ABSTRACT
Human telomerase assembly is a highly dynamic process. Using biochemical approaches, we find that LARP3 and LARP7/MePCE are involved in the early stage of human telomerase RNA (hTR) and that their binding to RNA is destabilized when the mature form is produced. LARP3 plays a negative role in preventing the processing of the 3'-extended long (exL) form and the binding of LARP7 and MePCE. Interestingly, the tertiary structure of the exL form prevents LARP3 binding and facilitates hTR biogenesis. Furthermore, low levels of LARP3 promote hTR maturation, increase telomerase activity, and elongate telomeres. LARP7 and MePCE depletion inhibits the conversion of the 3'-extended short (exS) form into mature hTR and the cytoplasmic accumulation of hTR, resulting in telomere shortening. Taken together our data suggest that LARP3 and LARP7/MePCE mediate the processing of hTR precursors and regulate the production of functional telomerase.
Subject(s)
Autoantigens , RNA , Ribonucleoproteins , SS-B Antigen , Telomerase , Humans , Autoantigens/metabolism , Autoantigens/genetics , HeLa Cells , Protein Binding , Ribonucleoproteins/metabolism , Ribonucleoproteins/genetics , RNA/metabolism , RNA/genetics , Telomerase/metabolism , Telomerase/genetics , Telomere/metabolism , Telomere/genetics , Telomere ShorteningABSTRACT
Background/purpose: Skeletal stability after orthognathic surgery is essential for positive treatment outcome. This study evaluated the stability of osteotomy segments after surgery-first bimaxillary surgery for class III asymmetry. Materials and methods: Seventy adults with class III asymmetry consecutively corrected through surgery-first Le Fort I and bilateral sagittal split osteotomies were investigated. Cone-beam computed tomography before treatment (T0), 1-week after surgery (T1), and after all treatment (T2, ≥1-year after surgery) was used to assess surgical movement (T0 to T1) and skeletal stability (T1 to T2) regarding the translation and rotation of the maxillary, mandibular distal, and proximal segments. Results: At T1, the maxillary segment had moved forward and upward, turned to the deviated side, and rotated downward (all P < 0.01). The distal segment of mandible had moved forward and upward and rotated upward (all P < 0.001). The deviated proximal segment had moved upward, tilted to the opposite side, and rotated upward (all P < 0.001). The opposite proximal segment had moved upward and tilted to the deviated side (both P < 0.01). At T2, significant relapse occurred in the mandible. The distal segment moved forward and upward and rotated upward (all P < 0.001). The deviated proximal segment moved upward, tilted to the opposite side, and rotated upward (all P < 0.001). The opposite proximal segment moved upward and tilted to the deviated side (both P < 0.01). Conclusion: Clinically significant relapse of class III asymmetry was discovered on the mandibular distal and opposite proximal segments.
ABSTRACT
The main goal of the study is to evaluate the three stone scoring systems (S.T.O.N.E nephrolithometry scoring system (STONE), Guy's stone score (GSS) and Seoul National University Renal Stone Complexity (S-ReSC)) for the stone-free rate (SFR) of mini-PCNL. We retrospectively analyzed 72 patients who received mini-PCNL from February 2018 to October 2020. The SFR, complication rates, hospitalization days and recurrence rates were analyzed using three stone scoring systems. The result showed statistical significance in the association between scoring system and stone-free (STONE: OR 95%CI 0.409 (0.221-0.759), p = 0.0045; S-ReSC OR 95%CI 0.633 (0.401-0.999), p = 0.0497), but not GSS (OR 95%CI 0.776 (0.397-1.516), p = 0.4581). After adjusting the potential confounding factors, the area under curve (AUC) of STONE, GSS, and S-ReSC was 0.86, 0.78, and 0.81, respectively, and Akaike information criterion (AIC) of STONE, GSS, and S-ReSC was 64.65, 74.89, and 69.92, respectively. The accuracy rate of STONE, GSS, and S-ReSC was 0.81, 0.75, and 0.79, respectively. There was no statistically difference of predicting stone recurrence (p = 0.46, 0.53, 0.86), complications (p = 0.74, 0.51, 0.16) and hospitalization days (p = 0.77, 0.86, 0.87) in STONE, GSS, and S-ReSC, respectively. In conclusion, both the STONE and S-ReSC stone scoring systems are viable for predicting the SFR following mini-PCNL, especially after variable adjustment with the STONE system demonstrating superiority over S-ReSC.
