scholarly journals Engineering Molecular Beacons for Intracellular Imaging

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Cuichen Sam Wu ◽  
Lu Peng ◽  
Mingxu You ◽  
Da Han ◽  
Tao Chen ◽  
...  
Keyword(s):  
Clinical Medicine ◽  
De Novo ◽  
Molecular Probes ◽  
Molecular Beacons ◽  
Fluorescence Signal ◽  
The Novel ◽  
Dna Hairpin ◽  
Intracellular Imaging ◽  
Single Cell Imaging ◽  
Cellular Matrices

Molecular beacons (MBs) represent a class of nucleic acid probes with unique DNA hairpin structures that specifically target complementary DNA or RNA. The inherent “OFF” to “ON” signal transduction mechanism of MBs makes them promising molecular probes for real-time imaging of DNA/RNA in living cells. However, conventional MBs have been challenged with such issues as false-positive signals and poor biostability in complex cellular matrices. This paper describes the novel engineering steps used to improve the fluorescence signal and reduce to background fluorescence, as well as the incorporation of unnatural nucleotide bases to increase the resistance of MBs to nuclease degradation for application in such fields as chemical analysis, biotechnology, and clinical medicine. The applications of these de novo MBs for single-cell imaging will be also discussed.

scholarly journals Safety and efficacy of the treatment of in-stent restenosis and de novo complex lesions with the novel paclitaxel-coated scoring balloon (Angiosculpt X)

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
D.P Agip Fustamante ◽  
S Ortiz Cruces ◽  
S Camacho Freire ◽  
A Gutierrez Barrios ◽  
A Gomez Menchero ◽  
...  
Keyword(s):  
Real World ◽  
Cardiac Death ◽  
De Novo ◽  
Funding Source ◽  
The Novel ◽  
Safety And Efficacy ◽  
Stent Restenosis ◽  
Scoring Balloon ◽  
In Stent Restenosis ◽  
Complex Lesions

Abstract Background The AngioSculpt X (Spectranetics) is a novel paclitaxel-coated scoring balloon with encouraging preliminary data for the treatment of in-stent restenosis or de novo complex lesions. Purpose To assess the safety and efficacy of real-world patients with in-stent restenosis (ISR) or de novo complex lesions (vessels <2.5 mm, calcified lesions, bifurcation lesions...) treated with the novel paclitaxel-coated scoring balloon. Methods A “real-world”, prospective registry from two centers was performed including consecutive patients presenting with ISR or de novo complex lesions and treated with AngioSculpt X. Their clinical data were prospectively registered. Major adverse cardiac events (MACE) were defined as a composite of cardiac death, stent thrombosis, nonfatal myocardial infarction, target lesion revascularization (TLR) and target vessel revascularization (TVR). Results Overall, 87 real-world patients and 93 lesions (73% male, 68±10 years, 46% smoker, 83% hypertensive, 62% diabetic, 71% hyperlipidemic, 35% LVEF <60% impairment) were enrolled in the study. Clinical presentation was stable angina in 19%, unstable angina in 33%, NSTEMI in 29% and STEMI in 5%. Radial access account 84%. The median fluoroscopy time was 17 (IQ range 10,0 - 37.5) min. De novo complex lesions were treated in 35% (n=32) while ISR in 63% (n=57), (Prior BMS 19%; Sirolimus DES 9%; Everolimus DES 26%; Biolimus/Anfilimus DES 20%; Zotarolimus DES 26%) with a median time to ISR of 3.6 (IQ range 1.1 - 10.7) years. Total stent length was 28±18 mm, with an overlap spot affected in 18%, and 27% had >1 treatment for ISR. The most frequent artery treated was left anterior descending (41%) followed by left circumflex (35%) and right coronary artery (17%). Quantitative coronary angiography reference diameter of lesions was 2.7±0.5 mm and length 9.0±4.8 mm, with a % stenosis of 75±20. Predilatation/postdilatation was performed in 60/24% respectively. Device diameter was 2.9±0.4 mm and length 13.6±3.9 mm, deployed at 16±3 atmospheres, with an inflation time of 33±16 seconds. The balloon/artery ratio was 0.99±0.03. Crossover was decided on 18 cases (19%) due to remaining intimal flap, but the success rate (residual stenosis <30%) was 100%. Intracoronary imaging technique was performed in 12% (OCT=7, IVUS=4). At 7±6 month follow-up, there were 10 MACE (cardiac death=1, nonfatal myocardial infarction =4, TLR=4 and TVR=1). Conclusions Paclitaxel-coated scoring balloon offers a safe and valuable treatment option for ISR and de novo complex lesions. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Juan Ramόn Jiménez University Hospital

scholarly journals Targeted sequencing and integrative analysis to prioritize candidate genes in neurodevelopmental disorders

