Variants of transcription factor binding sites (TFBSs) constitute an important part of the human genome. Current evidence demonstrates close links between nucleotides within TFBSs and gene ...expression. There are multiple pathways through which genomic sequences located in TFBSs regulate gene expression, and recent genome-wide association studies have shown the biological significance of TFBS variation in human phenotypes. However, numerous challenges remain in the study of TFBS polymorphisms. This article aims to cover the current state of understanding as regards the genomic features of TFBSs and TFBS variants; the mechanisms through which TFBS variants regulate gene expression; the approaches to studying the effects of nucleotide changes that create or disrupt TFBSs; the challenges faced in studies of TFBS sequence variations; the effects of natural selection on collections of TFBSs; in addition to the insights gained from the study of TFBS alleles related to gout, its associated comorbidities (increased body mass index, chronic kidney disease, diabetes, dyslipidemia, coronary artery disease, ischemic heart disease, hypertension, hyperuricemia, osteoporosis, and prostate cancer), and the treatment responses of patients.
With emerging evidence on the efficacy of adding dapagliflozin to standard care for patients with heart failure with reduced ejection fraction (HFrEF), this study assessed the cost-effectiveness of ...add-on dapagliflozin to standard care versus standard care alone for HFrEF from the perspective of healthcare systems in the Asia-Pacific region.
A Markov model was applied to project the outcomes of treatment in terms of lifetime medical cost and quality-adjusted life-years. The transition probabilities between health states in the model were obtained from the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction trial. Country-specific costs and utilities were extracted for modeling. The incremental cost-effectiveness ratio against a country-specific willingness-to-pay threshold was applied to determine the cost-effectiveness of treatment. A series of sensitivity analyses were performed to ensure the robustness of the study results. Costs are presented in 2020 United States dollars.
The incremental cost-effectiveness ratios for add-on dapagliflozin versus standard care alone were $5277, $9980, $12,305, $16,705, and $23,227 per quality-adjusted life-year gained in Korea, Australia, Taiwan, Japan, and Singapore, respectively. When using add-on dapagliflozin to standard care versus standard care alone, ~ 100% of simulations were cost-effective at a willingness-to-pay threshold of one gross domestic product per capita of the given Asia-Pacific country; however, the probability of being cost-effective for using add-on dapagliflozin decreased when the time horizon for simulation was restricted to 18 months and when the cardiovascular mortality for the two treatments (43.8% and 33.0%, respectively) was assumed to be the same. The cost-effectiveness results were most sensitive to cardiovascular mortality of treatment.
Adding dapagliflozin to standard care is cost-effective for HFrEF in healthcare systems in the Asia-Pacific region, which supports the rational use of dapagliflozin for HFrEF in this region.
Background
Pulmonary vein isolation (PVI) is a cornerstone therapy for paroxysmal atrial fibrillation (PAF). The variations in nonlinear heart rate variability (HRV) between patients with and without ...recurrences remain unclear. We aimed to characterize the nonlinear HRV before and after PVI in patients with and without recurrence.
Methods
Twenty‐five drug‐refractory PAF patients (56.0 ± 9.1 years old, 20 males) who received PVI were enrolled. Holter electrocardiography were performed before, 1–3, and 6–12 months after PVI. After 8.2 ± 2.5 months of follow‐ups after PVI, patients were divided into two groups: the recurrence (n = 8) and non‐recurrence (n = 17) groups. Linear and nonlinear HRV variables were analyzed, including the Poincaré Plot analysis and the Detrended Fluctuation Analysis (DFA).
Results
The non‐recurrence group, but not the recurrence group, had decreased high‐frequency component (HF), the root mean square of successive RR interval differences (RMSSD), and the Poincaré Plot index SD1 1–3 months after PVI and increased DFAslope2 6–12 months after PVI. The non‐recurrence group's LF/HF ratio and DFAslope1 decreased significantly 1–3 and 6–12 months after PVI, respectively, whereas there was no significant change in the recurrence group after PVI.
