Search

The removal of mis-incorporated nucleotides by proofreading activity ensures DNA replication fidelity. Whereas the e-exonuclease DnaQ is a well-established proofreader in the model organism Escherichia coli, it has been shown that proofreading in a majority of bacteria relies on the polymerase and histidinol phosphatase (PHP) domain of replicative polymerase, despite the presence of a DnaQ homolog that is structurally and functionally distinct from E. coli DnaQ. However, the biological functions of this type of noncanonical DnaQ remain unclear. Here, we provide independent evidence that noncanonical DnaQ functions as an additional proofreader for mycobacteria. Using the mutation accumulation assay in combination with whole-genome sequencing, we showed that depletion of DnaQ in Mycolicibacterium smegmatis leads to an increased mutation rate, resulting in AT-biased mutagenesis and increased insertions/deletions in the homopolymer tract. Our results showed that mycobacterial DnaQ binds to the ß clamp and functions synergistically with the PHP domain proofreader to correct replication errors. Furthermore, the loss of dnaQ results in replication fork dysfunction, leading to attenuated growth and increased mutagenesis on subinhibitory fluoroquinolones potentially due to increased vulnerability to fork collapse. By analyzing the sequence polymorphism of dnaQ in clinical isolates of Mycobacterium tuberculosis (Mtb), we demonstrated that a naturally evolved DnaQ variant prevalent in Mtb lineage 4.3 may enable hypermutability and is associated with drug resistance. These results establish a coproofreading model and suggest a division of labor between DnaQ and PHP domain proofreader. This study also provides real-world evidence that a mutator-driven evolutionary pathway may exist during the adaptation of Mtb. [ABSTRACT FROM AUTHOR]

Background: Erythrocyte dysfunction is a characteristic of diabetes mellitus (DM). However, erythrocyte-associated biomarkers do not adequately explain the high prevalence of DM. Here, we describe red blood cell distribution width to albumin ratio (RAR) as a novel inflammatory biomarker for evaluating an association with DM prevalence and prognosis of all-cause mortality. Methods: Data analyzed in this study were extracted from the National Health and Nutrition Examination Survey (NHANES) 1999−2020. A total of 40,558 participants (non-DM and DM) were enrolled in the study; RAR quartiles were calibrated at Q1 [2.02,2.82] mL/g, Q2 (2.82,3.05] mL/g, Q3 (3.05,3.38] mL/g, and Q4 (3.38,12.08] mL/g. A total of 8,482 DM patients were followed (for a median of 84 months), of whom 2,411 died and 6,071 survived. The prevalence and prognosis associated with RAR and DM were analyzed; age and sex were stratified to analyze the prevalence of RAR in DM and the sensitivity of longterm prognosis. Results: Among non-DM (n=30,404) and DM (n=10,154) volunteers, DM prevalence in RAR quartiles was 8.23%, 15.20%, 23.92%, and 36.39%. The multivariable odds ratio (OR) was significant for RAR regarding DM, at 1.68 (95% CI 1.42, 1.98). Considering Q1 as a foundation, the Q4 OR was 2.57 (95% CI 2.11, 3.13). The percentages of DM morbidity varied across RAR quartiles for dead (n=2,411) and surviving (n=6,071) DM patients. Specifically, RAR quartile mortality ratios were 20.31%, 24.24%, 22.65%, and 29.99% (P<0.0001). The multivariable hazard ratio (HR) for RAR was 1.80 (95% CI 1.57, 2.05). Considering Q1 as a foundation, the Q4 HR was 2.59 (95% CI 2.18, 3.09) after adjusting for confounding factors. Sensitivity analysis revealed the HR of male DM patients to be 2.27 (95% CI 1.95, 2.64), higher than females 1.56 (95% CI 1.31, 1.85). DM patients who were 60 years of age or younger had a higher HR of 2.08 (95% CI1.61, 2.70) as compared to those older than 60 years, who had an HR of 1.69 (95% CI 1.47, 1.94). The HR of RAR in DM patients was optimized by a restricted cubic spline (RCS) model; 3.22 was determined to be the inflection point of an inverse L-curve. DM patients with a RAR >3.22 mL/g suffered shorter survival and higher mortality as compared to those with RAR ≤3.22 mL/g. OR and HR RAR values were much higher than those of regular red blood cell distribution width. Conclusions: The predictive value of RAR is more accurate than that of RDW for projecting DM prevalence, while RAR, a DM risk factor, has long-term prognostic power for the condition. Survival time was found to be reduced as RAR increased for those aged ≤60 years among female DM patients. [ABSTRACT FROM AUTHOR]