2021 ◽  
Author(s):  
Yi Zhang ◽  
Tao Wang ◽  
Yan Wang ◽  
Kun Xia ◽  
Jinchen Li ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Neurodevelopmental Disorders ◽  
De Novo ◽  
Genetic Data ◽  
Chinese Patients ◽  
The Novel ◽  
Mutational Spectrum ◽  
Functional Variants ◽  
Public Data ◽  
Chromosomal Genes

AbstractNeurodevelopmental disorders (NDDs) are a group of diseases characterized by high heterogeneity and frequently co-occurring symptoms. The mutational spectrum in patients with NDDs is largely incomplete. Here, we sequenced 547 genes from 1102 patients with NDDs and validated 1271 potential functional variants, including 108 de novo variants (DNVs) in 78 autosomal genes and seven inherited hemizygous variants in six X chromosomal genes. Notably, 36 of these 78 genes are the first to be reported in Chinese patients with NDDs. By integrating our genetic data with public data, we prioritized 212 NDD candidate genes with FDR < 0.1, including 17 novel genes. The novel candidate genes interacted or were co-expressed with known candidate genes, forming a functional network involved in known pathways. We highlighted MSL2, which carried two de novo protein-truncating variants (p.L192Vfs*3 and p.S486Ifs*11) and was frequently connected with known candidate genes. This study provides the mutational spectrum of NDDs in China and prioritizes 212 NDD candidate genes for further functional validation and genetic counseling.

scholarly journals A small azide-modified thiazole-based reporter molecule for fluorescence and mass spectrometric detection

2014 ◽  
Vol 10 ◽  
pp. 2470-2479 ◽  
Author(s):  
Stefanie Wolfram ◽  
Hendryk Würfel ◽  
Stefanie H Habenicht ◽  
Christine Lembke ◽  
Phillipp Richter ◽  
...  
Keyword(s):  
Molecular Probes ◽  
Protein Profiling ◽  
Structural Motif ◽  
Bioactive Metabolites ◽  
The Novel ◽  
Selective Labeling ◽  
Fluorescent Reporter ◽  
Size Stability ◽  
Model Protein ◽  
Universal Detection

Molecular probes are widely used tools in chemical biology that allow tracing of bioactive metabolites and selective labeling of proteins and other biomacromolecules. A common structural motif for such probes consists of a reporter that can be attached by copper(I)-catalyzed 1,2,3-triazole formation between terminal alkynes and azides to a reactive headgroup. Here we introduce the synthesis and application of the new thiazole-based, azide-tagged reporter 4-(3-azidopropoxy)-5-(4-bromophenyl)-2-(pyridin-2-yl)thiazole for fluorescence, UV and mass spectrometry (MS) detection. This small fluorescent reporter bears a bromine functionalization facilitating the automated data mining of electrospray ionization MS runs by monitoring for its characteristic isotope signature. We demonstrate the universal utility of the reporter for the detection of an alkyne-modified small molecule by LC–MS and for the visualization of a model protein by in-gel fluorescence. The novel probe advantageously compares with commercially available azide-modified fluorophores and a brominated one. The ease of synthesis, small size, stability, and the universal detection possibilities make it an ideal reporter for activity-based protein profiling and functional metabolic profiling.

scholarly journals A novel hybrid of Hypericum undulatum (Wavy-leaved St. John’s-wort, Hypericaceae) and its subsequent dispersal

2020 ◽  
Vol 2 (3) ◽  
Author(s):  
Andrew Jones ◽  
Fred Rumsey
Keyword(s):  
De Novo ◽  
Parental Species ◽  
Species Range ◽  
The Novel ◽  
The Core ◽  
St John’S Wort ◽  
St John's Wort ◽  
Core Site

The novel hybrid Hypericum undulatum Schousb. ex. Willd. x H. perforatum L. is described from Cardiganshire (v.c.46) and given the name H. x cereticae R.A. Jones, F.J. Rumsey & N. Robson.  Despite reduced fertility it shows indications of ongoing introgression and signs of recent dispersal up to 5 km from the core site. The hybrid has arisen recently at the northern extremes of the rarer (H. undulatum) parental species’ range, although at neither site are the parents currently sympatric and in the outlying population both are absent, supporting the belief that here it has not arisen de novo but has colonised through unknown agencies.

