Long-Acting Antiretroviral Nanoformulation Development and Subcellular Trafficking

The introduction of nanoformulated antiretroviral therapeutic regimens is a promising alternative to standard once a day oral treatment of HIV infection. Our lab has pioneered this effort and was successful in harnessing mononuclear phagocytes (monocytes, dendritic cells and macrophages) as nanoformulated drug carriers. The approach was developed as Trojan horses for drug transport, delivery and distribution to sites of viral replication in order to facilitate microbial elimination in HIV sanctuaries. However, the remaining challenges for current antiretroviral nanoformulations include to formulate a broad range of hydrophilic short-acting drugs, and to elucidate the mechanism of sequestered nanoparticles in macrophages at the subcellular level. To this end, we developed a two-step synthesis to create a long-acting lamivudine (2’,3’-dideoxy-3’-thiacytidine, 3TC). A stable hydrophobic pro-drug crystal formulation was produced by poloxamer drug encasement. Conversion of the hydrophilic 3TC significantly extended its bioavailability facilitated by chemical drug conjugation to a fatty acid and creating a myristoylated drug. A folate targeted poloxamer 407 coated a newly formed nanocrystalline pro-drug markedly improving cell uptake, bioavailability and pharmacokinetic profiles. Reduced cytotoxicity and robust antiretroviral activities were also achieved. The nanoparticle interactions at the subcellular level were investigated vial nanoformulated protease inhibitor. Quantitative SWATH-MS proteomics for complete recording of fragment ion peptide precursors in biological sample. and cell profiling were applied for endolysosomal trafficking for HIV-1 assembly and nanoformulation depot formation. We believe these findings unveil new opportunities for nanoformulated antiretroviral therapy and have brought the idea of long-acting antiretroviral therapy closer to the clinical translation

Alternating sums of binomial quotients

By combining telescoping and the linearization method, a class of alternating sums of binomial quotients are investigated. Several summation and transformation formulae are established. Asymptotic behavior for these sums is also examined

Bayesian approach to Gaussian process regression with uncertain inputs

Conventional Gaussian process regression exclusively assumes the existence of noise in the output data of model observations. In many scientific and engineering applications, however, the input locations of observational data may also be compromised with uncertainties owing to modeling assumptions, measurement errors, etc. In this work, we propose a Bayesian method that integrates the variability of input data into Gaussian process regression. Considering two types of observables -- noise-corrupted outputs with fixed inputs and those with prior-distribution-defined uncertain inputs, a posterior distribution is estimated via a Bayesian framework to infer the uncertain data locations. Thereafter, such quantified uncertainties of inputs are incorporated into Gaussian process predictions by means of marginalization. The effectiveness of this new regression technique is demonstrated through several numerical examples, in which a consistently good performance of generalization is observed, while a substantial reduction in the predictive uncertainties is achieved by the Bayesian inference of uncertain inputs

Influence of catwalk design parameters on the galloping of constructing main cables in long-span suspension bridges

A main cable of a long-span suspension bridge is semi-surrounded by a catwalk during construction. Thus, design parameters of a catwalk may have influences on the galloping stability of a main cable during construction. To study the influence of catwalk design parameters on the galloping of steepled main cables, two main foci have been conducted. Firstly, the aerodynamic coefficients of the catwalk with actual design parameters are obtained by numerical simulation based on computational fluid dynamics (CFD), and the numerical results are compared with those of the previous wind tunnel test. Several typical main cables with different cross sections of a long-span suspension bridge during construction are selected, and their Den Hartog coefficients are obtained based on the numerical simulation considering the aerodynamic influences of the catwalks. Then four typical working conditions of a main cable which have great potential to occur galloping are selected based on the galloping analyze, and their aerodynamic coefficients considering the influence of the catwalk with different design parameters are obtained. The influence of the catwalk design parameters on galloping of the main cables is analyzed based on the Den Hartog criterion. Results indicate that catwalk design parameters have evident influences on aerodynamic coefficients and galloping of the main cables. The parameters of the catwalk which are favorable for suppressing the galloping of the main cables are determined, which establish a good guideline for the galloping-resistant design of the catwalk-main cable system on suspension bridges

Opposing regulation of endolysosomal pathways by long-acting nanoformulated antiretroviral therapy and HIV-1 in human macrophages.

BACKGROUND: Long-acting nanoformulated antiretroviral therapy (nanoART) is designed to improve patient regimen adherence, reduce systemic drug toxicities, and facilitate clearance of human immunodeficiency virus type one (HIV-1) infection. While nanoART establishes drug depots within recycling and late monocyte-macrophage endosomes, whether or not this provides a strategic advantage towards viral elimination has not been elucidated. RESULTS: We applied quantitative SWATH-MS proteomics and cell profiling to nanoparticle atazanavir (nanoATV)-treated and HIV-1 infected human monocyte-derived macrophages (MDM). Native ATV and uninfected cells served as controls. Both HIV-1 and nanoATV engaged endolysosomal trafficking for assembly and depot formation, respectively. Notably, the pathways were deregulated in opposing manners by the virus and the nanoATV, likely by viral clearance. Paired-sample z-scores, of the proteomic data sets, showed up- and down- regulation of Rab-linked endolysosomal proteins. NanoART and native ATV treated uninfected cells showed limited effects. The data was confirmed by Western blot. DAVID and KEGG bioinformatics analyses of proteomic data showed relationships between secretory, mobility and phagocytic cell functions and virus and particle trafficking. CONCLUSIONS: We posit that modulation of endolysosomal pathways by antiretroviral nanoparticles provides a strategic path to combat HIV infection

Opposing regulation of endolysosomal pathways by long-acting nanoformulated antiretroviral therapy and HIV-1 in human macrophages.

BACKGROUND: Long-acting nanoformulated antiretroviral therapy (nanoART) is designed to improve patient regimen adherence, reduce systemic drug toxicities, and facilitate clearance of human immunodeficiency virus type one (HIV-1) infection. While nanoART establishes drug depots within recycling and late monocyte-macrophage endosomes, whether or not this provides a strategic advantage towards viral elimination has not been elucidated. RESULTS: We applied quantitative SWATH-MS proteomics and cell profiling to nanoparticle atazanavir (nanoATV)-treated and HIV-1 infected human monocyte-derived macrophages (MDM). Native ATV and uninfected cells served as controls. Both HIV-1 and nanoATV engaged endolysosomal trafficking for assembly and depot formation, respectively. Notably, the pathways were deregulated in opposing manners by the virus and the nanoATV, likely by viral clearance. Paired-sample z-scores, of the proteomic data sets, showed up- and down- regulation of Rab-linked endolysosomal proteins. NanoART and native ATV treated uninfected cells showed limited effects. The data was confirmed by Western blot. DAVID and KEGG bioinformatics analyses of proteomic data showed relationships between secretory, mobility and phagocytic cell functions and virus and particle trafficking. CONCLUSIONS: We posit that modulation of endolysosomal pathways by antiretroviral nanoparticles provides a strategic path to combat HIV infection

Understanding Public Service: An Government

Abstract . With the development of electronic technology and amount of shortcomings of traditional Public Administration (PA) have been exposed nowadays, E-government start to be being used extensively. In this paper, we analyzed the documents provided by a certain government based on the OntoClean methodology. Public service was divided into four social properties, and 17 categories. These definitions of taxonomy are contributive to the establishment and development of E-government and this ontology-based methodology can be applied in different scenarios, like commercial services, applying the same method