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41.
《Indian pacing and electrophysiology journal》2020,20(3):83-90
BackgroundPatients with outflow tract ventricular tachycardia (OTVT) with normal echocardiogram are labeled as idiopathic VT (IVT). However, a subset of these patients is subsequently diagnosed with underlying cardiac sarcoidosis (CS). Objective:Whether electrocardiogram (ECG) abnormalities in sinus rhythm (SR) can differentiate underlying CS from IVT.MethodsWe retrospectively analyzed the SR-ECGs of 42 patients with OTVT/premature ventricular complexes (PVC) and normal echocardiography. All underwent advanced imaging with cardiac magnetic resonance (CMR)/18FDG PET-CT for screening of CS. Twenty-two patients had significant abnormalities in cardiac imaging and subsequently had biopsy-proven CS (Cases). Twenty patients had normal imaging and were categorized as IVT (Controls). SR-ECGs of all patients were analyzed by 2 independent, blinded observers.ResultsBaseline characteristics were comparable. Among the ECG features analyzed – fascicular (FB) or bundle branch block (BBB) was seen in 9/22 Cases vs. 1/20 controls (p = 0.01). Among patients without FB or BBB, fragmented QRS (fQRS) was present in 9/13 cases but in none of the controls (p < 0.001). Low voltage QRS was more often seen among cases as compared to controls (10/22 vs. 3/20 p = 0.03). A stepwise algorithm based on these 3 sets of ECG findings helped to diagnose CS among patients presenting with OTVT/PVC with sensitivity of 91%, specificity of 75%, a PPV of 80%, and a NPV of 88%.ConclusionsIn patients presenting with OTVT/PVC: FB/BBB, fQRS, and low QRS voltage on the baseline ECG were more often observed among patients with underlying CS as compared to true IVT. These findings may help to distinguish underlying CS among Cases presenting with OTVT/PVC. 相似文献
42.
43.
Oluyomi Stephen Adeyemi Nthatisi Innocentia Molefe-Nyembe Abiodun Omokehinde Eseola Winfried Plass Oluwatosin Kudirat Shittu Ibrahim Olatunji Yunusa Olubunmi Atolani Ikponmwosa Owen Evbuomwan Oluwakemi J. Awakan Keisuke Suganuma Kentaro Kato 《The Yale journal of biology and medicine》2021,94(2):199
The Trypanosoma spp. cause animal and human trypanosomiasis characterized with appreciable health and economic burden mostly in developing nations. There is currently no effective therapy for this parasitic disease, due to poor drug efficacy, drug resistance, and unwanted toxicity, etc. Therefore, new anti-Trypanosoma agents are urgently needed. This study explored new series of imidazoles for anti-Trypanosoma properties in vitro and in vivo. The imidazoles showed moderate to strong and specific action against growth of T. congolense. For example, the efficacy of the imidazole compounds to restrict Trypanosoma growth in vitro was ≥ 12-fold specific towards T. congolense relative to the mammalian cells. Additionally, the in vivo study revealed that the imidazoles exhibited promising anti-Trypanosoma efficacy corroborating the in vitro anti-parasite capacity. In particular, three imidazole compounds (C1, C6, and C8) not only cleared the systemic parasite burden but cured infected rats after no death was recorded. On the other hand, the remaining five imidazole compounds (C2, C3, C4, C5, and C7) drastically reduced the systemic parasite load while extending survival time of the infected rats by 14 days as compared with control. Untreated control died 3 days post-infection, while the rats treated with diminazene aceturate were cured comparable to the results obtained for C1, C6, and C8. In conclusion, this is the first study demonstrating the potential of these new series of imidazoles to clear the systemic parasite burden in infected rats. Furthermore, a high selectivity index of imidazoles towards T. congolense in vitro and the oral LD50 in rats support anti-parasite specific action. Together, findings support the anti-parasitic prospects of the new series of imidazole derivatives. 相似文献
44.
Dariusz Brzezinski Marcin Kowiel David R. Cooper Marcin Cymborowski Marek Grabowski Alexander Wlodawer Zbigniew Dauter Ivan G. Shabalin Miroslaw Gilski Bernhard Rupp Mariusz Jaskolski Wladek Minor 《Protein science : a publication of the Protein Society》2021,30(1):115-124
The COVID‐19 pandemic has triggered numerous scientific activities aimed at understanding the SARS‐CoV‐2 virus and ultimately developing treatments. Structural biologists have already determined hundreds of experimental X‐ray, cryo‐EM, and NMR structures of proteins and nucleic acids related to this coronavirus, and this number is still growing. To help biomedical researchers, who may not necessarily be experts in structural biology, navigate through the flood of structural models, we have created an online resource, covid19.bioreproducibility.org, that aggregates expert‐verified information about SARS‐CoV‐2‐related macromolecular models. In this article, we describe this web resource along with the suite of tools and methodologies used for assessing the structures presented therein. 相似文献
45.
