دراسة قصيدة ياسالكا لمخدوم محمد هاشم التتوي رحمه الله: دراسة تحليلية وأدبية

The Poem “Ya Salikayah” is a collection of verses. Hazrat Makhdoom Muhammad Hashim Thattavi has compiled it and the main thing is that he has compiled these verses by in keeping with the literature and eloquence and rules. Such a compilation is not just a matter of every ordinary person rather, this work can be done by a person who is well aware of the rules of making of poetry and verses. Hazrat Makhdoom Muhammad Hashim Thattavi was well aware of these rules but he had mastered it. The thesis writer has described the expression style and thoughts of Hazrat Makhdoom Muhammad Hashim Thattavi in his thesis and also tried to prove that Hazrat Makhdoom Muhammad Hashim Thattavi had special kind of proficiency in Arabic despite he was Non-Arab which can be seen in his these verses. These verses show the special style of Hazrat Makhdoom Muhammad Hashim Thattavi which thesis writer has proven and also proved that he has compiled this collection of verses in the best style. According to the research of thesis writer this poem is not still in the form of a book but in the form of a pen and paper format. And thesis writer has also tried to prove that the thoughts which are in these verses belong to Hazrat Makhdoom Thattavi himself. He used to shape thoughts into ideas before compiling these verses and then used to put his sincere poetry in it and compile it. It is estimated from these verses that it is affected when the audience hears and reads these verses.

Determination of Novel Substrtae Candidates for Protein Kinases to Explore Their Functional Implications in Cancer Theraputics

With the advent of novel technologies and initiatives, increasing numbers of kinases associated with divergent structural features are available. However, their underlying phosphorylation targets and structure-based functional classifications require identifying additional elements. Here, the value of detecting structural relationships of Polo like kinase 1 (PLK1) is reviewed for target identification, cancer therapeutics and development of inhibition strategies. PLK1 is a key player in orchestrating the wide variety of cell-cycle events, ranging from centrosome maturation, mitotic entry, transcriptional control, spindle assembly, mitotic progression, cytokinesis and DNA damage checkpoint recovery. Despite the growing knowledge of PLK1 functional diversity; there have been a limited number of proteins known to be phosphorylated by PLK1. Integration of multiple data sources and techniques is required for high throughput analysis of PLK1 phosphoproteome. Particularly, structural localization of phosphorylation sites is fundamental in ascertaining structure-function relationships and prediction of novel players. To address the multifunctioning of PLK1, focused on molecular structural descriptions, a range of bioinformatics methodologies were devised. Collectively, about 4,521 phosphodependent proteins, sharing similarity to the consensus phosphorylation and polo-box domain (PBD) recognition motifs, have been demonstrated. Subsequent application of filters including similarity index, Gene Ontology enrichment and protein localization resulted in stringent pre-filtering of irrelevant candidates and resulting in the isolation of unique targets with well-defined roles in cell cycle machinery and carcinogenesis. These candidates were further refined structurally using molecular docking and dynamics simulation assays. Overall, identification of these phosphorylation targets has provided the basis of classifying PLK1 cell cycle related functions. PLK1 is known to overexpress in oesophageal (OE) cancer. However, its downstream targets playing unique roles in OE are rare and less informative. The use of collective knowledge has proven to be a promising means in this respect. It is a well established fact that PLK1 directly interacts with tumor suppressor p53 and co-regulated targets prune crosstalk between their functional associations. PLK1 inhibition triggers activation of p53 level in tumor cells, while inactive p53 results in mitotic arrest and DNA damage. To reveal specific PLK1 phosphorylation sites in p53 wild-type and mutant OE cell lines, phosphoproteomics screen was performed whichsuccessfully captured the functional contributions of PLK1 targets. Moreover, by comparative annotations, an unprecedented landscape of phosphorylated motifs was achieved, leading to the distinctiveness of p53 function and prediction of novel biomarkers. In an attempt to narrow down the list of PLK1 targets in oesophageal adenocarcinoma, RNA-sequencing data of four OE patients were integrated with mass spectrometry data of OE cell lines. This strategy extracted two novel phosphorylation targets, small ubiquitin-like modifier (SUMO1) and heat shock protein beta-1 (HSPB1), which were further verified by in vitro phosphorylation assays. Consequently, through Proximity ligation and co-immunoprecipitation assays, it was found that both SUMO1 and HSPB1 stably interact with PLK1. The potential PLK1 binding sites of these targets were analyzed through modeling and docking approaches. In an effort to characterize novel binding signatures of PLK1-PBD, we developed an in vitro next generation peptide phage library screen. Specific peptides were identified in the eluted PBD and control fractions. Subsequent BLAST analysis of PBD consensus sites identified several known and novel mitotic players, implicated in PLK1-dependent pathways. The bound peptides were evaluated at sequence and structure levels to delineate novel interactions and their corresponding binding sites. Based on the evidence that PLK1 expression is elevated in cancer cells, PLK1 serves as a potential therapeutic target for the development of cancer specific drugs. However, all the existing inhibitors either target PLK1-PBD or kinase domain, exclusively. Through integration of ensemble of bioinformatics techniques, bifunctional inhibitors have been predicted which target both domains of PLK1 in parallel. The identified inhibitors were deeply analyzed for their binding pattern and stability through molecular dynamics simulation assays. Overall, these bifunctional inhibitors may be more potent and serve as better therapeutic options, following experimental validation