Search results for: chimeric drug delivery vehicles

Authors: Priya Patel, Paresh Patel, Mihir Raval

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Silibinin, a flavanone as an antimicrotubular agent used in the treatment of cancer, was encapsulated in nanoparticles (NPs) of poly (lactide-co-glycolide) (PLGA) polymer using the spray-drying technique. The effects of various experimental parameters were optimized by box-behnken experimental design. Production yield, encapsulation efficiency and dissolution study along with characterization by scanning electron microscopy, DSC, FTIR followed by bioavailability study. Particle size and zeta potential were evaluated by using zetatrac particle size analyzer. Experimental design it was evaluated that inlet temperature and polymer concentration influence on the drug release. Feed flow rate impact on particle size. Results showed that spray drying technique yield 149 nm indicate nanosize range. The small size of the nanoparticle resulted in an enhanced cellular entry and greater bioavailability. Entrapment efficiency was found between 89.35% and 98.36%. Zeta potential shows good stability index of nanoparticle formulation. The in vitro release studies indicated the silibinin loaded PLGA nanoparticles provide controlled drug release over a period of 32 h. Pharmacokinetic studies demonstrated that after oral administration of silibinin-loaded PLGA nanoparticles to rats at a dose of 10 mg/kg, relative bioavailability was enhanced about 8.85-fold, compared to silibinin suspension as control hence, this investigation demonstrated the potential of the experimental design in understanding the effect of the formulation variables on the quality of silibinin loaded PLGA nanoparticles. These results describe an effective strategy of silibinin loaded PLGA nanoparticles and might provide a promising approach against the cancer.

Keywords: silibinin, cancer, nanoparticles, PLGA, bioavailability

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Authors: Tomas O. Ortega, Cecilia T. Reyes, Cecile O. Legaspi, Cylde G. Abayon, Anna Mae C. Relingo, Mary Eden M. Teruel

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A study was conducted to evaluate the performance in the delivery of environmental management programs of the local government of Malay, Aklan, Philippines. The samples were determined by adopting the Multi-Stage Random Probability Sampling technique. The 150 respondents were drawn from barangays with larger shares of the population based on the Philippine Statistical Authority’s Data on Census Population and Housing for the year 2015. The qualified sample respondents were selected using the Kish Grid. Female respondents were targeted for even numbered questionnaires while male respondents were targeted for odd numbers. The four major core concepts namely awareness, availment, satisfaction and need for action were used in measuring the rating of the respondents and presented in frequency and percentage distributions. The reasons for their response were likewise gathered. The study inferred that a large portion of the respondents was profoundly aware of the environmental management programs implemented by their local government unit especially the solid waste management and the clean-up programs/projects. Programs to control air pollution and waste water management obtained the least awareness ratings from the respondents. A high percentage of respondents had availed of environmental management programs, particularly solid waste management. Overall, majority of the respondents were satisfied with the environmental management programs rendered by the local government unit and therefore needs less action. It is recommended that the local government unit must strengthen air pollution control program. Appropriate action must be taken to support the people’s interest in this program most particularly to the individuals who burn their garbage. Seminars and training-workshops about appropriate waste disposal will most likely help settle this issue.

Keywords: availment, awareness, environmental management, need for action, satisfaction

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Authors: Getiye Dejenu Kibret, Daniel Demant, Andrew Hayen

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Introduction: In Ethiopia, more than half of newborn babies do not have access to Emergency Obstetric and Neonatal Care (EmONC) services. Understanding the effect of distance to health facilities on service use and neonatal survival is crucial to recommend policymakers and improve resource distribution. We aimed to investigate the effect of distance to health services on maternal service use and neonatal mortality. Methods: We implemented a data linkage method based on geographic coordinates and calculated straight-line (Euclidean) distances from the Ethiopian 2016 demographic and health survey clusters to the closest health facility. We computed the distance in ESRI ArcGIS Version 10.3 using the geographic coordinates of DHS clusters and health facilities. Generalised Structural Equation Modelling (GSEM) was used to estimate the effect of distance on neonatal mortality. Results: Poor geographic accessibility to health facilities affects maternal service usage and increases the risk of newborn mortality. For every ten kilometres (km) increase in distance to a health facility, the odds of neonatal mortality increased by 1.33% (95% CI: 1.06% to 1.67%). Distance also negatively affected antenatal care, facility delivery and postnatal counselling service use. Conclusions: A lack of geographical access to health facilities decreases the likelihood of newborns surviving their first month of life and affects health services use during pregnancy and immediately after birth. The study also showed that antenatal care use was positively associated with facility delivery service use and that both positively influenced postnatal care use, demonstrating the interconnectedness of the continuum of care for maternal and neonatal care services. Policymakers can leverage the findings from this study to improve accessibility barriers to health services.

Keywords: acessibility, distance, maternal health service, neonatal mortality

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Authors: Thomas A. Fuller

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Over the past fifteen years, virtual schooling has been introduced and implemented in varying degrees throughout the public education system in the United States. It is possible in some states for students to voluntarily take all of their course load online, without ever having to step in a classroom. Experts foresee a dramatic rise in the number of courses taken online by public school students in the United States, with some predicting that by 2019 as many as 50% of public high school courses will be delivered online. This electronic delivery of public education offers tremendous potential to the scientific community because it calls for innovation and is funded by public school revenue. Public accountability provides a ready supply of statistical data for measuring the progress of virtual schools as they are implemented into the public school arena. This allows for a survey of the current use of virtual schooling through examination of past statistical data, as well as forecasting forward for future years based upon this past data. Virtual schooling is on the rise in the United States, but its growth has been tempered by practical problems of implementation. The greatest and best use of virtual schooling thus far has been to supplement the courses offered by public schools (e.g., offering unique language courses, elective courses, and games-based math and science courses). The weaknesses of virtual schooling lay in the problematic accountability in allowing students to take courses online at home and the lack of supportive infrastructure in the public school arena. Virtual schooling holds great promise for the public school education system in the United States, as well as the scientific community. Online courses allow students access to a much greater catalog of courses than is offered through classroom instruction in their local public school. This promising sector needs assistance from the scientific community in implementing new pedagogical methodologies.