The development of molecular diagnostic tools to achieve individualized medicine requires identifying predictive biomarkers associated with subgroups of individuals who might receive beneficial or harmful effects from different available treatments. However, due to the large number of candidate biomarkers in the large‐scale genetic and molecular studies, and complex relationships among clinical outcome, biomarkers, and treatments, the ordinary statistical tests for the interactions between treatments and covariates have difficulties from their limited statistical powers. In this paper, we propose an efficient method for detecting predictive biomarkers. We employ weighted loss functions of Chen et al. to directly estimate individual treatment scores and propose synthetic posterior inference for effect sizes of biomarkers. We develop an empirical Bayes approach, namely, we estimate unknown hyperparameters in the prior distribution based on data. We then provide efficient screening methods for the candidate biomarkers via optimal discovery procedure with adequate control of false discovery rate. The proposed method is demonstrated in simulation studies and an application to a breast cancer clinical study in which the proposed method was shown to detect the much larger numbers of significant biomarkers than existing standard methods. 相似文献
46.
《Journal of molecular biology》2021,433(17):166967
Voltage-gated sodium (NaV) channels initiate and propagate action potentials in excitable tissues to mediate key physiological processes including heart contraction and nervous system function. Accordingly, NaV channels are major targets for drugs, toxins and disease-causing mutations. Recent breakthroughs in cryo-electron microscopy have led to the visualization of human NaV1.1, NaV1.2, NaV1.4, NaV1.5 and NaV1.7 channel subtypes at high-resolution. These landmark studies have greatly advanced our structural understanding of channel architecture, ion selectivity, voltage-sensing, electromechanical coupling, fast inactivation, and the molecular basis underlying NaV channelopathies. NaV channel structures have also been increasingly determined in complex with toxin and small molecule modulators that target either the pore module or voltage sensor domains. These structural studies have provided new insights into the mechanisms of pharmacological action and opportunities for subtype-selective NaV channel drug design. This review will highlight the structural pharmacology of human NaV channels as well as the potential use of engineered and chimeric channels in future drug discovery efforts. 相似文献
47.
Terry Kenakin 《Journal of receptor and signal transduction research》2013,33(3-4):132-139
The key to detecting and classifying drug effect at seven transmembrane (7TM) receptors is the pharmacological assay. Drug discovery had been rooted in testing of molecules on intact animal tissue until technology provided high-throughput binding assays for screening. While this allowed for the testing of large numbers of molecules, it also limited detection to molecules that interfere with the interaction of the receptor with a defined probe (i.e., radioligand). The ability to monitor functional changes in cells (recombinant or natural) provided a huge leap forward. Earlier functional assays were tied to specific signaling pathways (i.e., cyclic AMP and calcium) but now label-free assays in live cells provide the opportunity to detect more ligands and more fully characterize their efficacy. These ideas will be discussed in terms of harnessing the phenomenon of “functional selectivity” for therapeutic advantage. 相似文献
48.
Jian Liu Yu Wen Lina Gao Liang Gao Fengjun He Jingxian Zhou 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):72-84
Abstract Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragment-based virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC50 = 15.0?nM) and modest anti-proliferative activity (IC50 = 785.8?nM). Through two rounds of optimisation, the indazole derivative 9?u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC50 = 3.3?nM) and cellular activity (IC50 = 468.2?nM). Moreover, 9?u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1. 相似文献
49.
50.
You-Bin Si Yan Xiang Chao Tian Xiong-Yuan Si Jing Zhou Dong-Mei Zhou 《Soil & Sediment Contamination》2013,22(1):72-84
Glyphosate [N-(phosphonomethyl)-glycine] is a herbicide widely used in large quantities in agricultural applications. It is also known to form complexes with metal ions, although its influence on metal behavior, such as lead (Pb) in soil, is not well understood. In this study, the adsorption and co-adsorption of Pb and glyphosate were determined on two soils [a red (RS) soil, Udic Ferrisol, and a yellow-brown (YB) soil, Udic Luvisol] of distinctly different chemical characteristics at varying pH conditions. Results indicate that the adsorption of lead and glyphosate strongly depends on soil types: the RS soil, characterized by a relatively high iron/aluminum content but a low pH and organic matter content, shows a much lower adsorption capacity for Pb but a higher sorption for glyphosate than the YB soil. The co-existence of Pb and glyphosate in soils resulted in complex interactions among Pb, glyphosate, Pb-glyphosate complexes, and soil minerals. The presence of glyphosate decreased Pb adsorption on the two soils, which was attributed primarily to the formation of soluble Pb-glyphosate complexes having relatively low affinities to soil surfaces. On the other hand, addition of Pb increased the adsorption of glyphosate on both soils, which was attributed to: (1) a decreased solution pH due to the ion exchange between Pb2+ and H+ on soil surfaces; and (2) increased sorption sites where Pb was adsorbed and acted as a bridge between glyphosate and the soil. The present study illustrates that the complex interactions among glyphosate, Pb, and soil may have important implications for the mobility and bioavailability of Pb in soil and should thus be considered in future environmental risk assessments. 相似文献