Implementation of Work Discipline and Application of Employee Sanctions In PD. BPR Rokan Hulu

This study was conducted at BPR PD Rokan Hulu, utilizing a qualitative descriptive analysis based on interviews. The primary objective was to investigate the disciplinary practices and the application of punishment among employees within the institution. The findings reveal that to enhance disciplinary diversity, BPR PD Rokan Hulu has established robust regulations and enforced sanctions effectively. This initiative demonstrates BPR PD Rokan Hulu's commitment to promoting diversity through structured training programs and the implementation of punitive measures. Despite these efforts, the study identified that there are still instances of indiscipline among some employees. Specific violations observed include habitual tardiness, absenteeism without prior approval from supervisors, and unexplained departures during official work hours. These actions not only contravene the company's established regulations but also undermine the overall disciplinary framework intended to foster a productive and efficient work environment. The research highlights the significance of continuous monitoring and reinforcement of disciplinary measures to ensure adherence to organizational norms and standards. Furthermore, it suggests that while the implementation of rules and sanctions is vital, BPR PD Rokan Hulu could benefit from exploring additional strategies to address the root causes of indiscipline. This could include more personalized training sessions, enhanced communication channels between employees and management, and the development of a more inclusive company culture that encourages respect for regulations. In conclusion, while BPR PD Rokan Hulu has made commendable strides in enforcing discipline and applying necessary sanctions, there is room for improvement. Addressing the lingering issues of employee indiscipline requires a multifaceted approach that not only penalizes non-compliance but also actively fosters an organizational culture that values punctuality, responsibility, and adherence to established guidelines.This study was conducted at BPR PD Rokan Hulu, utilizing a qualitative descriptive analysis based on interviews. The primary objective was to investigate the disciplinary practices and the application of punishment among employees within the institution. The findings reveal that to enhance disciplinary diversity, BPR PD Rokan Hulu has established robust regulations and enforced sanctions effectively. This initiative demonstrates BPR PD Rokan Hulu's commitment to promoting diversity through structured training programs and the implementation of punitive measures. Despite these efforts, the study identified that there are still instances of indiscipline among some employees. Specific violations observed include habitual tardiness, absenteeism without prior approval from supervisors, and unexplained departures during official work hours. These actions not only contravene the company's established regulations but also undermine the overall disciplinary framework intended to foster a productive and efficient work environment. The research highlights the significance of continuous monitoring and reinforcement of disciplinary measures to ensure adherence to organizational norms and standards. Furthermore, it suggests that while the implementation of rules and sanctions is vital, BPR PD Rokan Hulu could benefit from exploring additional strategies to address the root causes of indiscipline. This could include more personalized training sessions, enhanced communication channels between employees and management, and the development of a more inclusive company culture that encourages respect for regulations. In conclusion, while BPR PD Rokan Hulu has made commendable strides in enforcing discipline and applying necessary sanctions, there is room for improvement. Addressing the lingering issues of employee indiscipline requires a multifaceted approach that not only penalizes non-compliance but also actively fosters an organizational culture that values punctuality, responsibility, and adherence to established guidelines.

Functional Characterization of Human Multidrug Resistance Atp-Binding Cassette Transporters

ABC (ATP-binding cassette) transporters comprise one of the largest class of transmembrane proteins. One of the most studied member of the human ABC transporters superfamily is ABCB1 which is also known as P-glycoprotein (P-gp) or multidrug resistance 1 (MDR1). Physiologically, P-gp protects the cells by exporting structurally and chemically unrelated substances out of the cell. P-gp also plays an important role in pharmacokinetics of drugs. Multidrug resistance (MDR) is a common phenomenon observed in cancer cells which is mediated by several molecular pumps including P-gp. Therefore, it is also called multidrug resistance transporter. A major problem in the treatment of diseases like cancer has been the development of resistance to chemotherapies. The present study comprises of three major sections. 1. In silico study for selection of interacting residues of human P-gp with benzophenone sulfonamide type of derivatives 2. Generation and functional characterization of mutants selected from in silico work 3. Screening of benzophenone sulfonamide derivatives for their P-gp inhibitory potential to see their effect on reversal of MDR. For in silico studies, two templates were used for molecular docking of a class of benzophenone sulfonamide derivatives in order to predict the residues in the binding pocket of human P-gp. The crystal structure of mouse P-gp (PDB: 4M1M) was used as a template to build the homology model of human P-gp. Benzophenone sulfonamides were initially docked into the modeled human P-gp. Additionally, the recently published CEM structure of humanmouse chimeric-P-gp was used to dock the same class. Docking results predicted certain important residues of the binding cavity involved in binding to benzophenone sulfonamide derivatives. Among the interacting residues tyrosine Y307 and Y310 were found directly interacting with active compounds of the benzophenone sulfonamide derivatives. Y310 was found in both the types of docking while Y307 was a major interacting partner in humanmouse chimeric structure and found in close vicinity in the modeled human P-gp structure. The second section of the thesis describes the generation of two arginine mutants Y307R and Y310R. Tyrosine Y307 and Y310 were selected for mutation on the basis of docking results. Both Y307 and Y310 were mutated to arginine to see if the mutant transporter showed any difference in transport of substrates and inhibitors including rhodamine 123, propafenone GPV31, verapamil and 3 novel benzonphenone sulfonamide derivatives. Y307R and Y310R mutants were expected to alter the binding of substrates or inhibitors and also affect the transport rate. As expected the two mutants Y307R and Y310R showed a decrease in transport of rhodamine123 which clearly demonstrated the importance of intact tyrosines at position 307 and 310 for transport activity of human P-gp for its renowned substrate rhodamine123. In addition, results with well-known inhibitor of P-gp verapamil and propafenone analogue showed that both mutants require low concentration of inhibitors to inhibit P-gp as compared to wild type transporter. When the inhibition experiments of P-gp were conducted using benzophenone sulfonamide derivatives again both mutants behaved like verapamil and propfenone analogue by showing lower IC50 values as compared to wild type transporter. It had been noticed that Y307R was equally expressed as that of wild type and Y310R showed a slight higher expression as that of P-gp which indicated that these two mutants did not mechanically alter the transporter.Third section of the thesis describes evaluation of benzophenone sulfonamide derivatives as inhibitors of P-gp. Such class of compounds were proven to be good inhibitors as they possess lower molecular weights and LopP values than the well-known inhibitor verapamil. IC50 values showing inhibitory activity of the active compounds (11, 13 and 14) in very low nanomolar range were found to be 0.029 µM ± 0.001, 0.07 µM ± 0.02 and 0.005 µM ± 0.002 respectively.