Type II topoisomerases are ubiquitous enzymes in all branches of life that can alter DNA superhelicity and unlink double-stranded DNA segments during processes such as replication and transcription. ...In cells, type II topoisomerases are particularly useful for their ability to disentangle newly-replicated sister chromosomes. Growing lines of evidence indicate that eukaryotic topoisomerase II (topo II) activity is monitored and regulated throughout the cell cycle. Here, we discuss the various roles of topo II throughout the cell cycle, as well as mechanisms that have been found to govern and/or respond to topo II function and dysfunction. Knowledge of how topo II activity is controlled during cell cycle progression is important for understanding how its misregulation can contribute to genetic instability and how modulatory pathways may be exploited to advance chemotherapeutic development.
Early initiation of antiviral therapy in elderly patients with influenza is associated with reduced risk of extra clinic visit, hospitalization and death. This study examined the cost-effectiveness ...of molecular POCT for detection of influenza viruses in Hong Kong elderly patients with influenza-like illness (ILI) in the outpatient clinics.
A decision analytic model was used to simulate outcomes of a hypothetical cohort of elderly patients presented with ILI at outpatient clinics during peak season of influenza with two diagnostic approaches: Rapid molecular assay (POCT-PCR group) and clinical judgement with no POCT. Outcome measures included influenza-associated direct medical cost, hospitalization and mortality rates, quality-adjusted life year loss (QALY loss), and incremental cost per QALY saved (ICER).
In base-case analysis, POCT-PCR group was expected to reduce hospitalization (1.38% versus 2.85%) and mortality rate (0.08% versus 0.16%) and save 0.00112 QALYs at higher cost (by USD33.2 per ILI patient), comparing with clinical judgement group. The ICER of POCT-PCR was 29,582 USD/QALY saved. One-way sensitivity analyses found ICER sensitive to: Hospitalization rate without prompt antiviral therapy; odds ratio of hospitalization with prompt therapy; influenza prevalence; patient age and mortality rate of hospitalized patients. POCT-PCR was cost-effective in 60.6% and 99.4% of 10,000 Monte Carlo simulations at willingness-to-pay threshold of 1x and 3x gross domestic product per capita of Hong Kong, respectively.
Molecular POCT for influenza detection in elderly patients with ILI at outpatient clinics during peak influenza season appeared to be cost-effective in Hong Kong.
Patients with systemic autoimmune diseases show increased incidence of atherosclerosis. However, the contribution of proatherogenic factors to autoimmunity remains unclear. We found that atherogenic ...mice (herein referred to as LDb mice) exhibited increased serum interleukin-17, which was associated with increased numbers of T helper 17 (Th17) cells in secondary lymphoid organs. The environment within LDb mice was substantially favorable for Th17 cell polarization of autoreactive T cells during homeostatic proliferation, which was considerably inhibited by antibodies directed against oxidized low-density lipoprotein (oxLDL). Moreover, the uptake of oxLDL induced dendritic-cell-mediated Th17 cell polarization by triggering IL-6 production in a process dependent on TLR4, CD36, and MyD88. Furthermore, self-reactive CD4+ T cells that expanded in the presence of oxLDL induced more profound experimental autoimmune encephalomyelitis. These findings demonstrate that proatherogenic factors promote the polarization and inflammatory function of autoimmune Th17 cells, which could be critical for the pathogenesis of atherosclerosis and other related autoimmune diseases.