scholarly journals Effect of the Novel Antifungal Drug F901318 (Olorofim) on Growth and Viability ofAspergillus fumigatus

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Saskia du Pré ◽  
Nicola Beckmann ◽  
Mariana Cruz Almeida ◽  
Graham E. M. Sibley ◽  
Derek Law ◽  
...  
Keyword(s):  
Prolonged Exposure ◽  
De Novo ◽  
Hyphal Growth ◽  
Cell Lysis ◽  
Antifungal Drug ◽  
The Novel ◽  
Content Type ◽  
New Class ◽  
Highly Active ◽  
Germination And Growth

ABSTRACTF901318 (olorofim) is a novel antifungal drug that is highly active againstAspergillusspecies. Belonging to a new class of antifungals called the orotomides, F901318 targets dihydroorotate dehydrogenase (DHODH) in thede novopyrimidine biosynthesis pathway. In this study, the antifungal effects of F901318 againstAspergillus fumigatuswere investigated. Live cell imaging revealed that, at a concentration of 0.1 μg/ml, F901318 completely inhibited germination, but conidia continued to expand by isotropic growth for >120 h. When this low F901318 concentration was applied to germlings or vegetative hyphae, their elongation was completely inhibited within 10 h. Staining with the fluorescent viability dye bis-(1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC) showed that prolonged exposure to F901318 (>24 h) led to vegetative hyphal swelling and a decrease in hyphal viability through cell lysis. The time-dependent killing of F901318 was further confirmed by measuring the fungal biomass and growth rate in liquid culture. The ability of hyphal growth to recover in drug-free medium after 24 h of exposure to F901318 was strongly impaired compared to that of the untreated control. A longer treatment of 48 h further improved the antifungal effect of F901318. Together, the results of this study indicate that F901318 initially has a fungistatic effect onAspergillusisolates by inhibiting germination and growth, but prolonged exposure is fungicidal through hyphal swelling followed by cell lysis.

scholarly journals Drug Repositioning: New Approaches and Future Prospects for Life-Debilitating Diseases and the COVID-19 Pandemic Outbreak

Viruses ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 1058
Author(s):  
Zheng Yao Low ◽  
Isra Ahmad Farouk ◽  
Sunil Kumar Lal
Keyword(s):  
Drug Development ◽  
De Novo ◽  
Drug Repositioning ◽  
Personalised Medicine ◽  
Technological Advancement ◽  
The Novel ◽  
Ongoing Research ◽  
Alternative Approach ◽  
Good Potential ◽  
Novel Drug

Traditionally, drug discovery utilises a de novo design approach, which requires high cost and many years of drug development before it reaches the market. Novel drug development does not always account for orphan diseases, which have low demand and hence low-profit margins for drug developers. Recently, drug repositioning has gained recognition as an alternative approach that explores new avenues for pre-existing commercially approved or rejected drugs to treat diseases aside from the intended ones. Drug repositioning results in lower overall developmental expenses and risk assessments, as the efficacy and safety of the original drug have already been well accessed and approved by regulatory authorities. The greatest advantage of drug repositioning is that it breathes new life into the novel, rare, orphan, and resistant diseases, such as Cushing’s syndrome, HIV infection, and pandemic outbreaks such as COVID-19. Repositioning existing drugs such as Hydroxychloroquine, Remdesivir, Ivermectin and Baricitinib shows good potential for COVID-19 treatment. This can crucially aid in resolving outbreaks in urgent times of need. This review discusses the past success in drug repositioning, the current technological advancement in the field, drug repositioning for personalised medicine and the ongoing research on newly emerging drugs under consideration for the COVID-19 treatment.

scholarly journals Characterization of More Selective Central Nervous System Nrf2-Activating Novel Vinyl Sulfoximine Compounds Compared to Dimethyl Fumarate

2020 ◽  
Vol 17 (3) ◽  
pp. 1142-1152 ◽  
Author(s):  
Karl E. Carlström ◽  
Praveen K. Chinthakindi ◽  
Belén Espinosa ◽  
Faiez Al Nimer ◽  
Elias S. J. Arnér ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
De Novo ◽  
Dimethyl Fumarate ◽  
The Novel ◽  
The Central Nervous System ◽  
Demyelinating Disorders ◽  
Target Effects