Subject(s)
Kidney Calculi , Humans , Retrospective Studies , Seoul/epidemiology , Universities , Kidney Calculi/diagnosis , Kidney Calculi/surgery , HospitalizationABSTRACT
OBJECTIVES: To assess the surgical accuracy of 3D virtually planned orthognathic surgery among patients with and without cleft. MATERIALS AND METHODS: This retrospective cohort study included cleft and non-cleft patients with class III malocclusion who underwent bimaxillary surgery. CBCT scans were acquired before and immediately after surgery. 3D virtual surgical planning (VSP) was performed using CBCT and digitalized dentition data. All orthognathic surgeries were performed by the same surgeons using interocclusal splints. The primary outcome variable was surgical accuracy, defined as the difference between the planned and surgically achieved maxillary movements, quantified in six degrees of freedom. Analysis of covariance was used to test for intergroup differences in surgical accuracy after correcting for differences in the magnitude of planned surgical maxillary movements. RESULTS: Twenty-eight cleft and 33 non-cleft patients were enrolled, with mean ages of 18.5 and 25.4 years, respectively (P=0.01). No significant gender difference was present between the groups (P=0.10). After adjustment for small differences in surgical movements, no significant differences in surgical accuracy were observed between cleft and non-cleft patients. CONCLUSION: The present study demonstrates that high surgical accuracy in maxillary movements can be achieved in both cleft and non-cleft patients using VSP and interocclusal splints. CLINICAL RELEVANCE: Orthognathic cases with cleft can be performed with 3D VSP to obtain a satisfactory surgical accuracy.
Subject(s)
Exostoses , Malocclusion, Angle Class III , Humans , Adolescent , Young Adult , Adult , Retrospective Studies , Movement , SplintsABSTRACT
Fetal loss (FL) from the 45th day of gestation until calving can impose a significant economic burden on dairy farmers, resulting in lost profits and increased production costs. Pregnancy-associated glycoprotein (PAG) is commonly used for detecting pregnancy in cows. PAG is secreted by binucleated trophoblast cells of the placenta and regulated by more than 24 genes. The purpose of this study was to determine the PAG threshold for FL and a probability of pregnancy maintenance until calving based on milk PAG levels. Our results reveal that primiparous and multiparous cows that maintained pregnancy until the 40th week exhibited higher PAG sample-negative (SN) values in their milk in the 6th week of gestation than did those that experienced FL later in gestation. Pregnant cows with higher PAG SN values in the 6th week of gestation were more likely to maintain their pregnancies. The area under the receiver operating characteristic curve for predicting the probability of pregnancy maintenance was 0.722 for our prediction model. On the other hand, a milk PAG SN value of <0.192 indicated 95 % confidence that FL would occur between the 7th and 40th weeks of gestation. Milk PAG testing is a noninvasive sampling technique that does not induce additional stress in lactating cows. The study reveals that PAG SN values increase significantly in Holstein cows during the 6th week of gestation. The predictive model developed was effective in forecasting pregnancy outcomes up to the 40th week of gestation or calving. The model's performance is moderately good for field application and could be a useful tool for dairy producers.
Subject(s)
Lactation , Milk , Humans , Pregnancy , Female , Cattle , Animals , Pregnancy Outcome , Pregnancy Maintenance , GlycoproteinsABSTRACT
Despite never imposing a lockdown, Taiwan achieved COVID-19 zero, with reporting only 56 local coronavirus disease 2019 (COVID-19) cases after testing 126,987 individuals in 2020, and further contained a large outbreak rapidly and successfully in 2021. At the onset of the COVID-19 pandemic, our infectious disease modeling results indicated that testing and contact tracing alone would fail to contain the pandemic. However, by supplementing this approach with general public surgical mask-wearing, the reproduction number (R0) could be suppressed to less than 1. This would effectively contain the virus's spread within Taiwan, particularly when combined with strict border control measures to prevent the overwhelming influx of imported COVID-19 cases and ensure the capacity of the medical and public health systems remains resilient. These modeling results became the theoretical basis behind the highly successful Taiwan model against COVID-19 during 2020-2021, supporting by negative excess mortality, seroepidemiological surveys, and molecular epidemiological analyses. This is a public health triumph demonstrating that a democratic and humane approach to the COVID-19 pandemic is not only feasible but highly effective. It also highlights the crucial role of infectious disease modeling in assisting the formulation of a successful national pandemic response.