Display omitted
•IL-17 and Th17 cells are increased in nonobese atherogenic (LDb) mice•Proatherogenic conditions within LDb mice enhance EAE in an IL17-dependent manner•oxLDL induces DC-mediated Th17 cell polarization via the TLR4-CD36-MyD88 pathway•Anti-oxLDL diminishes Th17 cell differentiation of autoreactive T cells in LDb mice
Topoisomerase II (topo II) is essential for disentangling newly replicated chromosomes. DNA unlinking involves the physical passage of one duplex through another and depends on the transient ...formation of double-stranded DNA breaks, a step exploited by frontline chemotherapeutics to kill cancer cells. Although anti-topo II drugs are efficacious, they also elicit cytotoxic side effects in normal cells; insights into how topo II is regulated in different cellular contexts is essential to improve their targeted use. Using chemical fractionation and mass spectrometry, we have discovered that topo II is subject to metabolic control through the TCA cycle. We show that TCA metabolites stimulate topo II activity in vitro and that levels of TCA flux modulate cellular sensitivity to anti-topo II drugs in vivo. Our work reveals an unanticipated connection between the control of DNA topology and cellular metabolism, a finding with ramifications for the clinical use of anti-topo II therapies.
Display omitted
•TCA cycle intermediates stimulate the strand passage activity of S. cerevisiae topo II•Stimulation of enzyme activity by TCA metabolites is specific to eukaryotic topo IIs•Topo II activity and drug response is impacted by changes in TCA cycle flux in cells
Lee et al. purify yeast metabolites that show activity against eukaryotic topoisomerase II (topo II). LC-MS/MS analysis identifies TCA cycle intermediates as stimulators of topo II activity. Modulating TCA cycle flux affects the cytotoxicity of topo II-targeting drugs, indicating that TCA cycle metabolism regulates topo II function in cells.
The rapid digitalization of products and services has given rise to smart, technological products and services in various industries. While researchers recognize the complexity of digital components ...embedded in smart services, there exists scarce research on the evolution of product development, smart technology’s use, and the mechanisms wherein changes in products and services are triggered and implemented. In this research, grounded on the theoretical basis of layered modular architecture, we study a digital venture in an event management industry and offer a substantive look at the three mechanisms—system-environment fitness, data exploitation, and user expansion—that are responsible for transforming smart technology from a conceptual idea into a real product and from a simple digital device into an integrated smart system. Our research findings offer theoretical insight into the dynamics and fluidity of mechanisms that are relevant to smart technology’s design, use, and outcomes.
Resveratrol, a polyphenol found in various plant sources, has gained attention as a possible agent responsible for the purported health benefits of certain foods, such as red wine. Despite annual ...multi-million dollar market sales as a nutriceutical, there is little consensus about the physiological roles of resveratrol. One suggested molecular target of resveratrol is eukaryotic topoisomerase II (topo II), an enzyme essential for chromosome segregation and DNA supercoiling homeostasis. Interestingly, resveratrol is chemically similar to ICRF-187, a clinically approved chemotherapeutic that stabilizes an ATP-dependent dimerization interface in topo II to block enzyme activity. Based on this similarity, we hypothesized that resveratrol may antagonize topo II by a similar mechanism. Using a variety of biochemical assays, we find that resveratrol indeed acts through the ICRF-187 binding locus, but that it inhibits topo II by preventing ATPase domain dimerization rather than stabilizing it. This work presents the first comprehensive analysis of the biochemical effects of both ICRF-187 and resveratrol on the human isoforms of topo II, and reveals a new mode for the allosteric regulation of topo II through modulation of ATPase status. Natural polyphenols related to resveratrol that have been shown to impact topo II function may operate in a similar manner.
Transforming growth factor-β (TGF-β) has a strong impact on the pathogenesis of pulmonary fibrosis. Therefore, in this study, we investigated whether derrone promotes anti-fibrotic effects on ...TGF-β1-stimulated MRC-5 lung fibroblast cells and bleomycin-induced lung fibrosis. Long-term treatment with high concentrations of derrone increased the cytotoxicity of MRC-5 cells; however, substantial cell death was not observed at low concentrations of derrone (below 0.05 μg/mL) during a three-day treatment. In addition, derrone significantly decreased the expressions of TGF-β1, fibronectin, elastin, and collagen1α1, and these decreases were accompanied by downregulation of α-SMA expression in TGF-β1-stimulated MRC-5 cells. Severe fibrotic histopathological changes in infiltration, alveolar congestion, and alveolar wall thickness were observed in bleomycin-treated mice; however, derrone supplementation significantly reduced these histological deformations. In addition, intratracheal administration of bleomycin resulted in lung collagen accumulation and high expression of α-SMA and fibrotic genes-including TGF-β1, fibronectin, elastin, and collagen1α1-in the lungs. However, fibrotic severity in intranasal derrone-administrated mice was significantly less than that of bleomycin-administered mice. Molecular docking predicted that derrone potently fits into the ATP-binding pocket of the TGF-β receptor type 1 kinase domain with stronger binding scores than ATP. Additionally, derrone inhibited TGF-β1-induced phosphorylation and nuclear translocations of Smad2/3. Overall, derrone significantly attenuated TGF-β1-stimulated lung inflammation in vitro and bleomycin-induced lung fibrosis in a murine model, indicating that derrone may be a promising candidate for preventing pulmonary fibrosis.
