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1.
Diabetes ; 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31597640

RESUMO

Abnormalities of methyl CpG-binding protein 2 (Mecp2) cause neurological disorders with metabolic dysfunction, however, its role in adipose tissues remains unclear. Here, we report upregulated Mecp2 in white adipose tissues (WAT) of obese humans, as well as in obese mice and during in vitro adipogenesis. Normal chow-fed adipocyte-specific Mecp2 knockout mice (Mecp2 Adi KO mice) showed a lean phenotype, with downregulated lipogenic genes and upregulated thermogenic genes identified using RNA-sequencing. Consistently, deficiency of Mecp2 in adipocytes protected mice from HFD-induced obesity and inhibited in vitro adipogenesis. Furthermore, Mecp2 Adi KO mice showed increased browning under different stimuli, including cold treatment. Mechanistically, Mecp2 bound to the promoter of secretory leukocyte protease inhibitor (Slpi) and negatively regulated its expression. Knockdown of Slpi in iWAT of Mecp2 Adi KO mice prevented cold-induced browning. Moreover, recombinant SLPI treatment reduced the HFD-induced obesity via enhancing browning. Together, our results suggest a novel non-CNS function of Mecp2 in obesity by suppressing browning, at least partially, through regulating adipokine Slpi.

2.
Mol Pharm ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31613633

RESUMO

Maximizing the pharmacological efficacy of albendazole (ABZ), an anti-echinococcosis drug, is essential in the long-term treatment of patients with echinococcosis. As a weakly alkaline drug, ABZ has a pH-dependent solubility that decreases dramatically from gastric fluid (pH 1.4) to intestinal fluid (pH 6.5), where it is absorbed. In this study, we endeavored to develop an optimized tablet formulation of ABZ to improve its dissolution and oral bioavailability from two aspects: a faster initial dissolution in the gastric pH condition (i.e., the "spring") and a more prolonged drug supersaturation in the intestinal pH condition (i.e., the "parachute"). To achieve this goal, ABZ-HCl salt was selected first, which demonstrated a higher intrinsic dissolution rate under pH 1.4 compared with the ABZ free base that is used in the commercial product Albenda. Second, by comparing the ABZ supersaturation kinetics under pH 6.5 in the presence of various polymers including poly(vinylpyrrolidone) (PVP), PVP/VA, hydroxypropyl methylcellulose (HPMC), and HPMC acetate succinate (HPMC-AS), HPMC-AS was found to be the most effective crystallization inhibitor for ABZ, likely due to the hydrophobic interaction between ABZ and HPMC-AS in an aqueous environment. The newly designed tablet formulation containing ABZ-HCl and HPMC-AS showed ∼3 times higher oral bioavailability compared with that of Albenda in Beagle dogs. More significantly, the anti-echinococcosis efficacy of the improved formulation was 2.4 times higher than that of Albenda in a secondary hepatic alveolar echinococcosis Sprague-Dawley rat model. The strategy of simultaneously improving the spring and parachute of an oral formulation of ABZ, by using a highly soluble salt and an effective polymeric crystallization inhibitor, was once again proven to be a viable and readily translatable approach to optimize the unsatisfactory oral medicines due to solubility and bioavailability limitations.

