•An anti-tumor protein, p-53, is functionally inactivated in most tumors.•We have examined the effects of pharmacodynamic interaction between Nutlin-3a and aspirin in cancer patients.•The ...mathematical result shows that p-53 protein gets over-activated and starts suppressing other useful growth cells if a high dose of aspirin along with nutlin-3a is administered in a cancer patient.•In order to avoid any harmful effect of such interaction in the activation of p-53 protein, a low dose of aspirin should be administered along with nutlin-3a.
p53, an anti-tumour protein, is significantly inactivated in most tumours. A small molecule of nutlin-3a is used to activate its function by repressing (Mouse double minute 2 homolog) Mdm2 protein which inhibits its activity. In cancer patients, a high risk of drug-drug interactions (DDIs) is observed owing to their multi-dosing prescriptions, which may lead them to harmful effects. In the presented work, we have aimed to investigate the effect of pharmacodynamical interaction between two anti-cancer drugs, nutlin-3a and aspirin in the activation of p53 protein.
We have adapted control system techniques and designed a Proportional-Integral-Derivative (PID) controller. This controller is used to activate p53 protein. A drug interaction parameter is used to incorporate the effect of both drugs. Extensive simulation is performed using two different doses of aspirin, i.e. a low and a high dose of aspirin.
The result shows no harmful effects of pharmacodynamical interaction when a low dose is administered along with nutlin-3a. When a high dose of aspirin is administered it acts as input disturbance and leads to undesirable over-expression of p53 protein. This can further harm other growth cells, thus inducing harmful effects. A comparative analysis is also tabulated with different dosing regimens which shows that a combination of nutlin-3a and a low dose of aspirin provides better results than a high dose of aspirin.
Overall, the work provides an insight to the activation of p53 protein in cancer patients under the presence of pharmacodynamical interaction and might contribute to the effective management of cancer patients.
•The PBPK modeling is used in the process of Drug discovery and development.•The comprehensive PBPK model known as a whole body physiologically based pharmacokinetic (WB-PBPK) model is proposed by ...Dedrick and Bischoff in 1968, but did not implement and verified.•The WBPBPK model is developed with the integration of ADME models alongside the reference PBPK model.•The developed WB PBPK model is used to anticipate a systemic exposure of the drug in all compartments of the body.•The validity of the model is confirmed by the comparison of simulations of a model and clinical data of Belinostat, Allopurinol, and Paracetamol.•Preference point of this WB-PBPK model over conventional PBPK models is its prediction of concentrations of drugs as a function of time.
The Physiologically based pharmacokinetic (PBPK) modeling is a supporting tool in drug discovery and improvement. Simulations produced by these models help to save time and aids in examining the effects of different variables on the pharmacokinetics of drugs. For this purpose, Sheila and Peters suggested a PBPK model capable of performing simulations to study a given drug absorption. There is a need to extend this model to the whole body entailing all another process like distribution, metabolism, and elimination, besides absorption. The aim of this scientific study is to hypothesize a WB-PBPK model through integrating absorption, distribution, metabolism, and elimination processes with the existing PBPK model.Absorption, distribution, metabolism, and elimination models are designed, integrated with PBPK model and validated. For validation purposes, clinical records of few drugs are collected from the literature. The developed WB-PBPK model is affirmed by comparing the simulations produced by the model against the searched clinical data. . It is proposed that the WB-PBPK model may be used in pharmaceutical industries to create of the pharmacokinetic profiles of drug candidates for better outcomes, as it is advance PBPK model and creates comprehensive PK profiles for drug ADME in concentration-time plots.
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Automotive-engine control and fault diagnostics largely depend upon the accuracy of the nonlinear models used. The structure of these nonlinear models is generally agreed upon. However, the model ...parameters are mostly difficult to obtain. This paper presents the development of second-order sliding-mode technique with real twisting algorithm for estimation of more than one parameter from a single dynamical equation of the nonlinear model. The system under study is a mean-value engine model of a naturally breathing gasoline engine. The parameters estimated are throttle body's discharge coefficient, load torque, and indicated torque as a function of inlet manifold pressure. The estimated variables are used to compensate for the unmodeled dynamics, modeling inaccuracies, and approximations which arise from the assumptions made for the development of mathematical model of a real-world system. The resulting model is a better description of the actual engine dynamics and gives good agreement to real engine data. The data are acquired from a production model vehicle equipped with an electronic control unit compliant to OBD-II standard. The observer designed is simple enough for implementation, and estimated parameters can also be used for engine-controller design and fault-diagnosis work.
Present work describes the bioleaching potential of metals from low-grade mining ore containing smithsonite, sphaerocobaltite, azurite and talc as main gangue minerals with adapted consortium of
...Sulfobacillus thermosulfidooxidans
strain-RDB and
Thermoplasma acidophilum
. Bioleaching potential improved markedly by added energy source, acid preleaching and adaptation of microbial consortium with mixed metal ions. During whole leaching period including acid preleaching stage of 960 h and bioleaching stage of 212 days about 76% Co, 70% Zn, 84% Cu, 72% Ni and 63% Fe leached out.