Type IIA topoisomerases are essential DNA processing enzymes that must robustly and reliably relax DNA torsional stress. While cellular processes constantly create varying torsional stress, how this ...variation impacts type IIA topoisomerase function remains obscure. Using multiple single-molecule approaches, we examined the torsional dependence of eukaryotic topoisomerase II (topo II) activity on naked DNA and chromatin. We observed that topo II is ~50-fold more processive on buckled DNA than previously estimated. We further discovered that topo II relaxes supercoiled DNA prior to plectoneme formation, but with processivity reduced by ~100-fold. This relaxation decreases with diminishing torsion, consistent with topo II capturing transient DNA loops. Topo II retains high processivity on buckled chromatin (~10,000 turns) and becomes highly processive even on chromatin under low torsional stress (~1000 turns), consistent with chromatin's predisposition to readily form DNA crossings. This work establishes that chromatin is a major stimulant of topo II function.
We reviewed data on the American diet from 1800 to 2019.
We examined food availability and estimated consumption data from 1800 to 2019 using historical sources from the federal government and ...additional public data sources.
Processed and ultra-processed foods increased from <5 to >60% of foods. Large increases occurred for sugar, white and whole wheat flour, rice, poultry, eggs, vegetable oils, dairy products, and fresh vegetables. Saturated fats from animal sources declined while polyunsaturated fats from vegetable oils rose. Non-communicable diseases (NCDs) rose over the twentieth century in parallel with increased consumption of processed foods, including sugar, refined flour and rice, and vegetable oils. Saturated fats from animal sources were inversely correlated with the prevalence of NCDs.
As observed from the food availability data, processed and ultra-processed foods dramatically increased over the past two centuries, especially sugar, white flour, white rice, vegetable oils, and ready-to-eat meals. These changes paralleled the rising incidence of NCDs, while animal fat consumption was inversely correlated.
Objective: In 2 studies, we tested whether parental attention-deficit/hyperactivity disorder (ADHD) symptoms are associated with self-reports of more positive parenting, even after accounting for ...observed positive parenting behaviors. Method: In Study 1, 96 mothers with sons 8-11 years of age participated; 44% of the boys were diagnosed with ADHD. The majority of mothers and sons were European Caucasian. In Study 2, 48 parents (24 mother-father pairs) with children 6-12 years of age participated. All children in Study 2 were diagnosed with ADHD, and 75% of the children were boys. More than 90% of the families were Caucasian. In both studies, parents self-reported on their positive parenting, and positive parenting was observed in parent-child interactions. Results: In models including relevant demographic variables, other parental psychopathologies, and both inattentive and hyperactive/impulsive symptoms, parents with higher levels of hyperactive/impulsive symptoms self-reported engaging in significantly more positive parenting behaviors than were observed. Parental inattentive symptoms were not uniquely associated with self-reports of positive parenting. This pattern was found for both mothers and fathers, and across families with and without children diagnosed with ADHD. Conclusions: Results suggest that high levels of parental ADHD symptoms may be associated with over-estimation of positive parenting behaviors. Reasons for the distinction between the types of ADHD symptoms associated with higher self-reports of positive parenting and the clinical implications of the findings are discussed.
PDF