Keywords: virtual schools, online classroom, electronic delivery, technological innovation

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Authors: Salwa M. Almomen, Mona A. Almaghrabi, Saja M. Alhabardi, Adel A. Alrwisan

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Background: Hepatotoxicity is a major reason for medication withdrawal from the markets. Unfortunately, serious adverse hepatic effects can occur after marketing with limited indicators during clinical development. Therefore, finding possible predictors for hepatotoxicity might guide the monitoring program of various stakeholders. Methods: We examined the clinical review documents for drugs approved in the US from 2011 to 2016 to evaluate their hepatic safety profile. Predictors: we assessed whether these medications meet Hy’s Law with hepatotoxicity grade ≥ 3, labeled hepatic adverse effects at approval, or accelerated approval status. Outcome: post-marketing regulatory action related to hepatotoxicity, including product withdrawal or updates to warning, precaution, or adverse effects sections. Statistical analysis: drugs were included in the analysis from the time of approval until the end of 2019 or the first post-marketing regulatory action related to hepatotoxicity, whichever occurred first. The hazard ratio (HR) was estimated using Cox-regression analysis. Results: We included 192 medications in the study. We classified 48 drugs as having grade ≥ 3 hepatotoxicities, 43 had accelerated approval status, and 74 had labeled information about hepatotoxicity prior to marketing. The adjusted HRs for post-marketing regulatory action for products with grade ≥ 3 hepatotoxicity was 0.61 (95% confidence interval [CI], 0.17-2.23), 0.92 (95%CI, 0.29-2.93) for a drug approved via accelerated approval program, and was 0.91 (95%CI, 0.33-2.56) for drugs with labeled hepatotoxicity information at approval time. Conclusion: This study does not provide conclusive evidence on the association between post-marketing regulatory action and grade ≥ 3 hepatotoxicity, accelerated approval status, or availability of labeled information at approval due to sampling size and channeling bias.

Keywords: accelerated approvals, hepatic adverse effects, drug-induced liver injury, hepatotoxicity predictors, post-marketing withdrawal

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Authors: Michael A. Unbehauen, Gregory D. Sloan, Alberto J. Squatrito

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Missile proliferation and global stability are intrinsically linked. Missile threats continually appear at the forefront of global security issues. North Korea’s recently demonstrated nuclear and intercontinental ballistic missile (ICBM) capabilities, for the first time since the Cold War, renewed public interest in strategic missile defense capabilities. To protect from limited ICBM attacks from so-called rogue actors, the United States developed the Ground-based Midcourse Defense (GMD) system. This study examines if the GMD missile defense shield has contributed to a safer world or triggered a new arms race. Based upon increased missile-related developments and the lack of adherence to international missile treaties, it is generally perceived that the GMD system is a destabilizing factor for global security. By examining the current state of arms control treaties as well as existing missile arsenals and ongoing efforts in technologies to overcome U.S. missile defenses, this study seeks to analyze the contribution of GMD to global stability. A thorough investigation cannot ignore that, through the establishment of this limited capability, the U.S. violated longstanding, successful weapons treaties and caused concern among states that possess ICBMs. GMD capability contributes to the perception that ICBM arsenals could become ineffective, creating an imbalance in favor of the United States, leading to increased global instability and tension. While blame for the deterioration of global stability and non-adherence to arms control treaties is often placed on U.S. missile defense, the facts do not necessarily support this view. The notion of a renewed arms race due to GMD is supported neither by current missile arsenals nor by the inevitable development of new and enhanced missile technology, to include multiple independently targeted reentry vehicles (MIRVs), maneuverable reentry vehicles (MaRVs), and hypersonic glide vehicles (HGVs). The methodology in this study encapsulates a period of time, pre- and post-GMD introduction, while analyzing international treaty adherence, missile counts and types, and research in new missile technologies. The decline in international treaty adherence, coupled with a measurable increase in the number and types of missiles or research in new missile technologies during the period after the introduction of GMD, could be perceived as a clear indicator of GMD contributing to global instability. However, research into improved technology (MIRV, MaRV and HGV) prior to GMD, as well as a decline of various global missile inventories and testing of systems during this same period, would seem to invalidate this theory. U.S. adversaries have exploited the perception of the U.S. missile defense shield as a destabilizing factor as a pretext to strengthen and modernize their militaries and justify their policies. As a result, it can be concluded that global stability has not significantly decreased due to GMD; but rather, the natural progression of technological and missile development would inherently include innovative and dynamic approaches to target engagement, deterrence, and national defense.

Keywords: arms control, arms race, global security, GMD, ICBM, missile defense, proliferation

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Authors: Levent Basayigit, Sinan Demir, Burhan Kara, Yusuf Ucar

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Cannabis is mostly used for drug production. In some countries, an excessive amount of illegal cannabis is cultivated and sold. Most of the illegal cannabis cultivation occurs on the lands far from settlements. In farmlands, it is cultivated with other crops. In this method, cannabis is surrounded by tall plants like corn and sunflower. It is also cultivated with tall crops as the mixed culture. The common method of the determination of the illegal cultivation areas is to investigate the information obtained from people. This method is not sufficient for the determination of illegal cultivation in remote areas. For this reason, more effective methods are needed for the determination of illegal cultivation. Remote Sensing is one of the most important technologies to monitor the plant growth on the land. The aim of this study is to monitor cannabis cultivation area using satellite imagery. The main purpose of this study was to develop an applicable method for monitoring the cannabis cultivation. For this purpose, cannabis was grown as single or surrounded by the corn and sunflower in plots. The morphological characteristics of cannabis were recorded two times per month during the vegetation period. The spectral signature library was created with the spectroradiometer. The parcels were monitored with high-resolution satellite imagery. With the processing of satellite imagery, the cultivation areas of cannabis were classified. To separate the Cannabis plots from the other plants, the multiresolution segmentation algorithm was found to be the most successful for classification. WorldView Improved Vegetative Index (WV-VI) classification was the most accurate method for monitoring the plant density. As a result, an object-based classification method and vegetation indices were sufficient for monitoring the cannabis cultivation in multi-temporal Earthwiev images.