3.
ACS Infect Dis ; 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31576751

RESUMO

Alveolar echinococcosis (AE) is a chronic infectious parasitic disease that is fatal and still being neglected. Currently, the AE treatment recommended by the WHO is complete excision of the lesions, followed by the oral administration of albendazole (ABZ), the only effective first-line anti-AE drug, for two years. Unfortunately, complete excision of AE lesions is impossible in most cases, leaving the long-term use of ABZ as the only alternative. However, only about one-third of patients experience complete remission or cure with such treatments, largely because of the low oral bioavailability of ABZ caused by its very low solubility. To improve the oral bioavailability of ABZ, a novel nanocrystalline (NC) formulation of ABZ was obtained by spray-drying ABZ with a triblock copolymer poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (Poloxamer 188), and its physical structure was confirmed by scanning electron microscopy (SEM), small-angle X-ray scattering (SAXS), wide-angle X-ray diffraction (WAXRD), and polarized optical microscopy (POM). The significantly reduced ABZ crystallite size coupled with prolonged ABZ supersaturation significantly improved the drug dissolution performance compared with that of the commercial ABZ oral product (Albenda), and the NC formulation showed an approximately 4.2-fold higher AUC than Albenda in a pharmacokinetic comparison in Beagle dogs as measured by the plasma concentration of albendazole sulfoxide, the active antiparasitic metabolite. Even more encouragingly, after 30 days of once-daily oral administration of the NC and Albenda formulations to SD rats with hepatic alveolar echinococcosis, the NC formulation demonstrated a cyst inhibition effect 3.7-fold greater than that of Albenda. We therefore conclude that the NC formulation could potentially be developed into an improved anti-AE drug therapy.

4.
Science ; 366(6462): 246-250, 2019 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-31601770

RESUMO

The function and pharmacology of γ-aminobutyric acid type A receptors (GABAARs) are of great physiological and clinical importance and have long been thought to be determined by the channel pore-forming subunits. We discovered that Shisa7, a single-passing transmembrane protein, localizes at GABAergic inhibitory synapses and interacts with GABAARs. Shisa7 controls receptor abundance at synapses and speeds up the channel deactivation kinetics. Shisa7 also potently enhances the action of diazepam, a classic benzodiazepine, on GABAARs. Genetic deletion of Shisa7 selectively impairs GABAergic transmission and diminishes the effects of diazepam in mice. Our data indicate that Shisa7 regulates GABAAR trafficking, function, and pharmacology and reveal a previously unknown molecular interaction that modulates benzodiazepine action in the brain.

5.
Org Biomol Chem ; 17(42): 9305-9312, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31633136

RESUMO

The chiral primary amine catalyzed asymmetric Michael reaction of thiazolones and α,ß-unsaturated ketones was reported. Two different optimal catalytic systems were obtained corresponding to cyclic and linear α,ß-unsaturated ketones. By employing chiral primary amines as the catalysts and amino-acid derivatives as the additives, a variety of Michael adducts containing the scaffold of the thiazole ring were prepared in moderate to good yields and with excellent diastereo- and enantioselectivities (up to 95% yield, all up to >19/1 dr, up to 96% ee). The reaction was scaled up to obtain 1.73 grams of the Michael adduct with the maintenance of yield and stereoselectivity.

6.
Free Radic Biol Med ; 145: 374-384, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31606431

RESUMO

Oxidation of methionine residues to methionine sulfoxide scavenges reactive species, thus protecting against oxidative stress. Reduction of the sulfoxide back to methionine by methionine sulfoxide reductases creates a cycle with catalytic efficiency. Protection by the methionine sulfoxide reductases is well documented in cultured cells, from microorganisms to mammals. However, knocking out one or two of the 4 mammalian reductases had little effect in mice that were not stressed. We hypothesized that the minimal effect is due to redundancy provided by the 4 reductases. We tested the hypothesis by creating a transgenic mouse line lacking all 4 reductases and predicted that this mouse would be exceptionally sensitive to oxidative stress. The mutant mice were phenotypically normal at birth, exhibited normal post-natal growth, and were fertile. Surprisingly, rather than being more sensitive to oxidative stress, they were more resistant to both cardiac ischemia-reperfusion injury and to parenteral paraquat, a redox-cycling agent. Resistance was not a result of hormetic induction of the antioxidant transcription factor Nrf2 nor activation of Akt. The mechanism of protection may be novel.

