Design and Evaluation of HIV Microbicides Loaded mucoadhesive Nanoformulation

Title from PDF of title page, viewed on March 21, 2016Dissertation advisor: Bi-Botti C. YouanVitaIncludes bibliographical references (pages 150-174)Thesis (Ph.D.)--School of Pharmacy and Department of Chemistry. University of Missouri--Kansas City, 2015HIV/AIDS had caused more than 25 million deaths since it was first recognized. Women are more susceptible to HIV infection in comparison with men due to human physiology, social, economic disadvantages. To protect women from HIV transmission, there is an urgent need to develop a formulation with proper vaginal retention time for the topical application of anti-HIV microbicides. The aim of this dissertation is to test the hypothesis that a mucoadhesive polymer based nanomedicine can prolong the contact time with the vaginal tissue, provide the controlled release of the drug, and is safe in vivo. Various formulation and are investigated, their physicochemical properties, mucoadhesive properties, and safety are evaluated. In Chapter 3, a chitosan (CS) based nanoparticle (NP) delivery system suitable for the encapsulation of tenofovir (TFV) is designed and optimized. The physicochemical characteristics of the NPs including encapsulation efficiency (EE%), diameter, morphology, in vitro drug release as well as in vitro cytotoxicity are evaluated. the size of CS NPs ranged from 168 nm to 277 nm. It is shown that NPs are safe to both vaginal epithelial cell line and Lactobacillus over 48 h. The mucoadhesion is about 12%. The CS NPs are mucoadhesive and safe as a microbicide carrier, the drawback of the CS NPs is the low EE%. In Chapter 4, the hypothesis that TFV loaded thiolated chitosan (TCS) NPs exhibit superior biophysical properties for mucoadhesion compared to those of native chitosan NPs is tested. The NPs are prepared by ionic gelation. The particle mean diameter, EE%, release profile, in vitro cytotoxicity, cellular uptake, uptake mechanism, and percent mucoadhesion are assessed. The particles are spherical with diameters ranged from 148 nm to 255 nm. The EE% and drug loading is 25% and 1.62% (w/w), respectively. The NPs provide a controlled release over of the drug following Higuchi model. The TCS NPs are not cytotoxic to both vaginal epithelial cell line and Lactobacillus over 48 h. The cellular uptake is time dependent. It is mainly occurred via caveolin mediated endocytosis. The mucoadhesive properties of TCS NPs is 5-fold higher than that of CS NPs. Compare to the CS NPs, the TCS NPs exhibit relatively higher EE%, drug loading, and mucoadhesion. In Chapter 5, we develop a TCS coated multilayer microparticles (MPs). Sodium alginate MPs are prepared by spray drying. The multilayer MPs are developed by coating the optimal alginate MPs with the TCS solution using a layer-by-layer method. The morphological analysis, drug loading, in vitro drug release, cytotoxicity, mucoadhesion and in vivo toxicity are evaluated. The MPs diameter ranges from 2 μm to 3 μm with a drug loading of 7-12% (w/w). The MPs show a controlled drug release. The MPs are found to have a high mucoadhesion (~50 folds at a higher ratio, and ~20 folds at a lower ratio of mucin: MPs) compare to non-layered sodium alginate MPs in both vaginal fluid and semen fluid simulant buffers. The multilayer MPs are non-cytotoxic to vaginal and endocervical epithelial cells. Histological analysis of the female C57BL/6 mice genital tract and other organs shows no damage upon once-daily administration of MPs up to 24 h and 7 days. The drug loading of the TCS MPs is significantly enhanced (from 1.62% to 12.73%) compare to that of the TCS NPs. However, the mucoadhesion of the MPs is slightly lower than that of the NPs due to the larger particle size. In chapter 6, the TCS core/shell nanofibers (NFs) are fabricated by a coaxial electrospinning technique. The drug loading is13%-25% (w/w), the EE% is about 100% because no loss of material during the electrospinning process. The NFs exhibit smooth surface with average diameters in the range of 50 to 100 nm. The NFs are non-cytotoxic at the concentration of 1 mg/ml. The core-shell NFs exhibit a release kinetic following Weibull model, and are 40-60 fold more bioadhesive than NFs made solely with PEO. H&E and immunohistochemical (CD45) staining analysis of genital tract indicates non-toxicity and non-inflammatory effects of the NFs daily treatment for up to 7 days. The TCS NFs exhibit both high drug loading and high mucoadhesion; these data highlight the potential of TCS NFs templates for the topical vaginal delivery of anti-HIV/AIDS microbicides. Overall, the present work demonstrates TFV loaded NF can be considered as a good candidate for the delivery of water-soluble small-molecule drugs, and a promising vaginal delivery system for the prevention of HIV transmission.Introduction -- Current state of the art in HIV microbicides delivery -- Engineering tenofovir loaded chitosan nanoparticles for the prevention of HIV transmition -- Comparative biophysical properties of tenofovir loaded thiolated and non-thiolated chitosan nanoparticles intended for HIV prevention -- Thiolated chitosan coated sodium alginate multilayer microparticles for enhanced drug loading and mucoadhesion -- Tenofovir containing thiolated chitosan core/shell nanofibers: in vitro and in vivo evaluations -- Summary and conclusion