Subject(s)
COVID-19 , Communicable Diseases , Humans , COVID-19/epidemiology , COVID-19/prevention & control , SARS-CoV-2 , Taiwan/epidemiology , Pandemics/prevention & control , Communicable Disease Control , Communicable Diseases/epidemiologyABSTRACT
BACKGROUND: Prior to 2022, Taiwan had effectively contained the domestic COVID-19 epidemic. However, during 2022, the country encountered multiple large outbreaks of COVID-19, with patients experiencing their first or second infection (reinfection) were both predominantly caused by the Omicron variant. Data are lacking on the risk factors and mortality of COVID-19 reinfection in Omicron era. METHODS: In this retrospective population-based cohort study, we recruited COVID-19 patients with their first episode confirmed between April 1, 2022 and June 11, 2022. A reinfection patient was defined as an individual who infected again by SARS-CoV-2 with an interval of more than 90 days. Demographic characteristics, severity of underlying diseases, and vaccination status were adjusted to identify risk factors for reinfection and to further evaluate the hazard of all-cause mortality within 30 days between reinfection and non-reinfection patients. RESULTS: There were 28,588 reinfection patients matched with 142,940 non-reinfection patients included in this study. We found that being female, younger in age, having more severe underlying diseases, and not being fully vaccinated against COVID-19 were risk factors for reinfection. After adjusting for confounding factors, reinfection patients were at a significantly higher risk of all-cause mortality within 30 days (aHR = 4.29, 95% CI: 3.00-6.12, p < 0.001) comparing with non-reinfection patients. CONCLUSION: During the SARS-CoV-2 Omicron era, reinfection patients were observed to have an increased risk of all-cause mortality. To reduce the disease burden and minimize the risk of reinfection, it is crucial for vulnerable patients to receive full vaccination and adhere to recommended precautions.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Female , Male , COVID-19/epidemiology , Taiwan/epidemiology , Cohort Studies , Reinfection/epidemiology , Retrospective Studies , Risk FactorsABSTRACT
PURPOSE: This study aimed to compare facial 3D soft tissue changes in subjects with Class III deformities who underwent bimaxillary clockwise (CW) and counterclockwise (CCW) rotational orthognathic surgery. METHODS: Asian Class III subjects who completed bimaxillary surgical orthodontic treatments were enrolled and categorized into CW and CCW groups based on maxillary occlusal plane alterations. Preoperative and 9-month follow-up cone-beam computed tomography (CBCT) and 3D stereophotogrammetry were obtained, superimposed, and quantified for skeletal movements and soft tissue changes in six facial regions. Inverse probability of treatment weighting (IPTW) adjusted for potential confounding factors. RESULTS: Thirty-seven subjects were included (CW group, n = 20; CCW group, n = 17). Postsurgical chin volume significantly reduced in the CW group compared to the CCW group (mean difference 6362 mm3; p = 0.037), and intergonial width significantly decreased in the CW group (mean difference 6.2 mm; p = 0.005). The postoperative alar width increased by 1.04 mm and 1.22 mm in the CW and CCW groups, respectively (p = 0.70). However, these changes were not significantly correlated to the direction of MMC pitch. CONCLUSION: Clockwise rotation of the bimaxillary complex demonstrated a significant advantage in reducing chin volume and intergonial width compared to counterclockwise rotation, leading to a reduced frontal lower face width among Asian Class III subjects.
ABSTRACT
Penile enlargement has been a controversial issue throughout history. We presented a patient who had undergone a procedure involving the injection of subcutaneous liquid silicone over the penile shaft four years prior. He developed long-term negative consequences from inflammatory granulomas. The patient's condition worsened over time, causing pain and impairing his sexual function. Eventually, he was diagnosed with penile SCC caused by chronic inflammation. Although it is rare, it is important to be aware of this probability because, compared to penile granuloma resection for symptom relief, penile SCC requires a comprehensive survey and more aggressive surgical intervention.