Background: This research depicts the linkage of public leadership on public health delivery (PHD) and collaborative administration. The research is also focused to examine the effect of public leadership on public health delivery through the intervening variable of collaborative administration by using both social information processing theory and collaboration theory. Methods: This research is based on quantitative method. Data was collected from 464 public hospital administration in the context of Pakistan. This study evaluated data using SPSS, AMOS, and PROCESS Macro. Results: Public leadership has a positive profound effect on public health delivery and collaborative administration, and that collaborative administration significantly promotes public health delivery. The outcomes also exposed that public leadership has substantial influence on public health delivery through intervening collaborative administration. Conclusions: Whilst public leadership demonstrated positive outcomes on public health delivery and collaborative administration, there is a need for more rigor studies on collaborative governance leadership, collaborative ethics and collaborative norms in the public health service. [ABSTRACT FROM AUTHOR]

Collaborative governance has received attention among scholars and practitioners for resolving governance issues across the globe. The government of Pakistan emphasizes local collaborative governance practices for resolving complex local problems through efficient public service delivery. This research is planned to examine the impact of local collaborative governance on public service delivery, institutional capacity building and how local collaborative governance influences public service delivery through the mediating mechanism of institutional capacity building. Using collaborative governance theory and collecting data from multisector organizations in the context of Pakistan, the results of this study revealed that local collaborative governance is significantly related to the dimensions of public service delivery and institutional capacity building. This research findings revealed that local collaborative governance engenders public service delivery through the dimensions of institutional capacity building including service capacity, evaluative capacity, and M&O capacity. [ABSTRACT FROM AUTHOR]

Collaborative governance has received attention among scholars and practitioners for resolving governance issues across the globe. The government of Pakistan emphasizes local collaborative governance practices for resolving complex local problems through efficient public service delivery. This research is planned to examine the impact of local collaborative governance on public service delivery, institutional capacity building and how local collaborative governance influences public service delivery through the mediating mechanism of institutional capacity building. Using collaborative governance theory and collecting data from multisector organizations in the context of Pakistan, the results of this study revealed that local collaborative governance is significantly related to the dimensions of public service delivery and institutional capacity building. This research findings revealed that local collaborative governance engenders public service delivery through the dimensions of institutional capacity building including service capacity, evaluative capacity, and M&O capacity. [ABSTRACT FROM AUTHOR]

Concurrent chemoradiotherapy (CRT) based on cisplatin is recognized as the current standard treatment for locally advanced cervical cancer. The treatment of cervical cancer has reached a plateau in the last 20 years. Previous studies have proven that the epidermal growth factor receptor is correlated with chemo- and radioresistance and treatment failure. Hence, the purpose of this study was to investigate the efficacy and safety of icotinib combined with CRT in the treatment of locally advanced cervical cancer. Eligibility criteria included patients treated in the radiotherapy department of Taizhou Central Hospital of Zhejiang Province for stage IIB to IIIB cervical cancers who had not received anti-tumor treatment before and a performance status of 0 to 2. Patients were given icotinib 125 mg three times a day for 6 weeks, which was one week before the start of radiotherapy (500 centigrays in 28 fractions) and chemotherapy (40 mg/m² administered weekly for 3-5 cycles). There were 29 patients who completed the I+CRT treatment, and it was tolerated well. The median follow-up time was 50 months and 27 patients (93.10%) achieved complete responses. The 5-year cumulative overall survival rate and disease-free survival rate were 58.4% and 60.9%, respectively. The treatment with I+CRT is safe and effective for locally advanced cervical cancer. As far as we know, this is the first study to report the 5-year survival rate of locally advanced cervical cancer with targeted therapy combined with chemoradiotherapy. [ABSTRACT FROM AUTHOR]