Keywords: Cannabis, drug, remote sensing, object-based classification

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Authors: Barış Ozluoymak, Emin Guzel, Ahmet İnce

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Since chemical fertilizers are used for meeting the deficiency of plant nutrients, its many harmful effects are not taken into consideration for the structure of the earth. These fertilizers are hampering the work of the organisms in the soil immediately after thrown to the ground. This interference is first started with a change of the soil pH and micro organismic balance is disrupted by reaction in the soil. Since there can be no fragmentation of plant residues, organic matter in the soil will be increasingly impoverished in the absence of micro organismic living. Biological activity reduction brings about a deterioration of the soil structure. If the chemical fertilization continues intensively, soils will get worse every year; plant growth will slow down and stop due to the intensity of chemical fertilizers, yield decline will be experienced and farmer will not receive an adequate return on his investment. In this research, a prototype of automatic farm manure spreading machine for orange orchards that not just manufactured in Turkey was designed, constructed, tested and eliminate the human drudgery involved in spreading of farm manure in the field. The machine comprised several components as a 5 m3 volume hopper, automatic controlled hydraulically driven chain conveyor device and side delivery conveyor belts. To spread the solid farm manure automatically, the machine was equipped with an electronic control system. The hopper and side delivery conveyor designs fitted between orange orchard tree row spacing. Test results showed that the control system has significant effects on reduction in the amount of unnecessary solid farm manure use and avoiding inefficient manual labor.

Keywords: automatic control system, conveyor belt application, orchard, solid farm manure

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Authors: Polycarp Igbojekwe

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The main objective of this study was to determine if emotional labour has become a criterion in performance appraisal, job description, selection, and training schemes in the hotel industry in Nigeria. Our main assumption was that majority of hotel organizations have not built emotional labour into their human resources management schemes. Data were gathered by the use of structured questionnaires designed in Likert format, and interviews. The focus group was managers of the selected hotels. Analyses revealed that majority of the hotels have not built emotional labour into their human resources schemes particularly in the 1, 2, and 3-star hotels. It was observed that service employees of 1, 2, and 3-star hotels have not been adequately trained to perform emotional labour; a critical factor in quality service delivery. Managers of 1, 2, and 3-star hotels have not given serious thought to emotional labour as a critical factor in quality service delivery. The study revealed that suitability of an individual’s characteristics is not being considered as a criterion for selection and performance appraisal for service employees. The implication of this is that, person-job-fit is not seriously considered. It was observed that there has been a disconnect between required emotional competency, its recognition, evaluation, and training. Based on the findings of this study, it is concluded that selection, training, job description and performance appraisal instruments in use in hotels in Nigeria are inadequate. Human resource implications of the findings in this study are presented. It is recommended that hotel organizations should re-design and plan the emotional content and context of their human resources practices to reflect the emotional demands of front line jobs in the hotel industry and the crucial role emotional labour plays during service encounters.

Keywords: emotional labour, employee selection, job description, performance appraisal, person-job-fit, employee compensation

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Authors: Farida Habib, Haya Alfozan, Eman Miligi, Najla Alotaibi

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Background: Women’s satisfaction with maternity services, especially care during labor and birth, has become highly significant to healthcare providers, administrators, and policymakers. Purpose: The aims of this study were to assess maternal satisfaction regarding the quality of care during labor and to compare the level of maternal satisfaction between women who delivered by physicians and those delivered by midwives. Methodology: A descriptive, cross-sectional, correlational design was used. A convenient sample of 180 low-risk cases of immediate postpartum women who delivered at King Abdul-Aziz medical city was recruited. Women whose babies were diagnosed with serious health problems were excluded from the study. Data were collected using a self-administered questionnaire. The validity and reliability of the questionnaire were ensured. The questionnaire included three parts, namely: demographics data, medical history, and obstetrical history, and the last part is the satisfaction assessment tool. Ethical confederations were ensured. Maternal satisfaction during labor was classified in terms of health care, health workers' communication, and the environment. Results: Regarding health care, women were highly satisfied with care received from nurse (M = 4.21 + 0.88), medical care received (M = 4.17 + 0.79), and comfort techniques (M = 4.04 + 0.91). Regarding health workers' communication, women were highly satisfied with the provider to treat with dignity and respect (M = 4.03 + 0.91) and orientation to the toilet, bathroom, washing area (M = 4.00 + 0.93). Regarding the environment, women were highly satisfied with the experience of their baby's birth (M = 4.18 + 0.98) and supplies with drugs and supplies (M = 4.09 + 0.97). There was no statistically significant difference in maternal satisfaction between women who delivered by physicians and those delivered by midwives. Conclusion: Women were generally satisfied with their labor and delivery experience. There was no difference in maternal satisfaction on the labor process between women who delivered by physicians and those delivered by midwives.

Keywords: maternity, satisfaction, labor, delivery

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Authors: Sagar Jitendra Mahendrakar

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Integrating quality assurance (QA) practices into DevOps culture has become increasingly important in modern software development environments. Collaboration, automation and continuous feedback characterize the seamless integration of DevOps development and operations teams to achieve rapid and reliable software delivery. In this context, quality assurance plays a key role in ensuring that software products meet the highest quality, performance and reliability standards throughout the development life cycle. This brief explores key principles, challenges, and best practices related to quality assurance in a DevOps culture. This emphasizes the importance of quality transfer in the development process, as quality control processes are integrated in every step of the DevOps process. Automation is the cornerstone of DevOps quality assurance, enabling continuous testing, integration and deployment and providing rapid feedback for early problem identification and resolution. In addition, the summary addresses the cultural and organizational challenges of implementing quality assurance in DevOps, emphasizing the need to foster collaboration, break down silos, and promote a culture of continuous improvement. It also discusses the importance of toolchain integration and capability development to support effective QA practices in DevOps environments. Moreover, the abstract discusses the cultural and organizational challenges in implementing QA within DevOps, emphasizing the need for fostering collaboration, breaking down silos, and nurturing a culture of continuous improvement. It also addresses the importance of toolchain integration and skills development to support effective QA practices within DevOps environments. Overall, this collection works at the intersection of QA and DevOps culture, providing insights into how organizations can use DevOps principles to improve software quality, accelerate delivery, and meet the changing demands of today's dynamic software. landscape.

Keywords: quality engineer, devops, automation, tool

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Authors: Shamila Manie, Soraya Maart, Ayesha Osman

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Introduction: People diagnosed with multidrug resistant pulmonary tuberculosis (MDR-PTB) is subjected to prolonged hospitalization in South Africa. It has thus become essential for research to shift its focus from a purely medical approach, but to include social and environmental factors when looking at the impact of the disease on those affected. Aim: To explore the factors affecting individuals with multi-drug resistant pulmonary tuberculosis during long-term hospitalization using the comprehensive ICF core-sets for obstructive pulmonary disease (OPD) and cardiopulmonary (CPR) conditions at Brooklyn Chest Hospital (BCH). Methods: A quantitative descriptive, cross-sectional study design was utilized. A convenient sample of 19 adults at Brooklyn Chest Hospital were interviewed. Results: Most participants reported a decrease in exercise tolerance levels (b455: n=11). However it did not limit participation. Participants reported that a lack of privacy in the environment (e155) was a barrier to health. The presence of health professionals (e355) and the provision of skills development services (e585) are facilitators to health and well-being. No differences exist in the functional ability of HIV positive and negative participants in this sample. Conclusion: The ICF Core Sets appeared valid in identifying the barriers and facilitators experienced by individuals with MDR-PTB admitted to BCH. The hospital environment must be improved to add to the QoL of those admitted, especially improving privacy within the wards. Although the social grant is seen as a facilitator, greater emphasis must be placed on preparing individuals to be economically active in the labour for when they are discharged.