ABSTRACT
BACKGROUND: Footbaths can be used to manage digital dermatitis (DD), a common cause of lameness in dairy cattle. Copper sulfate and chelated copper-zinc (CZS) solutions in footbaths are potentially harmful to the environment. HYPOTHESIS/OBJECTIVES: To determine if a quaternary ammonium salt-based disinfectant (QASD) footbath is as effective as a chelated CZS solution in controlling DD in dairy cows. ANIMALS: Fifty-one lactating Holstein cows were randomly assigned to one of two treatment groups, with DD status based on the M-stage scoring system and locomotion score balanced between treatment groups. MATERIALS AND METHODS: The groups were treated with a 1% QASD or a 2.5% chelated CZS. Footbaths were performed once per week for 15 weeks. Logistic regression was used to analyse clinical improvement. All cows received appropriate medical treatment for DD and other hoof diseases. RESULTS: Clinical improvement rates were 67% in the QASD group and 38% in the CZS group (p = 0.03). Logistic regression analysis showed that the odds (95% confidence interval) for clinical improvement rate in the CZS group were 0.30 (0.095-0.948) times that of the QASD group (p = 0.04). The M0 score in the QASD and CZS groups increased significantly (p < 0.05) at the end of the 15 week study period. In the QASD group, the proportion of M2, M3 and M4 scores were significantly decreased (p < 0.05). CONCLUSION AND CLINICAL RELEVANCE: Over a 15 week period, QASD for footbathing was associated with a lower prevalence of active DD lesions than when using CZS.
Subject(s)
Ammonium Compounds , Cattle Diseases , Digital Dermatitis , Disinfectants , Female , Animals , Cattle , Copper/therapeutic use , Disinfectants/therapeutic use , Digital Dermatitis/drug therapy , Digital Dermatitis/pathology , Lactation , Taiwan , Farms , Cattle Diseases/drug therapy , Cattle Diseases/pathology , Zinc/therapeutic use , Ammonium Compounds/therapeutic useABSTRACT
Air pollution, particularly ambient fine particulate matter (PM2.5) pollution, poses a significant risk to public health, underscoring the importance of comprehending the long-term impact on health burden and expenditure at national and subnational levels. Therefore, this study aims to quantify the disease burden and healthcare expenditure associated with PM2.5 exposure in Taiwan and assess the potential benefits of reducing pollution levels. Using a comparative risk assessment framework that integrates an auto-aggressive integrated moving average model, we evaluated the avoidable burden of cardiopulmonary diseases (including ischemic heart disease, stroke, chronic obstructive pulmonary disease, lung cancer, and diabetes mellitus) and related healthcare expenditure under different air quality target scenarios, including status quo and target scenarios of 15, 10, and 5 µg/m3 reduction in PM2.5 concentration. Our findings indicate that reducing PM2.5 exposure has the potential to significantly alleviate the burden of multiple diseases. Comparing the estimated attributable disease burden and healthcare expenditure between reference and target scenarios from 2022 to 2050, the avoidable disability-adjusted life years were 0.61, 1.83, and 3.19 million for the 15, 10, and 5 µg/m3 target scenarios, respectively. Correspondingly, avoidable healthcare expenditure ranged from US$ 0.63 to 3.67 billion. We also highlighted the unequal allocation of resources and the need for policy interventions to address health disparities due to air pollution. Notably, in the 5 µg/m3 target scenario, Kaohsiung City stands to benefit the most, with 527,368 disability-adjusted life years avoided and US$ 0.53 billion saved from 2022 to 2050. Our findings suggest that adopting stricter emission targets can effectively reduce the health burden and associated healthcare expenditure in Taiwan. Overall, this study provides policymakers in Taiwan with valuable insights for mitigating the negative effects of air pollution by establishing a comprehensive framework for evaluating the co-benefits of air pollution reduction on healthcare expenditure and disease burden.