7.
Bioinformatics ; 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31529043

RESUMO

MOTIVATION: In recent years, multiple circular RNAs biogenesis mechanisms have been discovered. While each reported mechanism has been experimentally verified in different circular RNAs, no single biogenesis mechanism has been proposed that can universally explain the biogenesis of all tens of thousands of discovered circular RNAs. Under the hypothesis that human circular RNAs can be categorized according to different biogenesis mechanisms, we designed a contextual regression model trained to predict the formation of circular RNA from a random genomic locus on human genome, with potential biogenesis factors of circular RNA as the features of the training data. RESULTS: After achieving high prediction accuracy, we found through the feature extraction technique that the examined human circular RNAs can be categorized into seven subgroups, according to the presence of the following sequence features: RNA editing sites, simple repeat sequences, self-chains, RNA binding protein binding sites and CpG islands within the flanking regions of the circular RNA back-spliced junction sites. These results support all of the previously reported biogenesis mechanisms of circRNA and solidify the idea that multiple biogenesis mechanisms co-exist for different subset of human circRNAs. Furthermore, we uncover a potential new links between circRNA biogenesis and flanking CpG island. We have also identified RNA binding proteins putatively correlated with circRNA biogenesis. AVAILABILITY: Scripts and tutorial are available at https://github.com/chl556/Contextual_Regression_for_CircRNA. This program is under GNU General Public License v3.0.

8.
Opt Express ; 27(16): 23067-23079, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31510589

RESUMO

Nanophotonic waveguide enhanced Raman spectroscopy (NWERS) is a sensing technique that uses a highly confined waveguide mode to excite and collect the Raman scattered signal from molecules in close vicinity of the waveguide. The most important parameters defining the figure of merit of an NWERS sensor include its ability to collect the Raman signal from an analyte, i.e. "the Raman conversion efficiency" and the amount of "Raman background" generated from the guiding material. Here, we compare different photonic integrated circuit (PIC) platforms capable of on-chip Raman sensing in terms of the aforementioned parameters. Among the four photonic platforms under study, tantalum oxide and silicon nitride waveguides exhibit high signal collection efficiency and low Raman background. In contrast, the performance of titania and alumina waveguides suffers from a strong Raman background and a weak signal collection efficiency, respectively.

9.
J Mol Cell Cardiol ; 136: 95-101, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31536744

RESUMO

TRIM72 is a membrane repair protein that protects against ischemia reperfusion (I/R) injury. We previously identified Cys144 (C144) on TRIM72 as a site of S-nitrosylation. To study the importance of C144, we generated a knock-in mouse with C144 mutated to a serine (TRIM72 C144S). We subjected ex vivo perfused mouse hearts to 20 min of ischemia followed by 90 min of reperfusion and observed less injury in TRIM72 C144S compared to WT hearts. Infarct size was smaller (54 vs 27% infarct size) and cardiac functional recovery (37 vs 62% RPP) was higher for the TRIM72 C144S mouse hearts. We also demonstrated that TRIM72 C144S hearts were protected against I/R injury using an in vivo LAD occlusion model. As TRIM72 has been reported to be released from muscle we tested whether C144 is involved in TRIM72 release. After I/R there was significantly less TRIM72 in the perfusate normalized to total released protein from the TRIM72 C144S compared to WT hearts, suggesting that C144 of TRIM72 regulates myocardial TRIM72 release during I/R injury. In addition to TRIM72's protective role in I/R injury, TRIM72 has also been implicated in cardiac hypertrophy and insulin resistance, and secreted TRIM72 has recently been shown to impair insulin sensitivity. However, insulin sensitivity (measured by glucose and insulin tolerance) of TRIM72 C144S mice was not impaired. Further, whole body metabolism, as measured using metabolic cages, was not different in WT vs TRIM72 C144S mice and we did not observe enhanced cardiac hypertrophy in the TRIM72 C144S mice. In agreement, protein levels of the TRIM72 ubiquitination targets insulin receptor ß, IRS1, and focal adhesion kinase were similar between WT and TRIM72 C144S hearts. Overall, these data indicate that mutation of TRIM72 C144 is protective during I/R and reduces myocardial TRIM72 release without impairing insulin sensitivity or enhancing the development of hypertrophy.

