Nishaan - The Target 3 Movie Hd 1080p
Katja Gains
Particle-based delivery systems have been investigated for their potential to increase the efficacy of patient diagnoses and treatments. In many cases, these systems increase the bioavailability and/or decrease the toxicity of clinically relevant drugs. These developments have led to improvements in patient compliance, morbidity, mortality, and quality of life. To date, particle-based delivery systems have been evaluated in hundreds of clinical trials around the world. Unlike conventional delivery systems, particle-based delivery systems offer increased surface area, colloidal stability, and system tunability, all of which can be tailored to target the disease state of interest and specific patient population.
Although there are examples of successful particle-based drug products, there are numerous obstacles that consistently shunt the ability for these systems to be translated from benchside to bedside. Two consistent obstacles are drug toxicity and scale-up manufacturing. Drug toxicity is largely caused by inefficient targeting, inopportune routes of administration (i.e. oral delivery for a pulmonary disease), and unfavorable release mechanisms. Scale-up manufacturing is a continual industrial interest, given that particle-based drug products are increasing in popularity, however scale-up procedures are still in development and face their own challenges. A potential method to overcome the obstacles faced in drug delivery is the development of new polymers, either by synthesis of novel entities or derivatization of current ones. To ensure biocompatibility, the latter is a common practice. Biopolymers such as chitosan, hyaluronic acid, poly(lactic-co-glycolic acid) (PLGA), and naturally occurring polysaccharides undergo modifications to achieve desirable characteristics for drug delivery. Acetalated dextran (Ac-Dex) is a synthetic biopolymer derived from dextran, a naturally produced hydrophilic polysaccharide. Following a one-step reaction, the hydroxyl moieties of dextran are converted to acetal groups, transitioning the biopolymer from hydrophilic to lipophilic solubility. Hydroxyl moieties still present on the backbone can provide a handle for ligand attachment to actively target specific sites of the body. Additionally, controlling the reaction time and altering the molecular weight of the dextran backbone can alter the degradation kinetics, providing flexibility to achieve desirable release kinetics for a therapeutic of interest. Overall, Ac-Dex demonstrates cost-effective and efficient synthesis, easy tunability for targeting, and flexibility in controlling release kinetics, all of which propitiate its promise as a drug carrier.
The purpose of this dissertation was to utilize the advantages of Ac-Dex to investigate its potential as a drug carrier to overcome challenges that exist in the field of drug delivery. Manuscript 1 focuses on decreasing drug toxicity using active targeting. Here, Ac-Dex nanoparticles (NP) were synthesized and coated with phosphatidylserine to instigate macrophage uptake for the potential to treat diseases that use these cells as reservoirs, such as tuberculosis and HIV. Manuscript 2 focuses on the synthesis of Ac-Dex microparticles (MP), followed by an exploration of their ability to modulate the release of water-soluble cargo. Ac-Dex MP were synthesized via spray drying and were loaded with a water-soluble dye. Following the synthesis, MP were evaluated for their characteristics and drug release behaviors in multiple pH environments. Manuscript 3 uses Ac-Dex as an economical model drug carrier and focused on studying the effects of tangential flow filtration (TFF) parameters (factors) on the characteristics of NP (responses) to explore its promise as a scale-up purification technique. The final manuscript focuses on the physical characterization and development of nanocomposite microparticle system for localized delivery of the small molecule Eact, a potential therapeutic for pulmonary arterial hypertension.
You need to use Visual Studio 2019 and its SQL Server Integration Services Projects extension to develop SSIS projects targeting 2016 version. It supports the following SSIS run-time versions: 2012, 2014, 2016, 2017, 2017, 2019, 2022.