ABSTRACT
Background: Studies on disease burden in Taiwan are lacking. We aimed to quantify the burden of cardiovascular disease (CVD) attributable to high body mass index (BMI) in Taiwan. Methods: Using a comparative risk assessment approach from the Global Burden of Disease study, we estimated the population attributable fraction (PAF), attributable CVD burden, and disability-adjusted life years (DALYs) according to sex, age, and area of residence in Taiwan. The BMI distribution for the population was obtained from the National Health Interview Survey in 2013. CVD was defined as an ischemic heart disease or stroke. Results: The attributable PAF for CVD from high BMI was 18.0% (19.6% in men and 15.6% in women), and it was highest (42.7%) in those aged 25-30 years. Adults aged 60-65 years had the highest absolute DALYs (11,546). The average relative age-standardized attributable burden was 314 DALYs per 100,000 person-years, and it was highest in those aged 75-80 years (1,407 DALYs per 100,000 person-years). Those living in Taitung County had the highest PAF of 21.9% and the highest age-standardized attributable burden (412 DALYs). Conclusions: In Taiwan, an 18% reduction in CVDs could be achieved if obesity/overweight was prevented. Prevention was most effective in early adulthood. The absolute CVD burden from obesity/overweight was highest in middle-aged men, and the relative burden was highest in older adults. Resource allocation in targeted populations and specific areas to eliminate CVD and health inequities is urgently required.
ABSTRACT
BACKGROUND: Tobacco use and secondhand smoke (SHS) are risk factors of kidney stone disease (KSD). The hypothesis is that tobacco produces chemicals that increase oxidative stress and vasopressin, which leads to decreased urine output, and contributes to stone formation. The aim of this study was to examine the effects of smoking and SHS on the development of KSD. MATERIALS AND METHODS: We analyzed a total of 25,256 volunteers with no history of KSD participated in the Taiwan Biobank. The presence of underlying and follow-up KSD was surveyed by a self-administrated questionnaire. They were classified into three groups on the basis of smoking and SHS exposure, accessed with survey questionnaires; never-smokers with no SHS exposure, never-smokers with SHS exposure and ever-smokers groups. RESULTS: KSD was noted in 352 (2.0%), 50 (3.3%) and 240 (4.1%) subjects in the never-smokers with no SHS exposure, never-smokers with SHS exposure and ever-smokers groups, respectively, with a mean follow-up of 4 years. The odds ratio (OR) of KSD was higher in the never-smokers with SHS exposure (OR, 1.622; 95% confidence interval [95% CI], 1.225 to 2.255) and ever-smokers groups (OR, 1.282; 95% CI, 1.044 to 1.574) than in the never-smokers with no SHS exposure group after adjustment of confounders. In addition, never-smokers with SHS exposure had similar effects on the development of KSD than ever-smokers (OR, 1.223; 95% CI, 0.852 to 1.756). CONCLUSION: Our study suggests that both smoking and SHS are a risk factor for developing KSD and that the impact of SHS is not inferior to that of smoking. TRIAL REGISTRATION: The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20,210,058).
Subject(s)
Kidney Calculi , Tobacco Smoke Pollution , Humans , Tobacco Smoke Pollution/adverse effects , Longitudinal Studies , Smoking/adverse effects , Smoking/epidemiology , Cohort Studies , Kidney Calculi/etiology , Kidney Calculi/chemically inducedABSTRACT
BACKGROUND: Taiwan experienced a relatively low incidence of COVID-19 before 2022. However, from April 2022 to March 2023, the country was struck by a nationwide outbreak that occurred in three waves. Despite the considerable magnitude of the epidemic, the epidemiological characteristics of this outbreak have yet to be clearly understood. METHODS: This was a nationwide, population-based, retrospective cohort study. We recruited patients who had been confirmed as domestically-acquired COVID-19 patients from April 17, 2022, to March 19, 2023. The three epidemic waves were analyzed in terms of numbers of cases, cumulative incidence, numbers of COVID-19-related deaths, mortality, gender, age, residence, SARS-CoV-2 variant sub-lineages, and reinfection status. RESULTS: The numbers of COVID-19 patients (cumulative incidence per million