Keywords: multidrug resistant tuberculosis, MDR ICF core sets, health-related quality of life (HRQoL), hospitalization

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Authors: Sina Gharevali

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Staphylococcus aureus is one of the most important factors for nosocomial infections and infections acquired in a hospital setting role as is. Drug-resistant bacteria methicillin, which in 1961 was reported in many parts of the world, Made the role as the last drug, vancomycin, in the treatment of infections caused by the Staphylococcus aureus chain be taken into consideration. The aim of this study was to evaluate the antimicrobial effects of copper nanoparticles and compared it with antibiotics on Staphylococcus aureus resistant to vancomycin in vitro and animal model. In this study, this test was performed, and the most effective antibiotic for vancomycin-resistant Staphylococcus aureus was determined by disk diffusion method. After various concentrations of copper nanoparticles and antibiotics were prepared and vancomycin resistant Staphylococcus aureus bacteria with serial dilution method for determining antibiotic ciprofloxacin. Minimum Inhibitory Concentration and Minimum Bactericidal Concentrationcopper nanoparticles was performed. The agar dilution method for bacterial growth in different concentrations of copper nanoparticles and antibiotics ciprofloxacin was performed. The agar dilution method for bacterial growth in different concentrations of copper nanoparticles and antibiotics ciprofloxacin was performed. Then the broth dilution method for the antibiotic ciprofloxacin, nano-particles, and nano-particles of copper and copper-established antibiotic synergy MIC and MBC were obtained. MBC was obtained from the experimental animal model test method, and the results were compared. The results showed that copper nanoparticles compared with the antibiotic ciprofloxacin in vitro and animal model more effective in inhibiting the growth of Staphylococcus aureus resistant to vancomycin and ciprofloxacin and extent of the impact of the Synthetic effect of lower copper nanoparticles. Which can then be used to treat clinical research as a candidate.

Keywords: nanoparticles, copper, staphylococcus, aureus

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Authors: Jaeyoung Lee, Minji Je

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Objectives: The adolescents not attending school are named out-of-school adolescents. They are more vulnerable to health management and are likely to be exposed to a number of risk factors. This study was conducted to investigate the problem behavior of out-of-school adolescents and analyze the difference caused by gender. Methods: In this study, the problem behaviors of out-of-school adolescents, the vulnerable class, were defined in 8 types and based on this definition, the survey on run away from home, drop out, prostitution, violence, internet game addiction, theft, drug addiction, and smoking was conducted. The study was conducted in a total of 507 out-of-school adolescents, including 342 males, and 165 females. The type, frequency and start time of the 8 problem behaviors were identified. The collected data were analyzed with chi-square test and t-test using SPSS statistics 22. Results: Among the problem behaviors of the subjects, violence ( =17.41, p < .001), internet game addiction ( =16.14, p < .001), theft ( =22.48, p < .001), drug addiction ( =4.17, p=.041), and smoking ( =3.90, p=.048) were more significantly high in male out-of-school adolescents than female out-of-school adolescents. In addition, the frequency of the problem behavior was higher in male out-of-school adolescents with statistical significance than in female out-of-school adolescents (t=5.08, p= < .001). In terms of the start time of the problem behavior, only internet game addiction was higher in male out-of-school adolescents with the statistical significance than in female out-of-school adolescents ( =6.22, p=.032). No statistically significant difference was found in other problem behaviors (p > .05). Conclusions: In this study, it was found that gender difference in problem behaviors of out-of-school adolescents exists, and its frequency and difference of types were identified. When the social countermeasures were provided for those adolescents, a distinguished approach is required depending on the patterns of problem behavior and gender. When preparing policy alternatives and interventions for out-of-school adolescents, it is required to reflect the results of this study.

Keywords: addictive behavior, adolescent, gender, problem behavior

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Authors: Muhammad Sohail Sajid, Mahvish Maqbool, Hafiz Muhammad Rizwan, Muhammad Saqib, Haroon Ahmad

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Ticks are blood-sucking ectoparasite that causes a decrease in production and economic losses and affects mammals, reptiles, and birds. Hyalomma anatolicum is the main vector for CCHF transmission and Pakistan has faced several outbreaks of CCHF in the recent past. Ferritin (fer)is a highly conserved molecule that is ubiquitous in most tick tissues and responsible for iron metabolism and storage. It was hypothesized that the development of acaricidal resistance and residual effects of commercially used acaricides could be controlled by using alternative control methods, including RNA interference. The current study aimed to evaluate the fer silencing effects on tick feeding, average body weight, egg mass index, and mortality. Ticks, collected through the standard collection protocols were further subjected to RNA isolation using the Trizol method. Commercially available kit procedures were followed for cDNA and dsRNA synthesis. The soaking/Immersion method was used for dsRNA delivery. Our findings have shown a 27% reduction in body weight of fer silenced group and showed a significant association of fer and body weight. Silencing of fer had a significant effect on the engorgement percentage (P= 0.0007), oviposition (P=0.008), egg mass (P= 0.004) and hatching (P= 0.001). The soaking method was used for dsRNA delivery and 15°C was found to be an optimum temperature for inducing gene silencing in ticks as at this temperature, maximum survivability after immersion was attained. This study along with previous studies, described that iron toxicity due to the silencing of fer could play an important role in the control of ticks and fer can be used as a potent candidate for vaccine development.

