Abstract
The development of an effective oral therapeutics is an immediate need for the control and elimination of visceral leishmaniasis (VL). We exemplify the preparation and optimization of ...2-hydroxypropyl-β-cyclodextrin (HPCD) modified solid lipid nanoparticles (SLNs) based oral combinational cargo system of Amphotericin B (AmB) and Paromomycin (PM) against murine VL. The emulsion solvent evaporation method was employed to prepare HPCD modified dual drug-loaded solid lipid nanoparticles (m-DDSLNs). The optimized formulations have a mean particle size of 141 ± 3.2 nm, a polydispersity index of 0.248 ± 0.11 and entrapment efficiency for AmB and PM was found to be 96% and 90% respectively. The morphology of m-DDSLNs was confirmed by scanning electron microscopy and transmission electron microscopy. The developed formulations revealed a sustained drug release profile upto 57% (AmB) and 21.5% (PM) within 72 h and were stable at both 4 °C and 25 °C during short term stability studies performed for 2 months. Confocal laser scanning microscopy confirmed complete cellular internalization of SLNs within 24 h of incubation. In vitro cytotoxicity study against J774A.1 macrophage cells confirmed the safety and biocompatibility of the developed formulations. Further, m-DDSLNs did not induce any hepatic/renal toxicities in Swiss albino mice. The in vitro simulated study was performed to check the stability in simulated gastric fluids and simulated intestinal fluids and the release was found almost negligible. The in vitro anti-leishmanial activity of m-DDSLNs (1 µg/ml) has shown a maximum percentage of inhibition (96.22%) on intra-cellular amastigote growth of
L. donovani
. m-DDSLNs (20 mg/kg × 5 days,
p.o.
) has significantly (
P
< 0.01) reduced the liver parasite burden as compared to miltefosine (3 mg/kg × 5 days,
p.o.
) in
L. donovani
-infected BALB/c mice. This work suggests that the superiority of as-prepared m-DDSLNs as a promising approach towards the oral delivery of anti-leishmanial drugs.
The recent technological advancements such as IoT-enabled sensor nodes, Global Positioning System, Wi-Fi transceivers, and lightweight lithium-ion batteries enable the use of Unmanned Aerial Vehicles ...(UAV) for data collection in wireless sensor networks. In a UAV-assisted wireless sensor network (UAV-WSN), the sensor nodes are installed at the ground and a UAV works as the sink node. The UAV-based sink flies over the sensed region and receives the data packets of surrounding ground nodes. A UAV-WSN offers improved data collection efficiency as the UAV-based sink avoids the ground obstacles and establishes line-of-sight communication with the ground sensor nodes. However, the UAV’s flight trajectory needs to be optimized to achieve minimized UAV energy consumption during flight operation and minimized node energy consumption in data transmission. This paper presents a hybrid data routing protocol for UAV-WSN that considers optimized planning of the UAV’s flight trajectory in parallel with energy-efficient data communication amid ground sensor nodes and the UAV. The presented scheme utilizes multi-objective NSGA-II optimization heuristics to optimize UAV’s flight trajectory. The developed NSGA-II model evolves into an optimal UAV flight trajectory that simultaneously achieves the objectives of minimized UAV energy consumption, minimized node energy consumption, and maximized average RSSI. A maximized RSSI further brings about a significant increase in network throughput rate. Simulation results depict that the proposed UAV-WSN scheme achieves improved network lifetime and network throughput rate compared to other state-of-the-art protocols.
The OAS1/2/3 cluster has been identified as a risk locus for severe COVID-19 among individuals of European ancestry, with a protective haplotype of approximately 75 kilobases (kb) derived from ...Neanderthals in the chromosomal region 12q24.13. This haplotype contains a splice variant of OAS1, which occurs in people of African ancestry independently of gene flow from Neanderthals. Using trans-ancestry fine-mapping approaches in 20,779 hospitalized cases, we demonstrate that this splice variant is likely to be the SNP responsible for the association at this locus, thus strongly implicating OAS1 as an effector gene influencing COVID-19 severity.
The present study was focused on investigating niosomal gels loaded with cholinergic drug; pilocarpine HCl, for prolonged precorneal residence time and improved bioavailability for glaucoma ...treatment. Pilocarpine HCl niosomes were prepared using various nonionic surfactants (span 20, span 60 and span 80), in the presence of cholesterol in different molar ratios by ether injection method. The selected formulations were incorporated into carbopol 934 and locust bean gum-based gels. TEM analysis confirmed that niosomes formed were spherical in shape and has a definite internal aqueous space with uniform particle size. Formulation F4 composed of span 60 and cholesterol (1:1) gave the highest entrapment (93.26 ± 1.75%) and slower release results after 8 hours (Q8h = 60.35 ± 1.87%) among other formulations. The in-vitro drug permeation studies showed that there was a prolonged release of drug from niosomal gels as compared to niosomes itself. Considering the in-vitro drug release, niosomal gel formulation G2 was the best among the studied formulations. The release data were fitted to an empirical equation, which indicated that the release follows non-Fickian diffusion mechanism. The stability study revealed that incorporation of niosomes in gel increased their stability than the niosome itself. No signs of redness, inflammation, swelling or increased tear production were observed over the study period for tested formulation by Draize's test. The intraocular pressure (IOP) lowering activity of G2 formulation showed relative bioavailability 2.64 times more than bioavailability of marketed Pilopine HS® gel. These results suggest that the niosomal gels containing pilocarpine HCl are promising ocular carriers for glaucoma treatment.