population) were 4,819,625 (207,165.3) in the first wave, 3,587,558 (154,206.5) in the second wave, and 1,746,698 (75,079.5) in the third wave, showing a progressive decline. The numbers of COVID-19-related deaths and mortalities also decreased throughout the three waves. The coverage of vaccination was observed to increase over time. CONCLUSION: During the three waves of COVID-19 epidemic, the numbers of cases and deaths gradually declined, while the vaccine coverage increased. It may be appropriate to consider easing restrictions and returning to normality. However, continued monitoring of the epidemiological situation and tracking the emergence of new variants are crucial to prevent the possibility of another epidemic.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19/epidemiology , Taiwan/epidemiology , Retrospective StudiesABSTRACT
OBJECTIVES: The aim of this study was to investigate the prognostic value of reclassified new type III monomicrobial gram-negative necrotizing fasciitis (NF) and the microbial factors associated with an increased risk of mortality. METHODS: This study included 235 NF cases treated at National Taiwan University Hospital. We compared the mortality risk of NF caused by different causal microorganisms and examined the bacterial virulence genes profile and antimicrobial susceptibility pattern associated with an increase in mortality risk. RESULTS: Type III NF (n = 68) had a mortality risk two-fold higher than type I (polymicrobial, n = 64) or type II (monomicrobial gram-positive, n = 79) NF (42.6% vs 23.4% or 19.0%, P = 0.019 and 0.002, respectively). Mortality differed by causal microorganism (Escherichia coli [61.5%], Klebsiella pneumoniae [40.0%], Aeromonas hydrophila [37.5%], Vibrio vulnificus [25.0%], polymicrobial [23.4%], group A streptococci [16.7%], and Staphylococcus aureus [16.2%], in decreasing rank, P <0.001). Type III NF caused by E. coli, identified as extraintestinal pathogenic E. coli (ExPEC) via virulence gene analyses, was associated with a particularly high mortality risk (adjusted odds ratio: 6.51, P = 0.003) after adjusting for age and comorbidities. Some (38.5%/7.7%) of the E. coli strains were non-susceptible to third/fourth-generation cephalosporins but remained susceptible to carbapenems. CONCLUSION: Type III NF, especially cases caused by E. coli or K. pneumoniae, are associated with a comparatively higher mortality risk than type I or type II NF. Wound gram stain-based rapid diagnosis of type III NF may inform empirical antimicrobial therapy to include a carbapenem.
Subject(s)
Escherichia coli Infections , Extraintestinal Pathogenic Escherichia coli , Fasciitis, Necrotizing , Streptococcal Infections , Humans , Fasciitis, Necrotizing/diagnosis , Klebsiella pneumoniae/genetics , Escherichia coli/genetics , Streptococcal Infections/microbiology , Carbapenems/pharmacology , Carbapenems/therapeutic use , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Escherichia coli Infections/microbiologyABSTRACT
(1) Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a risk factor for predicting cardiovascular diseases. Metabolic syndrome is characterized by a state of chronic inflammation that is related to an increased risk of cardiovascular events and death. In the present study, we aimed to analyze the correlation between cardiometabolic risk factors and Lp-PLA2 levels. (2) We collected the related retrospective medical data of Chinese adults, of which 3983 were men and 2836 were women (aged ≥ 18 years), who underwent health check-ups, and discussed the sex and age-related differences. (3) Data analysis showed that Lp-PLA2 was significantly related to lipoproteins and glutamic pyruvic transaminase (GPT), and that a linear trend was observed with increasing Lp-PLA2 levels for all ages and sexes. However, fasting glucose was significantly related to Lp-PLA2 only in the younger population. The two obesity-related parameters (waist-to-height ratio and waist circumference) also had a greater correlation with Lp-PLA2 levels in the younger groups; however, the correlation weakened in the elderly population. Meanwhile, the correlation between mean arterial pressure and creatinine level and Lp-PLA2 was significant only in younger men. (4) The results show that the expression patterns of Lp-PLA2 differ between sexes and across age groups.