Keywords: ticks, iron, ferritin, engorgement, oviposition, immersion, RNA interference

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Authors: Danylo Brindak, Viktor Liashko, Olexander Chepurniy

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Despite considerable experience in implementation of the best international approaches and services within response to epidemy of multi-drug resistant tuberculosis, the results of situation analysis indicate the presence of faults in this area. In 2014, Ukraine (for the first time) was included in the world’s five countries with the highest level of drug-resistant tuberculosis. The effectiveness of its treatment constitutes only 35% in the country. In this context, the increase in allocation of funds to control the epidemic of multidrug-resistant tuberculosis does not produce perceptible positive results. During 2001-2016, only the Global Fund to fight AIDS, Tuberculosis, and Malaria allocated to Ukraine more than USD 521,3 million for programs of tuberculosis and HIV/AIDS control. However, current conditions in post-Semashko system create little motivation for rational use of resources or cost control at inpatient TB facilities. There is no motivation to reduce overdue hospitalization and to target resources to priority sectors of modern tuberculosis control, including a model of care focused on the patient. In the presence of a line-item budget at medical institutions, based on the input factors as the ratios of beds and staff, there is a passive disposal of budgetary funds by health care institutions and their employees who have no motivation to improve quality and efficiency of service provision. Outpatient treatment of tuberculosis is being implemented in Ukraine since 2011 and has many risks, namely creation of parallel systems, low consistency through dependence on funding for the project, reduced the role of the family doctor, the fragmentation of financing, etc. In terms of reforming approaches to health system financing, which began in Ukraine in late 2016, NGO Infection Control in Ukraine conducted piloting of a new, motivating method of remuneration of employees in primary health care. The innovative aspect of this funding mechanism is cost according to results of treatment. The existing method of payment on the basis of the standard per inhabitant (per capita ratio) was added with motivating costs according to results of work. The effectiveness of such treatment of TB patients at the outpatient stage is 90%, while in whole on the basis of a current system the effectiveness of treatment of newly diagnosed pulmonary TB with positive swab is around 60% in the country. Even though Ukraine has 5.24 TB beds per 10 000 citizens. Implemented pilot model of ambulatory treatment will be used for the creation of costs system according to results of activities, the integration of TB and primary health and social services and their focus on achieving results, the reduction of inpatient treatment of tuberculosis.

Keywords: health care reform, multi-drug resistant tuberculosis, outpatient treatment efficiency, tuberculosis

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Authors: Kanduru Lokesh, Venkitasamy Kesavan

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The unique structural features of spiro-oxindoles with diverse biological activities have made them privileged structures in new drug discovery. The key structural characteristic of these compounds is the spiro ring fused at the C-3 position of the oxindole core with varied heterocyclic motifs. Structural diversification of heterocyclic scaffolds to synthesize new chemical entities as pharmaceuticals and agrochemicals is one of the important goals of synthetic organic chemists. Nitrogen and oxygen containing heterocycles are by far the most widely occurring privileged structures in medicinal chemistry. The structural complexity and distinct three-dimensional arrangement of functional groups of these privileged structures are generally responsible for their specificity against biological targets. Structurally diverse compound libraries have proved to be valuable assets for drug discovery against challenging biological targets. Thus, identifying a new combination of substituents at C-3 position on oxindole moiety is of great importance in drug discovery to improve the efficiency and efficacy of the drugs. The development of suitable methodology for the synthesis of spiro-oxindole compounds has attracted much interest often in response to the significant biological activity displayed by the both natural and synthetic compounds. So creating structural diversity of oxindole scaffolds is need of the decade and formidable challenge. A general way to improve synthetic efficiency and also to access diversified molecules is through the annulation reactions. Annulation reactions allow the formation of complex compounds starting from simple substrates in a single transformation consisting of several steps in an ecologically and economically favorable way. These observations motivated us to develop the annulation reaction protocol to enable the synthesis of a new class of spiro-oxindole motifs which in turn would enable the enhancement of molecular diversity. As part of our enduring interest in the development of novel, efficient synthetic strategies to enable the synthesis of biologically important oxindole fused spirocarbocyclic systems, We have developed an efficient methodology for the construction of highly functionalized spirocarbocyclic oxindoles through [4+2] annulation of phthalides via Hauser annulation. functionalized spirocarbocyclic oxindoles was accomplished for the first time in the literature using Hauser annulation strategy. The reaction between methyleneindolinones and arylsulfonylphthalides catalyzed by cesium carbonate led to the access of new class of biologically important spiro[indoline-3,2'-naphthalene] derivatives in very good yields. The synthetic utility of the annulated product was further demonstrated by fluorination Using NFSI as a fluorinating agent to furnish corresponding fluorinated product.

Keywords: Hauser-Kraus annulation, spiro carbocyclic oxindoles, oxindole-ester, fluoridation

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Authors: Shilpee Jain, Sachin Latiyan, Kaushik Suneet

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Unlike traditional robots, medical microbots are not only smaller in size, but they also possess various unique properties, for example, biocompatibility, stability in the biological fluids, navigation opposite to the bloodstream, wireless control over locomotion, etc. The idea behind their usage in the medical field was to build a minimally invasive method for addressing the post-operative complications, including longer recovery time, infection eruption and pain. Herein, the present study demonstrates the fabrication of dual nature magneto-conducting Fe3O4 magnetic nanoparticles (MNPs) and SU8 derived carbon-based Janus microbots for the efficient intracellular delivery of biomolecules. The low aspect ratio with feature size 2-5 μm microbots were fabricated by using a photolithography technique. These microbots were pyrolyzed at 900°C, which converts SU8 into amorphous carbon. The pyrolyzed microbots have dual properties, i.e., the half part is magneto-conducting and another half is only conducting for sufficing the therapeutic payloads efficiently with the application of external electric/magnetic field stimulations. For the efficient intracellular delivery of the microbots, the size and aspect ratio plays a significant role. However, on a smaller scale, the proper control over movement is difficult to achieve. The dual nature of Janus microbots allowed to control its maneuverability in the complex fluids using external electric as well as the magnetic field. Interestingly, Janus microbots move faster with the application of an external electric field (44 µm/s) as compared to the magnetic field (18 µm/s) application. Furthermore, these Janus microbots exhibit auto-fluorescence behavior that will help to track their pathway during navigation. Typically, the use of MNPs in the microdevices enhances the tendency to agglomerate. However, the incorporation of Fe₃O₄ MNPs in the pyrolyzed carbon reduces the chances of agglomeration of the microbots. The biocompatibility of the medical microbots, which is the essential property of any biosystems, was determined in vitro using HeLa cells. The microbots were found to compatible with HeLa cells. Additionally, the intracellular uptake of microbots was higher in the presence of an external electric field as compared to without electric field stimulation. In summary, the cytocompatible Janus microbots were fabricated successfully. They are stable in the biological fluids, wireless controllable navigation with the help of a few Guess external magnetic fields, their movement can be tracked because of autofluorescence behavior, they are less susceptible to agglomeration and higher cellular uptake could be achieved with the application of the external electric field. Thus, these carriers could offer a versatile platform to suffice the therapeutic payloads under wireless actuation.