Simulation study of BESIII with stitched CMOS pixel detector using ACTS

Reconstruction of tracks of charged particles with high precision is very crucial for HEP experiments to achieve their physics goals. As the tracking detector of BESIII experiment, the BESIII drift chamber has suffered from aging effects resulting in degraded tracking performance after operation for about 15 years. To preserve and enhance the tracking performance of BESIII, one of the proposals is to add one layer of thin CMOS pixel sensor in cylindrical shape based on the state-of-the-art stitching technology, between the beam pipe and the drift chamber. The improvement of tracking performance of BESIII with such an additional pixel detector compared to that with only the existing drift chamber is studied using the modern common tracking software ACTS, which provides a set of detector-agnostic and highly performant tracking algorithms that have demonstrated promising performance for a few high energy physics and nuclear physics experiments

Mechanism of enhanced performance on a hybrid direct carbon fuel cell using sawdust biofuels

The authors gratefully acknowledge the financial support by the Royal Society of Edinburgh for a RSE BP Hutton Prize in Energy Innovation.Biomass is expected to play a significant role in power generation in the near future. With the uprising of carbon fuel cells, hybrid direct carbon fuel cells (HDCFCs) show its intrinsic and incomparable advantages in the generation of clean energy with higher efficiency. In this study, two types of biomass treated by physical sieve and pyrolysis from raw sawdust are investigated on an anode-supported HDCFC. The structure and thermal analysis indicate that raw sawdust has well-formed cellulose I phase with very low ash. Electrochemical performance behaviors for sieved and pyrolyzed sawdust combined with various weight ratios of carbonate are compared in N2 and CO2 purge gas. The results show that the power output of sieved sawdust with 789 mWcm−2 is superior to that of pyrolyzed sawdust in CO2 flowing, as well as in N2 flowing. The anode reaction mechanism for the discrepancy of two fuels is explained and the emphasis is also placed on the modified oxygen-reduction cycle mechanism of catalytic effects of Li2CO3 and K2CO3 salts in promoting cell performance.PostprintPeer reviewe

The Genomes of Oryza sativa: A History of Duplications

We report improved whole-genome shotgun sequences for the genomes of indica and japonica rice, both with multimegabase contiguity, or almost 1,000-fold improvement over the drafts of 2002. Tested against a nonredundant collection of 19,079 full-length cDNAs, 97.7% of the genes are aligned, without fragmentation, to the mapped super-scaffolds of one or the other genome. We introduce a gene identification procedure for plants that does not rely on similarity to known genes to remove erroneous predictions resulting from transposable elements. Using the available EST data to adjust for residual errors in the predictions, the estimated gene count is at least 38,000–40,000. Only 2%–3% of the genes are unique to any one subspecies, comparable to the amount of sequence that might still be missing. Despite this lack of variation in gene content, there is enormous variation in the intergenic regions. At least a quarter of the two sequences could not be aligned, and where they could be aligned, single nucleotide polymorphism (SNP) rates varied from as little as 3.0 SNP/kb in the coding regions to 27.6 SNP/kb in the transposable elements. A more inclusive new approach for analyzing duplication history is introduced here. It reveals an ancient whole-genome duplication, a recent segmental duplication on Chromosomes 11 and 12, and massive ongoing individual gene duplications. We find 18 distinct pairs of duplicated segments that cover 65.7% of the genome; 17 of these pairs date back to a common time before the divergence of the grasses. More important, ongoing individual gene duplications provide a never-ending source of raw material for gene genesis and are major contributors to the differences between members of the grass family

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic

Mlinear: Rethink the Linear Model for Time-series Forecasting

Recently, significant advancements have been made in time-series forecasting research, with an increasing focus on analyzing the inherent characteristics of time-series data, rather than solely focusing on designing forecasting models.In this paper, we follow this trend and carefully examine previous work to propose an efficient time series forecasting model based on linear models. The model consists of two important core components: (1) the integration of different semantics brought by single-channel and multi-channel data for joint forecasting; (2) the use of a novel loss function that replaces the traditional MSE loss and MAE loss to achieve higher forecasting accuracy.On widely-used benchmark time series datasets, our model not only outperforms the current SOTA, but is also 10 $\times$ speedup and has fewer parameters than the latest SOTA model.Comment: 8 pages,1 figure,4 table