Phenome-wide association studies (PheWAS) are a high-throughput approach to evaluate comprehensive associations between genetic variants and a wide range of phenotypic measures. PheWAS has varying ...sample sizes for quantitative traits, and variable numbers of cases and controls for binary traits across the many phenotypes of interest, which can affect the statistical power to detect associations. The motivation of this study is to investigate the various parameters which affect the estimation of statistical power in PheWAS, including sample size, case-control ratio, minor allele frequency, and disease penetrance.
We performed a PheWAS simulation study, where we investigated variations in statistical power based on different parameters, such as overall sample size, number of cases, case-control ratio, minor allele frequency, and disease penetrance. The simulation was performed on both binary and quantitative phenotypic measures. Our simulation on binary traits suggests that the number of cases has more impact on statistical power than the case to control ratio; also, we found that a sample size of 200 cases or more maintains the statistical power to identify associations for common variants. For quantitative traits, a sample size of 1000 or more individuals performed best in the power calculations. We focused on common genetic variants (MAF > 0.01) in this study; however, in future studies, we will be extending this effort to perform similar simulations on rare variants.
This study provides a series of PheWAS simulation analyses that can be used to estimate statistical power for some potential scenarios. These results can be used to provide guidelines for appropriate study design for future PheWAS analyses.
This paper explores techniques for solving the maximum clique and vertex coloring problems on very large-scale real-life networks. Because of the size of such networks and the intractability of the ...considered problems, previously developed exact algorithms may not be directly applicable. The proposed approaches aim to reduce the network instances to a size that is tractable for existing solvers, while preserving optimality. Two clique relaxation structures are exploited for this purpose. In addition to the known
k
-core structure, a newly introduced clique relaxation,
k
-community, is used to further reduce the instance size. Experimental results on real-life graphs (collaboration networks, P2P networks, social networks, etc.) show the proposed procedures to be effective by finding, for the first time, exact solutions for instances with over 18 million vertices.
The expanding use of the phenome-wide association study (PheWAS) faces challenges in the context of using International Classification of Diseases billing codes for phenotype definition, imbalanced ...study population ethnicity, and constrained application of the results in research. We performed a PheWAS utilizing 136 deep phenotypes corroborated by comprehensive health check-ups in a Korean population, along with trans-ethnic comparisons through using the UK Biobank and Biobank Japan Project. Meta-analysis with Korean and Japanese population was done. The PheWAS associated 65 phenotypes with 14,101 significant variants (P < 4.92 × 10-10). Network analysis, visualization of cross-phenotype mapping, and causal inference mapping with Mendelian randomization were conducted. Among phenotype pairs from the genotype-driven cross-phenotype associations, we evaluated penetrance in correlation analysis using a clinical database. We focused on the application of PheWAS in order to make it robust and to aid the derivation of biological meaning post-PheWAS. This comprehensive analysis of PheWAS results based on a health check-up database will provide researchers and clinicians with a panoramic overview of the networks among multiple phenotypes and genetic variants, laying groundwork for the practical application of precision medicine.
The prevalence of fungal infections of skin has increased rapidly, affecting approximately 40 million people across the globe. A wide variety of antifungal drugs has been utilized in the effective ...management of numerous dermatological infections. Topical treatment of fungal infections has proved to be quite advantageous due to various factors like targeting the site of infection, minimizing systemic side effects, enhanced efficacy of treatment, and improved patient compliance. In spite the fact that these agents are therapeutically active on topical application, these have restricted drug delivery across the skin resulting in insufficient therapeutic index and may exert local as well as systemic side effects. The accomplishment of topical drug delivery needs to pacify two anomalous aspects, first the barrier nature of stratum corneum, and second, deposition of drug within the skin should be ideally achieved with limited percutaneous absorption. Thus, to facilitate the delivery of antifungal drugs and improve the treatment aspects, various novel delivery carriers have been developed. This article attempts to provide an in-depth knowledge of nanoparticulate and vesicular carriers. This article focuses on the different aspects of fungal infections and their effective treatment with antifungal drugs. Efficacy of various carrier systems (nanoparticulate and vesicular carriers) in delivering antifungal drugs topically has also been discussed. Besides, compiling various research reports, this article also includes formulation considerations inclusive of regulatory aspects of excipients used, the mechanisms of penetration, and patents reported.
Vector control measures are important in lowering the spread of infections spread by mosquito. Synthetic pesticides used to suppress vector populations during the larval stage have had adverse ...impacts on people and the environment. The early III instar larvae of Aedes aegypti and Anopheles stephensi were the targets of the current experiment, which assessed the larvicidal ability of petroleum ether, chloroform, methanol, and aqueous extracts of Annona squamosa leaves.
Using the standard World Health Organization (WHO) larval bioassay test, leaf extracts were evaluated for their activity against Ae. aegypti and An. stephensi to determine lethal doses. Phytochemical analysis and gas chromatography-mass spectrometry (GC-MS) were carried out to identify larvicidal components in the extract. Further analysis using a scanning electron microscope (SEM) was done to check the extracts toxicity for both mosquito larvae.
The larvicidal active components were identified by GC-MS as tetradecanoic acid, cis-vaccenic acid, and 2,4-di-tert-butylphenol etc. Methanol leaf extracts of A. squamosa (ASME) exhibited strong larvicidal activity against the early 3
instar larvae of Ae. aegypti and An. stephensi with Lethal concentration (LC
) values of 51.450 ppm and 107.121 ppm. Cell damages to the larva post exposure to ASME were examined.
This finding showed that the ASME has better larvicidal activity and its components that may be used to kill larvae as larvicides. The extracts toxicity towards damage of midgut of larva further suggests that this plant methanol leaf extracts could be effective in larval growth control approaches.
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