11.
Biofabrication ; 12(1): 015004, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31470437

RESUMO

The ability to fabricate perfusable, small-diameter vasculature is a foundational step toward generating human tissues/organs for clinical applications. Currently, it is highly challenging to generate vasculature integrated with smooth muscle and endothelium that replicates the complexity and functionality of natural vessels. Here, a novel method for directly printing self-standing, small-diameter vasculature with smooth muscle and endothelium is presented through combining tailored mussel-inspired bioink and unique 'fugitive-migration' tactics, and its effectiveness and advantages over other methods (i.e. traditional alginate/calcium hydrogel, post-perfusion of endothelial cells) are demonstrated. The biologically inspired, catechol-functionalized, gelatin methacrylate (GelMA/C) undergoes rapid oxidative crosslinking in situ to form an elastic hydrogel, which can be engineered with controllable mechanical strength, high cell/tissue adhesion, and excellent bio-functionalization. The results demonstrate the bioprinted vascular construct possessed numerous favorable, biomimetic characteristics such as proper biomechanics, higher tissue affinity, vascularized tissue manufacturing ability, beneficial perfusability and permeability, excellent vasculoactivity, and in vivo autonomous connection (∼2 weeks) as well as vascular remodeling (∼6 weeks). The advanced achievements in creating biomimetic, functional vasculature illustrate significant potential toward generating a complicated vascularized tissue/organ for clinical transplantation.

12.
J Immunol ; 203(4): 801-806, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31300510

RESUMO

Differentiation of T follicular helper (TFH) cells is regulated by a complex transcriptional network, with mutually antagonistic Bcl6-Blimp1 as a core regulatory axis. It is well established that Tcf1 acts upstream of Bcl6 for its optimal induction to program TFH cell differentiation. In this study, we show that whereas genetic ablation of Tcf1 in mice greatly diminished TFH cells in response to viral infection, compound deletion of Blimp1 with Tcf1 restored TFH cell frequency, numbers, and generation of germinal center B cells. Aberrant upregulation of T-bet and Id2 in Tcf1-deficient TFH cells was also largely rectified by ablating Blimp1. Tcf1 chromatin immunoprecipitation sequencing in TFH cells identified two strong Tcf1 binding sites in the Blimp1 gene at a 24-kb upstream and an intron-3 element. Deletion of the intron-3 element, but not the 24-kb upstream element, compromised production of TFH cells. Our data demonstrate that Tcf1-mediated Blimp1 repression is functionally critical for safeguarding TFH cell differentiation.

13.
Nucleic Acids Res ; 47(13): 6753-6768, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31334813

RESUMO

DNA methylation is an important epigenetic mark but how its locus-specificity is decided in relation to DNA sequence is not fully understood. Here, we have analyzed 34 diverse whole-genome bisulfite sequencing datasets in human and identified 313 motifs, including 92 and 221 associated with methylation (methylation motifs, MMs) and unmethylation (unmethylation motifs, UMs), respectively. The functionality of these motifs is supported by multiple lines of evidence. First, the methylation levels at the MM and UM motifs are respectively higher and lower than the genomic background. Second, these motifs are enriched at the binding sites of methylation modifying enzymes including DNMT3A and TET1, indicating their possible roles of recruiting these enzymes. Third, these motifs significantly overlap with "somatic QTLs" (quantitative trait loci) of methylation and expression. Fourth, disruption of these motifs by mutation is associated with significantly altered methylation level of the CpGs in the neighbor regions. Furthermore, these motifs together with somatic mutations are predictive of cancer subtypes and patient survival. We revealed some of these motifs were also associated with histone modifications, suggesting a possible interplay between the two types of epigenetic modifications. We also found some motifs form feed forward loops to contribute to DNA methylation dynamics.

14.
Stem Cell Res ; 39: 101496, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31326749

RESUMO

NGLY1 deficiency is a rare inherited disorder caused by mutations in the NGLY1 gene encoding N-glycanase 1 that is a hydrolase for N-linked glycosylated proteins. An induced pluripotent stem cell (iPSC) line was generated from the dermal fibroblasts of a 16-year-old patient with homozygous mutation of p.R401X (c.1201 A>T) in the NGLY1 gene. Our iPSC model offers a useful resource to study the disease pathophysiology and to develop therapeutics for treatment of NGLY1 patients.