Chlamydia trachomatis is involved in most sexually transmitted diseases. The species has emerged as a major public health threat due to its multidrug-resistant capabilities, and new therapeutic target inferences have become indispensable to combat its pathogenesis. However, no commercial vaccine is yet available to treat the C. trachomatis infection. In this study, we used the publicly available complete genome sequences of C. trachomatis and performed comparative proteomics and reverse vaccinology analyses to explore novel drug and vaccine targets against this devastating pathogen. We identified 713 core proteins from 71 C. trachomatis complete genome sequences and prioritized them based on their cellular essentiality, virulence, and available antibiotic resistance. The analyses led to the identification of 16 pathogen-specific proteins with no resolved 3D structures, though holding significant druggable potential. The sequences of the three shortlisted candidates' membrane proteins were used for designing vaccine constructs. The antigenicity, toxicity, and solubility profile-based lead epitopes were prioritized for multi-epitope-based vaccine constructs in combination with specific linkers, PADRE sequences, and molecular adjuvants for immunogenicity enhancement. The molecular-level interactions of the prioritized vaccine construct with human immune cells HLA and TLR4/MD were validated by molecular docking and molecular dynamic simulation analyses. Furthermore, the cloning and expression potential of the lead vaccine construct was predicted in the E. coli cloning vector system. Additional testing and experimental validation of these multi-epitope constructs appear promising against C. trachomatis-mediated infection.
The management of infectious diseases has become more critical due to the development of novel pathogenic strains with enhanced resistance. Prevotella melaninogenica, a gram-negative bacterium, was found to be involved in various infections of the respiratory tract, aerodigestive tract, and gastrointestinal tract. The need to explore novel drug and vaccine targets against this pathogen was triggered by the emergence of antimicrobial resistance against reported antibiotics to combat P. melaninogenica infections. The study involves core genes acquired from 14 complete P. melaninogenica strain genome sequences, where promiscuous drug and vaccine candidates were explored by state-of-the-art subtractive proteomics and reverse vaccinology approaches. A stringent bioinformatics analysis enlisted 18 targets as novel, essential, and non-homologous to humans and having druggability potential. Moreover, the extracellular and outer membrane proteins were subjected to antigenicity, allergenicity, and physicochemical analysis for the identification of the candidate proteins to design multi-epitope vaccines. Two candidate proteins (ADK95685.1 and ADK97014.1) were selected as the best target for the designing of a vaccine construct. Lead B- and T-cell overlapped epitopes were joined to generate potential chimeric vaccine constructs in combination with adjuvants and linkers. Finally, a prioritized vaccine construct was found to have stable interactions with the human immune cell receptors as confirmed by molecular docking and MD simulation studies. The vaccine construct was found to have cloning and expression ability in the bacterial cloning system. Immune simulation ensured the elicitation of significant immune responses against the designed vaccine. In conclusion, our study reported novel drug and vaccine targets and designed a multi-epitope vaccine against the P. melaninogenica infection. Further experimental validation will help open new avenues in the treatment of this multi-drug-resistant pathogen.
Nishan delivered his inaugural address as President and Vice-Chancellor at the University of Leicester in January 2020. During his address he announced the development of the Leicester Institute for Inclusion in Higher Education and pledged that the University would achieve a net zero carbon emission target by 2040.
The survival evolution in the pathgens is based on mechanism of antibiotic resistance. These genes were collected in ARG-ANNOT database that was used to identify the antibiotic resistance by subjecting prioritized proteins to BLASTp scanning. It was found that only 1 KEGG independent protein was involved in antibiotic resistance. These essential, virulent and antibiotic resistance genes could pave ways for further investigations and studies to design novel drug targets.
It is important to predict subcellular location of a protein for better understanding of its functions, disease mechanism and it is also valuable for developing new drug and vaccine targets (Yao et al., 2019). For potential drug targets, proteins located in the cytoplasm were prioritized while remaining proteins having sublocations that are extracellular or outermembrane were preferred as vaccine targets as they would more likely elicit greater immune responses (Nogueira et al., 2021). The subcellular location prediction of both the pathways dependent and independent revealed that 1 and 41 proteins were cytoplasmic, respectively. Similarly, 1 and 18 proteins were found to be outer membrane and extracellular, respectively.
(Sanchez-Trincado et al., 2017). A cellular immune response mediated by B-Cell and T-Cell can be triggered by regions of proteins known as epitope. Epitope prediction is one of the major corner stones in the development of novel vaccine targets (Li et al., 2014). In cell mediated immunity, two types of cells are involved (a) cytotoxic T-cells (b) helper T-cells. MHC-I and MHC-II molecules provide these cells with epitopes. IEDB database was employed to analyze the MHC binding epitopes of shortlisted two vaccine candidates. High binding affinity epitopes were selected. NetMHCPan EL 4.0 web server with criteria set at IC50
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