By the introduction of a generalized magnetic vector potential, which contains the contributions of both the magnetic and electric parts, and the use of the Ampere's law within the quasistatic approximation as the state equation, the partial differential equations for governing the electromagnetic properties of superconductors as well as the surrounding coolant were established and numerically discretized by resorting to the finite-element technique and finite-difference scheme, respectively, in the spatial and temporal domain. In conjunction with an analytic method to calculate the magnetic field generated by permanent magnet, we compiled a numerical tool for performing an intricate study of the mutual effect among the superconducting constituents in a superconducting levitation system with translational symmetry. Taking a superconducting unit with three constituents inside as a practice, we simulated the electromagnetic responses of this unit while moving in the nonuniform magnetic field generated by permanent magnet guideway and, identified the influences of the mutual effect on the levitation force as well as on the distributions of the magnetic flux density, the supercurrent density, and the levitation force density by comparing to an envisaged reference, one constituent was simulated with all the rest absent to remove the mutual effect. The insights attained by the present study, mostly being inaccessible from the experiments, are aimed to provide useful implications for the design of a superconducting levitation system for the transit and analogous purposes, which usually employ multiple superconductors to achieve the desired capability. [ABSTRACT FROM AUTHOR]

Decadal variability of carbonate chemistry variables has been studied for the open ocean using observations and models, but less is known about the variations in the coastal ocean due to observational gaps and the more complex environments. In this work, we use a Bayesian-neural-network approach to reconstruct surface carbonate chemistry variables for the Mid-Atlantic Bight (MAB) and the South Atlantic Bight (SAB) along the North American East Coast from 1982 to 2015. The reconstructed monthly time series data suggest that the rate of fCO2 increase in the MAB (18 ± 1 µatm per decade) is faster than those in the SAB (14 ± 1 µatm per decade) and the open ocean (14 ± 1 µatm per decade). Correspondingly, pH decreases faster in the MAB. The observed stagnation in the aragonite saturation state, Oarag decrease during 2005-2015 in the MAB, is attributed to the intrusion of water from southern and offshore regions with high Oarag, which offsets the decrease expected from anthropogenic CO2 uptake. Furthermore, seasonal asymmetry in the evolution of long-term change leads to the faster change in the amplitudes of the seasonal cycle in carbonate chemistry variables in coastal waters than those in the open ocean. In particular, the increase in the seasonal-cycle amplitude of dissolved inorganic carbon in the MAB is 2.9 times larger than that of the open ocean. This leads to the faster increase in the season-cycle amplitude of Oarag and earlier occurrence of undersaturation in coastal waters as acidification continues. [ABSTRACT FROM AUTHOR]

Growing evidence shows that generation of reactive oxygen species (ROS) derived from antibiotic-induced metabolic perturbation contribute to antibiotic lethality. However, our knowledge of the mechanisms by which antibiotic-induced oxidative stress actually kills cells remains elusive. Here, we show that oxidation of dCTP underlies ROS-mediated antibiotic lethality via induction of DNA double-strand breaks (DSBs). Deletion of mazG-encoded 5-OH-dCTP-specific pyrophosphohydrolase potentiates antibiotic killing of stationary-phase mycobacteria, but did not affect antibiotic efficacy in exponentially growing cultures. Critically, the effect of mazG deletion on potentiating antibiotic killing is associated with antibiotic-induced ROS and accumulation of 5-OH-dCTP. Independent lines of evidence presented here indicate that the increased level of DSBs observed in the ΔmazG mutant is a dead-end event accounting for enhanced antibiotic killing. Moreover, we provided genetic evidence that 5-OH-dCTP is incorporated into genomic DNA via error-prone DNA polymerase DnaE2 and repair of 5-OH-dC lesions via the endonuclease Nth leads to the generation of lethal DSBs. This work provides a mechanistic view of ROSmediated antibiotic lethality in stationary phase and may have broad implications not only with respect to antibiotic lethality but also to the mechanism of stress-induced mutagenesis in bacteria. [ABSTRACT FROM AUTHOR]

The combined effects of anthropogenic and biological CO2 inputs may lead to more rapid acidification in coastal waters compared to the open ocean. It is less clear, however, how redox reactions would contribute to acidification. Here we report estuarine acidification dynamics based on oxygen, hydrogen sulfide (H2S), pH, dissolved inorganic carbon and total alkalinity data from the Chesapeake Bay, where anthropogenic nutrient inputs have led to eutrophication, hypoxia and anoxia, and low pH. We show that a pH minimum occurs in middepths where acids are generated as a result of H2S oxidation in waters mixed upward from the anoxic depths. Our analyses also suggest a large synergistic effect from river-ocean mixing, global and local atmospheric CO2 uptake, and CO2 and acid production from respiration and other redox reactions. Together they lead to a poor acid buffering capacity, severe acidification and increased carbonate mineral dissolution in the USA's largest estuary. [ABSTRACT FROM AUTHOR]