15.
Stem Cell Res ; 38: 101461, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31132580

RESUMO

Niemann-Pick disease type A (NPA) is a rare autosomal recessive lysosomal storage disease caused by mutations in the SMPD1 gene, which encodes for the protein acid sphingomyelinase. A human induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of a 21-fetal-week-old female patient with NPA that has a heterozygous mutation of a p.L302P variant (c.905 T > C) using non-integrating Sendai virus technique. This iPSC line offers a useful resource to study the disease pathophysiology and as a cell-based model for drug development to treat NPA.

16.
Stem Cell Res ; 37: 101451, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31071499

RESUMO

Mucopolysaccharidosis Type II (MPS II), also known as Hunter syndrome, is a rare X-linked genetic disease caused by mutations in the IDS gene encoding iduronate 2-sulfatase (I2S). This is a multisystem disorder with significant variation in symptoms. Here, we document a human induced pluripotent stem cell (iPSC) line generated from dermal fibroblasts of a patient with Hunter syndrome containing a hemizygous mutation of a 1 bp insertion at nucleotide 208 in exon 2 of the IDS gene. The generation of this line will allow development of cell-based models for drug development, as well as the study of disease pathophysiology.

17.
Comput Math Methods Med ; 2019: 3130527, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31065291

RESUMO

Background: The T wave represents ECG repolarization, whose detection is required during myocardial ischemia, and the first significant change in the ECG signal is being observed in the ST segment followed by changes in other waves like P wave and QRS complex. To offer guidance in clinical diagnosis, decision-making, and daily mobile ECG monitoring, the T wave needs to be detected firstly. Recently, the sliding area-based method has received an increasing amount of attention due to its robustness and low computational burden. However, the parameter setting of the search window's boundaries in this method is not adaptive. Therefore, in this study, we proposed an improved sliding window area method with more adaptive parameter setting for T wave detection. Methods: Firstly, k-means clustering was used in the annotated MIT QT database to generate three piecewise functions for delineating the relationship between the RR interval and the interval from the R peak to the T wave onset and that between the RR interval and the interval from the R peak to the T wave offset. Then, the grid search technique combined with 5-fold cross validation was used to select the suitable parameters' combination for the sliding window area method. Results: With respect to onset detection in the QT database, F1 improved from 54.70% to 70.46% and 54.05% to 72.94% for the first and second electrocardiogram (ECG) channels, respectively. For offset detection, F1 also improved in both channels as it did in the European ST-T database. Conclusions: F1 results from the improved algorithm version were higher than those from the traditional method, indicating a potentially useful application for the proposed method in ECG monitoring.

18.
Pharm Res ; 36(7): 105, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31102031

RESUMO

PURPOSE: To reveal the underlying mechanism inducing the opposite trends of surface composition enrichment of spray dried amorphous solid dispersions (ASD) of sorafenib and regorafenib, two compounds only differ in hydrogen to fluorine substitution. METHODS: Sorafenib/PVP and regorafenib/PVP ASDs were prepared by spray drying. Morphology of ASDs was visually inspected and examined by SEM. The surface compositions of ASDs were analyzed by XPS. Glass transition temperature (Tg) of ASDs was determined by DSC. Water vapor sorption isotherms of ASDs were studied by moisture sorption analyzer. Molecular interaction between the drug and the polymer was analyzed by solution NMR. RESULTS: In 10% and 20% drug loading sorafenib/PVP ASDs, short time moisture exposure induced PVP enrichment on the surface, and the appearance of initial ASDs powder became gel-like after water uptake. While in 30% sorafenib/PVP and any regorafenib/PVP ASDs regardless of drug loading, moisture exposure induced surface drug enrichment, while their powder-like appearance and average particle size remained unchanged. Meanwhile, sorafenib/PVP had similar water vapor sorption isotherms as regorafenib/PVP, before and after moisture induced phase separation. NMR study demonstrated a hex atomic ring H-bonding interaction between the drug and PVP, with a 1:1 drug: monomer stoichiometry molar ratio, which persisted in sorafenib/PVP but not regorafenib/PVP system under 95%RH moisture. CONCLUSIONS: Moisture exposure could lead to drug or polymer enrichment on the surface of ASDs, while the viability of drug-polymer interaction persisting in water environment contributed to such surface composition enrichment.