Keywords: amorphous carbon, electric/magnetic stimulations, Janus microbots, magnetic nanoparticles, minimally invasive procedures

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Authors: Anukriti Verma, Bhawna Rathi, Shivani Sharda

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Reactive Arthritis (ReA) is a disorder that causes inflammation in joints due to certain infections at distant sites in the body. ReA begins with stiffness, pain, and inflammation in these areas especially the ankles, knees, and hips. It gradually causes several complications such as conjunctivitis in the eyes, skin lesions in hand, feet and nails and ulcers in the mouth. Nowadays the diagnosis of ReA is based upon a differential diagnosis pattern. The parameters for differentiating ReA from other similar disorders include physical examination, history of the patient and a high index of suspicion. There are no standard lab tests or markers available for ReA hence the early diagnosis of ReA becomes difficult and the chronicity of disease increases with time. It is reported that enteric disorders such as Inflammatory Bowel Disease (IBD) that is inflammation in gastrointestinal tract namely Crohn’s Disease (CD) and Ulcerative Colitis (UC) are reported to be linked with ReA. Several microorganisms are found such as Campylobacter, Salmonella, Shigella and Yersinia causing IBD leading to ReA. The aim of our study was to perform the in-silico analysis in order to find interactions between microorganisms and human host causing IBD leading to ReA. A systems biology approach for metabolic network reconstruction and simulation was used to find the essential genes of the reported microorganisms. Interactomics study was used to find the interactions between the pathogen genes and human host. Genes such as nhaA (pathogen), dpyD (human), nagK (human) and kynU (human) were obtained that were analysed further using the functional, pathway and network analysis. These genes can be used as putative drug targets and biomarkers in future for early diagnosis, prevention, and treatment of IBD leading to ReA.

Keywords: drug targets, inflammatory bowel disease, reactive arthritis, systems biology

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Authors: Harshit Garg, Shakshi Gupta

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One of the major problems in today’s world is the growing pollution. The cause for all environmental problems is the increasing pollution rate. Looking upon the statistics, one can find out that most of the pollution is caused by the vehicular pollution which is more than 70 % of the total pollution, effecting the environment as well as human health proportionally. One is aware of the fact that vehicles run on roads so why not having the roads which could adsorb that pollution, not only once but a number of times. Every problem has a solution which can be solved by the state of art of technology, that is one can use the innovative ideas and thoughts to make technology as a solution to the problem of vehicular pollution on roads. Solving the problem up to a certain limit/ percentage can be formulated into a new term called ECO ROADS.

Keywords: environment, pollution, roads, sustainibility

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Authors: Santram Lodhi, Alok Pal Jain, Awesh K. Yadav, Gopal Rai

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Rhodiola rosea L. (Crassulaceae) is commonly known as golden root or rose root. It is a perennial herbaceous plant and most investigated species of the genus Rhodiola. Rhodiola rosea contains flavonoids, terpenoids, phenylpropanoid glycosides and phenylethanol derivatives in the roots of the plant. The objective of present study was to investigate the protective effect of hydroalcoholic extract from Rhodiola rosea roots in DSS induced colitis in mice. The ulcerative colitis was induced by DSS (3%, w/v) in mice and estimated weight loss and stool consistency. Various parameters including Colon length, spleen weights and ulcer index were also measured. The histological observations were observed by H&E staining. Effect of hydroalcoholic extract on various antioxidant parameter of rat colon such as tissue myeloperoxidase (MPO), reduced GSH, SOD concentrations and lipid peroxidation were determined. Pro-inflammatory mediators, such as tumour necrosis factor-α (TNF-α) and nitric oxide (NO) were determined by ELISA. In DSS induced group, mice body weight decreased gradually as compared to the control group. Redness and edema were observed in the colons intensely and scores representing inflammation in this group. The extract treated showed with tissue levels of TNF-α, IL-6 and MPO activity were significantly (p<0.05) increased. The mice treated with higher doses of hydroalcoholic extract (300 mg/kg) significantly reduced the activity compared with standard drug sulfasalazine (100 mg/kg. B.wt). Conclusion: Results of this study were suggested that the efficacy of hydroalcoholic extract, especially at the higher dose, was similar to that of standard drug, which concerned its potential application as a natural medicine for the treatment of ulcerative colitis.

Keywords: phenylpropanoid, Rhodiola rosea, sulfasalazin, ulcerative colitis

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Authors: L. B. Naves, L. Almeida

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The development of Drugs Delivery System (DDS), has been wildly investigated in the last decades. In this paper, first a general overview of traditional and modern wound dressing is presented. This is followed by a review of what scientist have done in the medical environment, focusing the possibility to develop a new alternative for DDS through transdermal pathway, aiming to treat melanoma skin cancer.

Keywords: cancer therapy, dressing polymers, melanoma, wound healing

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Authors: Akhtar Nawaz, Sahar Noor, Iftikhar Hussain

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This paper considers advanced hybrid manufacturing planning both push and pull system in which each customer order has a due date by demand forecast and customer orders. We present a tool for model for tool development that requires an absolute due dates and customer orders in a manufacturing supply chain. It is vital for the manufacturing companies to face the problem of variations in demands, increase in varieties by maintaining safety stock and to minimize components obsolescence and uselessness. High inventory cost and low delivery lead time is expected in push type of system and on contrary high delivery lead time and low inventory cost is predicted in the pull type. For this tool for model we need an MRP system for the push and pull environment and control of inventories in push parts and lead time in the pull part. To retain process data quickly, completely and to improve responsiveness and minimize inventory cost, a tool is required to deal with the high product variance and short cycle parts. In practice, planning and scheduling are interrelated and should be solved simultaneously with supply chain to ensure that the due dates of customer orders are met. The proposed tool for model considers alternative process plans for job types, with precedence constraints for job operations. Such a tool for model has not been treated in the literature. To solve the model, tool was developed, so a new technique was required to deal with the issue of high product variance and short life cycles in assemble to order.