Background: Evidence exists that maternal zinc status during pregnancy is linked to adverse pregnancy outcomes including abortion, fetal growth restriction, and neural tube defects. However, it remains unclear whether maternal serum zinc concentration (SZC) during pregnancy is associated with risk of preterm birth.Objective: This study was designed to investigate the association between maternal SZC during pregnancy and risk of preterm birth.Methods: For this substudy of the China-Anhui Birth Cohort Study, 3081 maternal-singleton pairs with detailed birth records and available serum samples were identified. The maternal SZC was determined with flame atomic absorption spectroscopy. A total of 169 preterm births were identified. In this study, the women were divided into tertiles on the basis of their SZC: low (<76.7 μg/dL), medium (76.7-99.6 μg/dL), and high (≥99.7 μg/dL). The ORs for preterm birth were estimated by using multiple logistic regression models.Results: The median SZC was 87.3 μg/dL (range: 11.1-211 μg/dL). Incidences of preterm birth were 7.3% and 6.0% among subjects with low and medium SZCs, respectively, which were significantly higher than 3.1% among subjects with a high SZC [ORs (95% CIs) for low and medium SZCs: 2.45 (1.60, 3.74), P < 0.001, and 2.00 (1.29, 3.09), P < 0.01, respectively]. After adjustment for prepregnancy body mass index, maternal age, time of serum collection, gravidity, parity, and monthly income, adjusted ORs were 2.41 (95% CI: 1.57, 3.70; P < 0.001) and 1.97 (95% CI: 1.27, 3.05; P < 0.01) among subjects with low and medium maternal SZCs.Conclusions: Maternal serum zinc concentration during pregnancy is inversely associated with risk of preterm birth in the Chinese population, and the results are driven by maternal SZC in the first trimester. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a type of tumor that is highly lethal despite maximal therapy. Standard therapeutic approaches provide modest improvement in progression-free and overall survival, necessitating the investigation of novel therapies. Oncologic therapy has recently experienced a rapid evolution toward "targeted therapy", with drugs directed against specific targets which play essential roles in the proliferation, survival, and invasiveness of GBM cells, including numerous molecules involved in signal transduction pathways. Inhibitors of these molecules have already entered or are undergoing clinical trials. However, significant challenges in their development remain because several preclinical and clinical studies present conflicting results. In this article, we will provide an up-to-date review of the current targeted therapies in GBM. [ABSTRACT FROM AUTHOR]