Assuntos
Flúor/química , Hidrogênio/química , Sorafenibe/química , Umidade , Transição de Fase , Compostos de Fenilureia/química , Polímeros/química , Povidona/química , Piridinas/química , Solubilidade , Vapor , Propriedades de Superfície
19.
Nat Commun ; 10(1): 2071, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31061501

RESUMO

Translation and transcription are frequently dysregulated in cancer. These two processes are generally regulated by distinct sets of factors. The CBFB gene, which encodes a transcription factor, has recently emerged as a highly mutated driver in a variety of human cancers including breast cancer. Here we report a noncanonical role of CBFB in translation regulation. RNA immunoprecipitation followed by deep sequencing (RIP-seq) reveals that cytoplasmic CBFB binds to hundreds of transcripts and regulates their translation. CBFB binds to mRNAs via hnRNPK and enhances translation through eIF4B, a general translation initiation factor. Interestingly, the RUNX1 mRNA, which encodes the transcriptional partner of CBFB, is bound and translationally regulated by CBFB. Furthermore, nuclear CBFB/RUNX1 complex transcriptionally represses the oncogenic NOTCH signaling pathway in breast cancer. Thus, our data reveal an unexpected function of CBFB in translation regulation and propose that breast cancer cells evade translation and transcription surveillance simultaneously through downregulating CBFB.


Assuntos
Neoplasias da Mama/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/metabolismo , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo , Animais , Mama/patologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Regulação para Baixo , Fatores de Iniciação em Eucariotos/metabolismo , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Nus , RNA Mensageiro/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/genética , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Physiol Meas ; 40(5): 055002, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-30970338

RESUMO

OBJECTIVE: Ventricular contractions in healthy individuals normally follow the contractions of atria to facilitate more efficient pump action and cardiac output. With a ventricular ectopic beat (VEB), volume within the ventricles are pumped to the body's vessels before receiving blood from atria, thus causing inefficient blood circulation. VEBs tend to cause perturbations in the instantaneous heart rate time series, making the analysis of heart rate variability inappropriate around such events, or requiring special treatment (such as signal averaging). Moreover, VEB frequency can be indicative of life-threatening problems. However, VEBs can often mimic artifacts both in morphology and timing. Identification of VEBs is therefore an important unsolved problem. The aim of this study is to introduce a method of wavelet transform in combination with deep learning network for the classification of VEBs. APPROACH: We proposed a method to automatically discriminate VEB beats from other beats and artifacts with the use of wavelet transform of the electrocardiogram (ECG) and a convolutional neural network (CNN). Three types of wavelets (Morlet wavelet, Paul wavelet and Gaussian derivative) were used to transform segments of single-channel (1D) ECG waveforms to two-dimensional (2D) time-frequency 'images'. The 2D time-frequency images were then passed into a CNN to optimize the convolutional filters and classification. Ten-fold cross validation was used to evaluate the approach on the MIT-BIH arrhythmia database (MIT-BIH). The American Heart Association (AHA) database was then used as an independent dataset to evaluate the trained network. MAIN RESULTS: Ten-fold cross validation results on MIT-BIH showed that the proposed algorithm with Paul wavelet achieved an overall F1 score of 84.94% and accuracy of 97.96% on out of sample validation. Independent test on AHA resulted in an F1 score of 84.96% and accuracy of 97.36%. SIGNIFICANCE: The trained network possessed exceptional transferability across databases and generalization to unseen data.

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