Keywords: hybrid manufacturing system, supply chain system, make to order, make to stock, assemble to order

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Authors: A. Fomujong, P. Mobit, A. Ndlovu, R. Teboh

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Purpose: Film’s unique qualities, such as tissue equivalence, high spatial resolution, near energy independence and comparatively less expensive dosimeter, ought to make it the preferred and widely used in radiotherapy centers in low and middle income countries (LMICs). This, however, is not always the case, as other factors that are often maybe taken for granted in advanced radiotherapy centers remain a challenge in LMICs. We explored the unique qualities of film dosimetry that can make it possible for one Institution to benefit from another’s protocols via collaboration. Methods: For simplicity, two Institutions were considered in this work. We used a single batch of films (EBT-XD) and established a calibration protocol, including scan protocols and calibration curves, using the radiotherapy delivery system at Institution A. We then proceeded and performed patient-specific QA for patients treated on system A (PSQA-A-A). Films from the same batch were then sent to a remote center for PSQA on radiotherapy delivery system B. Irradiations were done at Institution B and then returned to Institution A for processing and analysis (PSQA-B-A). The following points were taken into consideration throughout the process (a) A reference film was irradiated to a known dose on the same system irradiating the PSQA film. (b) For calibration, we utilized the one-scan protocol and maintained the same scan orientation of the calibration, PSQA and reference films. Results: Gamma index analysis using a dose threshold of 10% and 3%/2mm criteria showed a gamma passing rate of 99.8% and 100% for the PSQA-A-A and PSQA-B-A, respectively. Conclusion: This work demonstrates that one could use established film dosimetry protocols in one Institution, e.g., an advanced radiotherapy center and apply similar accuracies to irradiations performed at another institution, e.g., a center located in LMIC, which thus encourages collaboration between the two for worldwide patient benefits.

Keywords: collaboration, film dosimetry, LMIC, radiotherapy, calibration

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Authors: Mario Gianni, Manuel A. Ruiz Garcia, Fiora Pirri

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In this work, we present a Bayesian non-parametric approach to model the motion control of ATVs. The motion control model is based on a Dirichlet Process-Gaussian Process (DP-GP) mixture model. The DP-GP mixture model provides a flexible representation of patterns of control manoeuvres along trajectories of different lengths and discretizations. The model also estimates the number of patterns, sufficient for modeling the dynamics of the ATV.

Keywords: Dirichlet processes, gaussian mixture models, learning motion patterns, tracked robots for urban search and rescue

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Authors: Thanusha D. Abeywickrama, Inoka C. Perera, Genji Kurisu

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Tuberculosis, considered being as the ninth leading cause of death worldwide, cause from a single infectious agent M. tuberculosis and the drug resistance nature of this bacterium is a continuing threat to the world. Therefore TB preventing treatment is expanding, where this study designed to analyze the regulatory mechanism of GntR transcriptional regulator gene Rv0792c, which lie between several genes codes for some hypothetical proteins, a monooxygenase and an oxidoreductase. The gene encoding Rv0792c was cloned into pET28a and expressed protein was purified to near homogeneity by Nickel affinity chromatography. It was previously reported that the protein binds within the intergenic region (BS region) between Rv0792c gene and monooxygenase (Rv0793). This resulted in binding of three protein molecules with the BS region suggesting tight control of monooxygenase as well as its own gene. Since monooxygenase plays a key role in metabolism, this gene may have a global regulatory role. The natural ligand for this regulator is still under investigation. In relation to the Rv0792 protein structure, a Circular Dichroism (CD) spectrum was carried out to determine its secondary structure elements. Percentage-wise, 17.4% Helix, 21.8% Antiparallel, 5.1% Parallel, 12.3% turn and 43.5% other were revealed from CD spectrum data under room temperature. Differential Scanning Calorimetry (DSC) was conducted to assess the thermal stability of Rv0792, which the melting temperature of protein is 57.2 ± 0.6 °C. The graph of heat capacity (Cp) versus temperature for the best fit was obtained for non-two-state model, which concludes the folding of Rv0792 protein occurs through stable intermediates. Peak area (∆HCal ) and Peak shape (∆HVant ) was calculated from the graph and ∆HCal / ∆HVant was close to 0.5, suggesting dimeric nature of the protein.

Keywords: CD spectrum, DSC analysis, GntR transcriptional regulator, protein structure

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Authors: Ruqaiya Khalil, Saman Usmani, Zaheer Ul-Haq

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The accurate characterization of ligand binding affinity is indispensable for designing molecules with optimized binding affinity. Computational tools help in many directions to predict quantitative correlations between protein-ligand structure and their binding affinities. Molecular dynamics (MD) simulation is a modern state-of-the-art technique to evaluate the underlying basis of ligand-protein interactions by characterizing dynamic and energetic properties during the event. Autoimmune diseases arise from an abnormal immune response of the body against own tissues. The current regimen for the described condition is limited to immune-modulators having compromised pharmacodynamics and pharmacokinetics profiles. One of the key player mediating immunity and tolerance, thus invoking autoimmunity is Interleukin-2; a cytokine influencing the growth of T cells. Molecular dynamics simulation techniques are applied to seek insight into the inhibitory mechanisms of newly synthesized compounds that manifested immunosuppressant potentials during in silico pipeline. In addition to estimation of free energies associated with ligand binding, MD simulation yielded us a great deal of information about ligand-macromolecule interactions to evaluate the pattern of interactions and the molecular basis of inhibition. The present study is a continuum of our efforts to identify interleukin-2 inhibitors of both natural and synthetic origin. Herein, we report molecular dynamics simulation studies of Interluekin-2 complexed with different antagonists previously reported by our group. The study of protein-ligand dynamics enabled us to gain a better understanding of the contribution of different active site residues in ligand binding. The results of the study will be used as the guide to rationalize the fragment based synthesis of drug-like interleukin-2 inhibitors as immune-modulators.

Keywords: immuno-modulators, MD simulation, protein-ligand interaction, structure-based drug design

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Authors: Yakup Ulusu, Numan Eczacıoğlu, İsa Gökçe, Helen Waller, Jeremy H. Lakey

