information on the virulence factors that contribute to the development of severe gastric symptoms and will assist in predicting clinical disease outcomes due to H. pylori infection.

Depression, Rather Than Cancer-Related Fatigue or Insomnia, Decreased the Quality of Life of Cancer Patients.

PURPOSE: Cancer-related fatigue is a common and distressing symptom that occurs during cancer treatment. This study aimed to find factors that are related to cancer-related fatigue, and its effect on patients' quality of life. MATERIALS AND METHODS: This study included 159 patients who completed questionnaires and interviews during their initial examination at the sleep clinic for cancer patients, Asan Medical Center, between December 2018 and January 2020. Their medical reports were reviewed retrospectively. Questionnaire data about depression, anxiety, insomnia, fear of disease progression, and dysfunctional beliefs about sleep, pain, and quality of life, were reviewed. Additionally, patient sleep structure data were analyzed. RESULTS: Factors such as depression (p < 0.001), anxiety (p < 0.001), fear of cancer progression (p < 0.001), fatigue (p=0.027), and time in bed during 24 hours (p=0.037) were significant expecting variables for low quality of life from logistic regression analysis. In pathway analysis, depression (p < 0.001), not cancer-related fatigue (p=0.537), act as a direct risk factor on quality of life. And also, depression was an overall risk factor for insomnia, fatigue, and daily activity of cancer patients. CONCLUSION: Cancer-related fatigue did not show significant effect on patient's quality of life in this study. However, the result of pathway analysis highlights the importance of assessing depression in the process of cancer treatment and providing appropriate interventions.

Bile Acid Nuclear Receptor Farnesoid X Receptor: Therapeutic Target for Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the causes of fatty liver, occurring when fat is accumulated in the liver without alcohol consumption. NAFLD is the most common liver disorder in advanced countries. NAFLD is a spectrum of pathology involving hepatic steatosis with/without inflammation and nonalcoholic steatohepatitis with accumulation of hepatocyte damage and hepatic fibrosis. Recent studies have revealed that NAFLD results in the progression of cryptogenic cirrhosis that leads to hepatocarcinoma and cardiovascular diseases such as heart failure. The main causes of NAFLD have not been revealed yet, metabolic syndromes including obesity and insulin resistance are widely accepted for the critical risk factors for the pathogenesis of NAFLD. Nuclear receptors (NRs) are transcriptional factors that sense environmental or hormonal signals and regulate expression of genes, involved in cellular growth, development, and metabolism. Several NRs have been reported to regulate genes involved in energy and xenobiotic metabolism and inflammation. Among various NRs, farnesoid X receptor (FXR) is abundantly expressed in the liver and a key regulator to control various metabolic processes in the liver. Recent studies have shown that NAFLD is associated with inappropriate function of FXR. The impact of FXR transcriptional activity in NAFLD is likely to be potential therapeutic strategy, but still requires to elucidate underlying potent therapeutic mechanisms of FXR for the treatment of NAFLD. This article will focus the physiological roles of FXR and establish the correlation between FXR transcriptional activity and the pathogenesis of NAFLD.