Conclusions
Significantly reduced vagal tone 1–3 months after PVI, increased long‐term fractal complexity 6–12 months after PVI, and decreased sympathetic tone as well as short‐term fractal complexity 1–3 and 6–12 months after PVI led to a better AF‐free survival after PVI. These findings suggest that neuromodulation and heart rate dynamics play crucial roles in AF recurrence following PVI.
After pulmonary vein isolation (PVI), reduced vagal tone at 1–3 months and reduced sympathetic tone at 1–3 and 6–12 months are associated with improved AF‐free survival. Moreover, increased DFAslope2 at 6–12 months and decreased DFAslope1 at 1–3 and 6–12 months can indicate the success of the PVI procedure.
This paper proposes an entropy-weighted local intensity clustering-based model for segmenting intensity inhomogeneous images caused by the bias field. The variational model minimizes an energy ...functional consisting of a regularization term of the total length of object boundaries and a data-fitting term partitioning the image. Specifically, the total length is approximated by the convolution of the heat kernel with the characteristic functions of the segmented regions of interest. The data-fitting term is derived from the multiplicative bias field resulting in a local intensity clustering property and further weighted by the local entropy. One of the most advantageous features of the proposed model is that it can simultaneously segment the image and estimate the bias field for intensity inhomogeneity correction. Moreover, a simple and efficient iterative convolution-thresholding scheme can be applied to realize the model, exhibiting the energy-decaying property. Finally, numerical simulations are carried out to validate the superior performance of the approach.
Annealed Rh nanoclusters on an ordered thin film of Al2O3/NiAl(100) were shown to exhibit a promoted reactivity toward the decomposition of methanol-d4, under both ultrahigh vacuum and ...near-ambient-pressure conditions. The Rh clusters were grown with vapor deposition onto the Al2O3/NiAl(100) surface at 300 K and annealed to 700 K. The decomposition of methanol-d4 proceeded only through dehydrogenation, with CO and deuterium as products, on Rh clusters both as prepared and annealed. Nevertheless, the catalytic reactivity of the annealed clusters, measured with the production of either CO or deuterium per surface Rh site from the reaction, became at least 2–3 times that of the as-prepared ones. The promoted reactivity results from an altered support effect associated with an annealing-induced mass transport at the surface. Our results demonstrate a possibility to practically prepare reactive Rh clusters, regardless of the cluster size, that can tolerate an elevated reaction temperature, with no decreased reactivity.
Amyloid precursor protein (APP) mutations associated with familial Alzheimer's disease (AD) usually lead to increases in amyloid β-protein (Aβ) levels or aggregation. Here, we identified a novel APP ...mutation, located within the Aβ sequence (Aβ(D7H)), in a Taiwanese family with early onset AD and explored the pathogenicity of this mutation. Cellular and biochemical analysis reveal that this mutation increased Aβ production, Aβ42/40 ratio and prolonged Aβ42 oligomer state with higher neurotoxicity. Because the D7H mutant Aβ has an additional metal ion-coordinating residue, histidine, we speculate that this mutation may promote susceptibility of Aβ to ion. When co-incubated with Zn(2+) or Cu(2+), Aβ(D7H) aggregated into low molecular weight oligomers. Together, the D7H mutation could contribute to AD pathology through a "double punch" effect on elevating both Aβ production and oligomerization. Although the pathogenic nature of this mutation needs further confirmation, our findings suggest that the Aβ N-terminal region potentially modulates APP processing and Aβ aggregation, and further provides a genetic indication of the importance of Zn(2+) and Cu(2+) in the etiology of AD.