Subject(s)
1-Alkyl-2-acetylglycerophosphocholine Esterase , Cardiometabolic Risk Factors , Adult , Male , Humans , Aged , Female , 1-Alkyl-2-acetylglycerophosphocholine Esterase/metabolism , Retrospective Studies , Risk Factors , Lipoproteins , BiomarkersABSTRACT
Deletion of the conserved C-terminus of the Rothmund-Thomson syndrome helicase RECQ4 is highly tumorigenic. However, while the RECQ4 N-terminus is known to facilitate DNA replication initiation, the function of its C-terminus remains unclear. Using an unbiased proteomic approach, we identify an interaction between the RECQ4 N-terminus and the anaphase-promoting complex/cyclosome (APC/C) on human chromatin. We further show that this interaction stabilizes APC/C co-activator CDH1 and enhances APC/C-dependent degradation of the replication inhibitor Geminin, allowing replication factors to accumulate on chromatin. In contrast, the function is blocked by the RECQ4 C-terminus, which binds to protein inhibitors of APC/C. A cancer-prone, C-terminal-deleted RECQ4 mutation increases origin firing frequency, accelerates G1/S transition, and supports abnormally high DNA content. Our study reveals a role of the human RECQ4 C-terminus in antagonizing its N-terminus, thereby suppressing replication initiation, and this suppression is impaired by oncogenic mutations.
Subject(s)
DNA Replication , Proteomics , Humans , Anaphase-Promoting Complex-Cyclosome , Chromatin , Peptide Initiation FactorsABSTRACT
The arginine dependency of cancer cells creates metabolic vulnerability. In this study, we examine the impact of arginine availability on DNA replication and genotoxicity resistance. Using DNA combing assays, we find that limiting extracellular arginine results in the arrest of cancer cells at S phase and a slowing or stalling of DNA replication. The translation of new histone H4 is arginine dependent and influences DNA replication. Increased proliferating cell nuclear antigen (PCNA) occupancy and helicase-like transcription factor (HLTF)-catalyzed PCNA K63-linked polyubiquitination protect arginine-starved cells from DNA damage. Arginine-deprived cancer cells display tolerance to genotoxicity in a PCNA K63-linked polyubiquitination-dependent manner. Our findings highlight the crucial role of extracellular arginine in nutrient-regulated DNA replication and provide potential avenues for the development of cancer treatments.
Subject(s)
DNA Damage , Histones , Proliferating Cell Nuclear Antigen/metabolism , Histones/metabolism , Ubiquitination , DNA ReplicationABSTRACT
Progressive massive pulmonary fibrosis among coal miners has unexpectedly increased. It would likely due to the greater generation of smaller rock and coal particles produced by powerful equipment used in modern mines. There is limited understanding of the relationship between micro- or nanoparticles with pulmonary toxicity. This study aims to determine whether the size and chemical characteristics of typical coal-mining dust contribute to cellular toxicity. Size range, surface features, morphology, and elemental composition of coal and rock dust from modern mines were characterized. Human macrophages and bronchial tracheal epithelial cells were exposed to mining dust of three sub- micrometer and micrometer size ranges at varying concentrations, then assessed for cell viability and inflammatory cytokine expression. Coal had smaller hydrodynamic size (180-3000 nm) compared to rock (495-2160 nm) in their separated size fractions, more hydrophobicity, less surface charge, and consisted of more known toxic trace elements (Si, Pt, Fe, Al, Co). Larger particle size had a negative association with in-vitro toxicity in macrophages (p < 0.05). Fine particle fraction, approximately 200 nm for coal and 500 nm for rock particles, explicitly induced stronger inflammatory reactions than their coarser counterparts. Future work will study additional toxicity endpoints to further elucidate the molecular mechanism causing pulmonary toxicity and determine a dose-response curve.
Subject(s)
Coal Mining , Drug-Related Side Effects and Adverse Reactions , Humans , Particle Size , Dust/analysis , Lung/chemistry , Coal/analysisABSTRACT
The transition dairy cows are challenged by various stresses such as decreased dry matter intake, liver dysfunction, increased inflammation, and oxidative stress, particularly in subtropical regions. These might increase the requirement for vitamin E and trace elements. To examine whether supplementation of vitamin E, selenium or copper, zinc, and manganese complex would help transition dairy cows to achieve greater reproduction performance by overcoming the immune function and postpartum disorders in subtropical Taiwan. A total of 24 Holstein Friesian dairy cows were enrolled in this study and divided into three groups (n = 8 cows/group): treatment 1 supplemented with organic selenium and vitamin E (SeE), treatment 2 supplemented with organic copper, zinc, and manganese complex (CZM) and control (CON). The results showed SeE supplementation improved immune function, reproductive performance, and milk yield, but not negative energy balance status. Supplementation of CZM improved milk yield and energy regulation through antioxidative capacity and immune function, but had no influence on reproductive performance.