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Besides having the appropriate amino acid sequence to perform the function of proteins, it is important to have correct conformation after this sequence to process. To consist of this conformation depends on the amino acid sequence at the primary structure, hydrophobic interaction, chaperones and enzymes in charge of folding etc. Misfolded proteins are not functional and tend to be aggregated. Cysteine originating disulfide cross-links make stable this conformation of functional proteins. When two of the cysteine amino acids come side by side, disulfide bond is established that forms a cystine bridge. Due to this feature cysteine plays an important role on the formation of three-dimensional structure of many proteins. There are two cysteine amino acids (C44, C69) in the Tol-A-III protein. Unlike protein disulfide bonds from within his own, any non-specific cystine bridge causes a change in the three dimensional structure of the protein. Proteins can be expressed in various host cells as directly or fusion (chimeric). As a result of overproduction of the recombinant proteins, aggregation of insoluble proteins in the host cell can occur by forming a crystal structure called inclusion body. In general fusion proteins are produced for provide affinity tags to make proteins more soluble and production of some toxic proteins via fusion protein expression system like pTolT. Proteins can be modified by using a site-directed mutagenesis. By this way, creation of non-specific disulfide crosslinks can be prevented at fusion protein expression system via the present cysteine replaced by another amino acid such as serine, glycine or etc. To do this, we need; a DNA molecule that contains the gene that encodes for the target protein, required primers for mutation to be designed according to site directed mutagenesis reaction. This study was aimed to be replaced cysteine encoding codon TGT with serine encoding codon AGT. For this sense and reverse primers designed (given below) and used site-directed mutagenesis reaction. Several new copy of the template plasmid DNA has been formed with above mentioned mutagenic primers via polymerase chain reaction (PCR). PCR product consists of both the master template DNA (wild type) and the new DNA sequences containing mutations. Dpn-l endonuclease restriction enzyme which is specific for methylated DNA and cuts them to the elimination of the master template DNA. E. coli cells obtained after transformation were incubated LB medium with antibiotic. After purification of plasmid DNA from E. coli, the presence of the mutation was determined by DNA sequence analysis. Developed this new plasmid is called PtolT-δ.

Keywords: site directed mutagenesis, Escherichia coli, pTolT, protein expression

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Authors: Marina Passero, Tianhua Zhai, Zuyi (Jacky) Huang

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Alzheimer’s disease has become a major public health issue, as indicated by the increasing populations of Americans living with Alzheimer’s disease. After decades of extensive research in Alzheimer’s disease, only seven drugs have been approved by Food and Drug Administration (FDA) to treat Alzheimer’s disease. Five of these drugs were designed to treat the dementia symptoms, and only two drugs (i.e., Aducanumab and Lecanemab) target the progression of Alzheimer’s disease, especially the accumulation of amyloid-b plaques. However, controversial comments were raised for the accelerated approvals of either Aducanumab or Lecanemab, especially with concerns on safety and side effects of these two drugs. There is still an urgent need for further drug discovery to target the biological processes involved in the progression of Alzheimer’s disease. Excessive cholesterol has been found to accumulate in the brain of those with Alzheimer’s disease. Cholesterol can be synthesized in both the blood and the brain, but the majority of biosynthesis in the adult brain takes place in astrocytes and is then transported to the neurons via ApoE. The blood brain barrier separates cholesterol metabolism in the brain from the rest of the body. Various proteins contribute to the metabolism of cholesterol in the brain, which offer potential targets for Alzheimer’s treatment. In the astrocytes, SREBP cleavage-activating protein (SCAP) binds to Sterol Regulatory Element-binding Protein 2 (SREBP2) in order to transport the complex from the endoplasmic reticulum to the Golgi apparatus. Cholesterol is secreted out of the astrocytes by ATP-Binding Cassette A1 (ABCA1) transporter. Lipoprotein receptors such as triggering receptor expressed on myeloid cells 2 (TREM2) internalize cholesterol into the microglia, while lipoprotein receptors such as Low-density lipoprotein receptor-related protein 1 (LRP1) internalize cholesterol into the neuron. Cytochrome P450 Family 46 Subfamily A Member 1 (CYP46A1) converts excess cholesterol to 24S-hydroxycholesterol (24S-OHC). Cholesterol has been approved for its direct effect on the production of amyloid-beta and tau proteins. The addition of cholesterol to the brain promotes the activity of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), secretase, and amyloid precursor protein (APP), which all aid in amyloid-beta production. The reduction of cholesterol esters in the brain have been found to reduce phosphorylated tau levels in mice. In this work, a computational pipeline was developed to identify the protein targets involved in cholesterol regulation in brain and further to identify chemical compounds as the inhibitors of a selected protein target. Since extensive evidence shows the strong correlation between brain cholesterol regulation and Alzheimer’s disease, a detailed literature review on genes or pathways related to the brain cholesterol synthesis and regulation was first conducted in this work. An interaction network was then built for those genes so that the top gene targets were identified. The involvement of these genes in Alzheimer’s disease progression was discussed, which was followed by the investigation of existing clinical trials for those targets. A ligand-protein docking program was finally developed to screen 1.5 million chemical compounds for the selected protein target. A machine learning program was developed to evaluate and predict the binding interaction between chemical compounds and the protein target. The results from this work pave the way for further drug discovery to regulate brain cholesterol to combat Alzheimer’s disease.

Keywords: Alzheimer’s disease, drug discovery, ligand-protein docking, gene-network analysis, cholesterol regulation

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Authors: Juan Antonio Mondragon Sanchez, Ruben Santamaria

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The DNA G-quadruplex is a four-stranded DNA structure formed by stacked planes of four base paired guanines (G-quartet). Guanine rich DNA sequences appear in many sites of genomic DNA and can potential form G-quadruplexes, such as those occurring at 3'-terminus of the human telomeric DNA. The formation and stabilization of a G-quadruplex by small ligands at the telomeric region can inhibit the telomerase activity. In turn, the ligands can be used to down regulate oncogene expression making G-quadruplex an attractive target for anticancer therapy. Many G-quadruplex ligands have been proposed with a planar core to facilitate the pi–pi stacking and electrostatic interactions with the G-quartets. However, many drug candidates are impossibilitated to discriminate a G-quadruplex from a double helix DNA structure. In this context, it is important to investigate the site topology for the interaction of a G-quadruplex with a ligand. In this work, we determine the free energy surface of a G-quadruplex-ligand to study the binding modes of the G-quadruplex (TG4T) with the daunomycin (DM) drug. The complex TG4T-DM is studied using classical molecular dynamics in combination with metadynamics simulations. The metadynamics simulations permit an enhanced sampling of the conformational space with a modest computational cost and obtain free energy surfaces in terms of the collective variables (CV). The free energy surfaces of TG4T-DM exhibit other local minima, indicating the presence of additional binding modes of daunomycin that are not observed in short MD simulations without the metadynamics approach. The results are compared with similar calculations on a different structure (the mutated mu-G4T-DM where the 5' thymines on TG4T-DM have been deleted). The results should be of help to design new G-quadruplex drugs, and understand the differences in the recognition topology sites of the duplex and quadruplex DNA structures in their interaction with ligands.

Keywords: g-quadruplex, cancer, molecular dynamics, metadynamics

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