Arsenic is an environmental factor associated with epithelial-mesenchymal transition (EMT). Since macrophages play a crucial role in regulating EMT, we studied the effects of arsenic on macrophage ...polarization. We first determined the arsenic concentrations to be used by cell viability assays in conjunction with previous studies. In our results, arsenic treatment increased the alternatively activated (M2) macrophage markers, including arginase 1 (
) gene expression, chemokine (C-C motif) ligand 16 (CCL16), transforming growth factor-β1 (TGF-β1), and the cluster of differentiation 206 (CD206) surface marker. Arsenic-treated macrophages promoted A549 lung epithelial cell invasion and migration in a cell co-culture model and a 3D gel cell co-culture model, confirming that arsenic treatment promoted EMT in lung epithelial cells. We confirmed that arsenic induced autophagy/mitophagy by microtubule-associated protein 1 light-chain 3-II (LC3 II) and phosphor-Parkin (p-Parkin) protein markers. The autophagy inhibitor chloroquine (CQ) recovered the expression of the inducible nitric oxide synthase (
) gene in arsenic-treated M1 macrophages, which represents a confirmation that arsenic indeed induced the repolarization of classically activated (M1) macrophage to M2 macrophages through the autophagy/mitophagy pathway. Next, we verified that arsenic increased M2 cell markers in mouse blood and lungs. This study suggests that mitophagy is involved in the arsenic-induced M1 macrophage switch to an M2-like phenotype.
Antimicrobial peptides (AMPs) are important components of the host innate defense mechanism against invading microorganisms. Although AMPs are known to act on bacterial membranes and increase ...membrane permeability, the action mechanism of most AMPs still remains unclear. In this report, we found that the TP4 peptides from Nile tilapia anchored on E. coli cells and enabled them permeable to SYTOX Green in few minutes after TP4 addition. TP4 peptides existed in small dots either on live or glutaraldehyde-fixed cells. TP4 peptides were driven into oligomers either in soluble or insoluble form by a membrane-mimicking anionic surfactant, sarkosyl, depending on the concentrations employed. The binding forces among TP4 components were mediated through hydrophobic interaction. The soluble oligomers were negatively charged on surface, while the insoluble oligomers could be fused with each other or piled on existing particles to form larger particles with diameters 0.1 to 20 μm by hydrophobic interactions. Interestingly, the morphology and solubility of TP4 particles changed with the concentration of exogenous sarkosyl or trifluoroethanol. The TP4 peptides were assembled into oligomers on or in bacterial membrane. This study provides direct evidence and a model for the oligomerization and insertion of AMPs into bacterial membrane before entering into cytosol.
A Rare Cause of Left Atrium Compression Chen, Sih-Yao; Toh, Han Siong; Chang, Wei-Ting ...
International Heart Journal,
07/2021, Letnik:
62, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Extrinsic compression of the left atrium (LA) due to esophageal achalasia has been considered a rare occurrence. Patients might present with dysphagia, dyspnea, and even hemodynamic compromise ...simultaneously. Prompt detection with a thorough differential diagnosis is crucial for subsequent management. In this case report, we present a patient with LA compression by esophageal achalasia and performed a literature review to gather information as regards the clinical manifestation, diagnosis, and treatment strategy of this rare disease.A 59-year-old man with intermittent palpitation, heartburn sensation, and difficulty swallowing came to our emergency department due to acute onset of chest compression and breathlessness after a large meal. As per his chest X-ray, dilated mediastinum and small gastric bubble were noted. Electrocardiogram implied left atrial enlargement, and the Holter monitor reported one episode of paroxysmal atrial fibrillation attack during his meal. Transthoracic echocardiogram showed a round-shaped, well-bordered, hyperechogenic, and heterogeneous mass compressing the LA irrespective of the systolic or diastolic phase. A chest contrast-enhanced computed tomography scan was then performed, wherein it showed diffuse esophageal dilatation with a smoothly thickening wall aligned compressing the LA. Meanwhile, the barium swallow esophagogram revealed contrast pooling at the esophagogastric junction with a bird beak shape. Accordingly, extrinsic compression of LA by esophageal achalasia was diagnosed.Esophageal achalasia compressing LA has been considered rare. Remarkably, given that a patient is presenting with dysphagia and concurrent chest tightness, palpitation, and dyspnea after swallowing food, the clinicians should keep this diagnosis in mind. Careful history review to clarify the causal relationship between the symptoms, specific findings on electrocardiogram and chest X-ray, and utilization of echocardiography and esophagography are beneficial for a prompt and accurate diagnosis.
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