Objective: The incidence of idiopathic precocious puberty (IPP) might have an increasing trend. But the causes and risk factors of IPP are unknown. The objective of our study is to evaluate the effects of growth environments and two environmental endocrine disruptors (EDCs), zearalenone (ZEA), and 1,1-dichloro-2,2,bisethylene (p,&pacute;-DDE), on patients with IPP. Design: Case-control study. Methods: The study consisted of 78 IPP patients at diagnosis and 100 control children matched for age and sex. A questionnaire was designed to collect data on growth environments, and serum ZEA and p,&pacute;-DDE were tested in all subjects. We analyzed data on growth environments, two EDCs, and biological interaction between growth environments and EDCs. Results: In growth environments, small for gestational age, maternal physical disease during pregnancy, early maternal menarche, early puberty of same-degree relatives, and father's absence in 4- to 6-year olds were risk factors for children with IPP (P<0.05). Serum ZEA concentration, ZEA, and p,&pacute;-DDEpositive rates in the IPP group were significantly higher than those in the control group (P<0.05). There was a biological interaction between growth environments and ZEA (relative excess risk due to interaction=34.562, attributable proportion due to interaction =0.745, synergy index=4.193). Conclusions: Results suggest possible effects of growth environments and two EDCs on the development of IPP. In addition, growth environments and ZEA have biological interaction that might increase the risk of developing IP [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2) is one of the most important prognostic and predictive factors for breast cancer patients. Recently, serum HER2 ECD level of patients detected by enzyme-linked immunoabsorbent assay (ELISA) has been shown to predict tumor HER2 status and reveal its association with tumor progression, recurrence and poor prognosis. In this study, we established a new method, dot blot assay, to measure the serum HER2 level in breast cancer patients and further to evaluate the clinical value for monitoring breast cancer progression. We found that the serum HER2 level measured by dot blot assay was significantly correlated with tissue HER2 status in breast cancer patients (P = 0.001), and also significantly correlated with HER2 level measured by ELISA (P = 1.06×10-11). Compared with ELISA method, the specificity and sensitivity of dot blot assay were 95.3% and 65.0%, respectively. The serum HER2 levels of patients with grade III or ERnegative were higher than those with grade I-II (P = 0.004) and ER-positive (P = 0.033), respectively. Therefore, the novel dot blot method to detect serum HER2 level is a valid and inexpensive assay with potential application in monitoring breast cancer progression in clinical situations. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate whether the sunscreen-containing 2–5% green tea extracts (GTEs) protect ultraviolet irradiation (UVR)-induced photoaging and photoimmunosuppression. Materials and methods: Twenty volunteers were exposed to repetitive solar-simulated UVR (ssUVR) on the upper back at a dosage of 1.5 minimal erythema doses (MED) per day for four consecutive days. Thirty minutes before each UVR and 6, 24, and 48 h after the last UV exposure, the products containing vehicle, and 2–5% GTEs were applied onto five sites on the dorsal skin, respectively. The skin biopsies were obtained 72 h after the last UVR. The thickness of the stratum corneum and epidermis was measured under the microscope and the expression of cytokeratins (CK)-5/6, CK16, metalloproteinases (MMP)-2, MMP-9, and the CD1a+ Langerhans cells (LCs) were determined using immunohistochemistry. Results: Our results showed that UVR substantially induced cutaneous erythema, thickening of the epidermis, overexpression of CK5/6, CK16, MMP-2, MMP-9, and depletion of CD1a+ LCs. The sunscreens containing different concentrations of GTEs conferred significant protection against the photoaging and photoimmunology-related biological events. Interestingly, the protective effects were not parallel to the concentrations of GTEs, with 2% and 3% GTEs showing the most efficacious photoprotection. Conclusions: GTEs-containing sunscreens have potential photoprotective effects on UVR-induced photoaging and photoimmunosuppression. [ABSTRACT FROM AUTHOR]

To assess long-term variations in arsenic methylation and oxidative DNA lesions of chronic high arsenic-exposed populations. A follow-up study was conducted in 64 chronic high arsenic-exposed subjects from 2004 to 2006. Urinary arsenic species and 8-hydroxydeoxyguanine were measured. Percentages of urinary inorganic arsenic, monomethylarsonate and urinary 8-hydroxydeoxyguanine (8-OHdG) level were significantly higher, but the percentage of dimethylarsinate, the primary methylation index (PMI) and secondary methylation index (SMI) was lower in the ninth year of arsenic exposure compared with the seventh year. Substantial differences in relative arsenic methylation capacity were observed between the seventh and ninth year. Percentages of arsenic species, PMI and SMI were significantly correlated between siblings, and between parents and children. Arsenic methylation may decrease, but oxidative DNA lesions may increase with the increase of cumulative arsenic exposure level. Both genetic and environmental factors may contribute to variability in arsenic methylation. [ABSTRACT FROM AUTHOR]

Abstract  The structure and stability of neutral polyoxometalate cages (Mo2O6) m (m=1–13) have been computed systematically. These neutral cages can be viewed topologically as polyhedra containing triangles (f 3) and squares (f 4). The relative stability of these polyhedra is associated with the location and separation of the f 3. The initial stable isomers were preselected by the number of shared triangle edges (N 33), and the predicted stability was validated further at the GGA-PW91/DND level of density function theory with the fine quality of mesh size. For large clusters, the square neighbor signature (P 4444), which is similar to the hexagon neighbor rule for fullerene, becomes more applicable. The calculated disproportionation energies indicate that Mo6O18 (O h, Lindqvist), Mo12O36 (O h, α Keggin), Mo18O54 (D 3h, Wells–Dawson) and Mo24O72 (O h) cages have enhanced stability.

[ABSTRACT FROM AUTHOR]