Abstract The Nrf2 transcription factor is a key regulator of redox reactions and considered the main target for the multiple sclerosis (MS) drug dimethyl fumarate (DMF). However, exploration of additional Nrf2-activating compounds is motivated, since DMF displays significant off-target effects and has a relatively poor penetrance to the central nervous system (CNS). We de novo synthesized eight vinyl sulfone and sulfoximine compounds (CH-1–CH-8) and evaluated their capacity to activate the transcription factors Nrf2, NFκB, and HIF1 in comparison with DMF using the pTRAF platform. The novel sulfoximine CH-3 was the most promising candidate and selected for further comparison in vivo and later an experimental model for traumatic brain injury (TBI). CH-3 and DMF displayed comparable capacity to activate Nrf2 and downstream transcripts in vitro, but with less off-target effects on HIF1 from CH-3. This was verified in cultured microglia and oligodendrocytes (OLs) and subsequently in vivo in rats. Following TBI, DMF lowered the number of leukocytes in blood and also decreased axonal degeneration. CH-3 preserved or increased the number of pre-myelinating OL. While both CH-3 and DMF activated Nrf2, CH-3 showed less off-target effects and displayed more selective OL associated effects. Further studies with Nrf2-acting compounds are promising candidates to explore potential myelin protective or regenerative effects in demyelinating disorders.

scholarly journals Massive rhizobial genomic variations associated with partner quality in Lotus–Mesorhizobium symbiosis

2020 ◽  
Author(s):  
Masaru Bamba ◽  
Seishiro Aoki ◽  
Tadashi Kajita ◽  
Hiroaki Setoguchi ◽  
Yasuyuki Watano ◽  
...  
Keyword(s):  
Core Genome ◽  
De Novo ◽  
Lotus Japonicus ◽  
The Novel ◽  
Associated Bacteria ◽  
Association Analyses ◽  
Genomic Variations ◽  
The Core ◽  
Genome Variations

ABSTRACTIn diverse mutualistic relationships, genetic variations in impact on the growth of interacting partners—variations in partner quality—are common, despite the theoretical prediction that selection favoring high-quality partners should eliminate such variations. Here, we investigated how variations in partner quality could be maintained in the nitrogen-fixing mutualism between Lotus japonicus and Mesorhizobium bacteria. We reconstructed de novo assembled full-genome sequences from nine rhizobial symbionts, finding massive variations in the core genome and the contrastingly similar symbiotic islands, indicating recent horizontal gene transfer (HGT) of the symbiosis islands into diverse Mesorhizobium lineages. A cross-inoculation experiment using nine sequenced rhizobial symbionts and 15 L. japonicus accessions revealed extensive quality variations represented by plant growth phenotypes, including genotype-by-genotype interactions. Quality variations were not associated with the presence/absence variations of known symbiosis-related genes in the symbiosis island, but rather, showed significant correlations with the core genome variations, supported by SNP- and kinship matrix-based association analyses. These findings highlight the novel role of HGT of symbiosis islands, which indirectly supply mutations of core genomes into L. japonicus-associated bacteria, thereby contributing to the maintenance of variations in partner quality.

scholarly journals De Novo Molecular Design of Caspase-6 Inhibitors by a GRU-Based Recurrent Neural Network Combined with a Transfer Learning Approach

2021 ◽  
Vol 14 (12) ◽  
pp. 1249
Author(s):  
Shuheng Huang ◽  
Hu Mei ◽  
Laichun Lu ◽  
Minyao Qiu ◽  
Xiaoqi Liang ◽  
...  
Keyword(s):  
Neural Network ◽  
Transfer Learning ◽  
Recurrent Neural Network ◽  
De Novo ◽  
Molecular Design ◽  
Generative Model ◽  
The Novel ◽  
De Novo Molecular Design ◽  
Caspase 6 ◽  
Gated Recurrent Unit

Due to their potential in the treatment of neurodegenerative diseases, caspase-6 inhibitors have attracted widespread attention. However, the existing caspase-6 inhibitors showed more or less inevitable deficiencies that restrict their clinical development and applications. Therefore, there is an urgent need to develop novel caspase-6 candidate inhibitors. Herein, a gated recurrent unit (GRU)-based recurrent neural network (RNN) combined with transfer learning was used to build a molecular generative model of caspase-6 inhibitors. The results showed that the GRU-based RNN model can accurately learn the SMILES grammars of about 2.4 million chemical molecules including ionic and isomeric compounds and can generate potential caspase-6 inhibitors after transfer learning of the known 433 caspase-6 inhibitors. Based on the novel molecules derived from the molecular generative model, an optimal logistic regression model and Surflex-dock were employed for predicting and ranking the inhibitory activities. According to the prediction results, three potential caspase-6 inhibitors with different scaffolds were selected as the promising candidates for further research. In general, this paper provides an efficient combinational strategy for de novo molecular design of caspase-6 inhibitors.

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