The highly efficient Interior Permanent Magnet Synchronous Motor (IPMSM) is ubiquitous choice in Electric Vehicles (EVs) for today’s automotive industry. IPMSM control requires accurate knowledge of ...an immeasurable critical Permanent Magnet (PM) flux linkage parameter. The PM flux linkage is highly influenced by operating temperature which results in torque derating and hence power loss, unable to meet road loads and reduced life span of electrified powertrain in EVs. In this paper, novel virtual sensing scheme for estimating PM flux linkage through measured stator currents is designed for an IPMSM centric electrified powertrain. The proposed design is based on a Uniform Robust Exact Differentiator (URED) centric Super Twisting Algorithm (STA), which ensures robustness and finite-time convergence of the time derivative of the quadrature axis stator current of IPMSM. Moreover, URED is able to eliminate chattering without sacrificing robustness and precision. The proposed design detects variation in PM flux linkage due to change in operating temperature and hence is also able to establish characteristics of fault detection. The effectiveness and accuracy in different operating environments of the proposed scheme for nonlinear mathematical IPMSM model with complex EV dynamics are verified thorough extensive simulation experiments using MATLAB/Simulink.
For sustainable development construction, recycle or reuse of waste materials is utilized. Many researchers conducted tried to create an innovative green concrete, utilizing waste materials. The aim ...of this research is to contribute and promote the use of plastic waste in concrete. The concrete’s flexural and workability were investigated by using different percentages of 0%, 0.2%, 0.4%, 0.6%, 0.8% and 1% of plastic fibers in concrete. In this study, M15 grade concrete beams were casted and cured for 7 and 28 days to analyze the flexural performance and workability. The outcomes demonstrated that the workability was slightly reduced by the utilizing plastic fibers where flexural strength improved by 16.5% at 0.6% addition of plastic fibers in concrete.
Fatty acid methyl ester (FAME) was produced from waste cooking oil (WCO) utilizing eggshells derived solid base catalyst. Eggshells derived multi modal CaO (MM-CaO) also provides a cost-effective way ...for the preparation of green fuel. The nano-scaled MM-CaO was prepared using ball milling followed by calcination at 800 °C for 2 h form eggshells powder. The characterization of calcined powder was executed by XRD, EDX, SEM and FTIR techniques. Diffractogram of MM-CaO showed cubic crystal structure and presence of calcium, carbon and oxygen was confirmed by EDX. The morphology of MM-CaO was revealed by SEM having bandgap energy (3.02 eV) which declared MM-CaO as photoactive in solar range. Catalytic transesterification process furnished 75.2% yield, whereas in photocatalytic process, 86.8% yield was obtained at optimum conditions (temperature 50 °C, reaction time 180 min and 1.5 g catalyst dose). The FAME formation was monitored by GC and FTIR analysis. Physiochemical properties of produced biodiesel were also determined and equated with standards. Results depicted that MM-CaO is highly efficient for conversion of WCO to biodiesel.
This paper examines the implementation of building information modeling (BIM) in construction industry. Various initiatives and approaches are used in different countries to promote the BIM ...implementation in their construction industries. The real implementation and use of BIM remains a major concern of the construction industry. This study investigates the implantation of BIM globally, in developed countries and the percentage of implementation of BIM in constriction industry of Sindh, Pakistan. This research demonstrates 131 responses from BIM users regarding BIM implementation whose collaboration aspects produce the highest positive impact. The adopted methodology is an online questionnaire survey and literature review which was conducted to find out the implementation of BIM in construction industries of developed countries. This research reveals that BIM implementation is increasing continuously over the past few years. A Number of developed countries are emerging successful BIM implementation strategies, United States, United Kingdom, Germany, France are generally leading the way. However, according to our study findings, only 11% of industries have implemented BIM in Sindh, Pakistan.
We propose a new paradigm in the drug design for the revival of the p53 pathway in cancer cells. It is shown that the current strategy of using small molecule based Mdm2 inhibitors is not enough to ...adequately revive p53 in cancerous cells, especially when it comes to the extracting pulsating behavior of p53. This fact has come to notice when a novel method for the drug dosage design is introduced using system oriented concepts. As a test case, small molecule drug Mdm2 repressor Nutlin 3a is considered. The proposed method determines the dose of Nutlin to revive p53 pathway functionality. For this purpose, PBK dynamics of Nutlin have also been integrated with p53 pathway model.
The p53 pathway is the focus of researchers for the last thirty years for its pivotal role as a frontline cancer suppressant protein due to its effect on cell cycle checkpoints and cell apoptosis in response to a DNA strand break. That is the reason for finding p53 being absent in more than 50% of tumor cancers. Various drugs have been proposed to revive p53 in cancer cells. Small molecule based drugs are at the foremost and are the subject of advanced clinical trials. The dosage design of these drugs is an important issue.
We use control systems concepts to develop the drug dosage so that the cancer cells can be treated in appropriate time. We investigate by using a computational model how p53 protein responds to drug Nutlin 3a, an agent that interferes with the MDM2-mediated p53 regulation. The proposed integrated model describes in some detail the regulation network of p53 including the negative feedback loop mediated by MDM2 and the positive feedback loop mediated by Mdm2 mRNA as well as the reversible represses of MDM2 caused by Nutlin. The reported PBK dynamics of Nutlin 3a are also incorporated to see the full effect. It has been reported that p53 response to stresses in two ways. Either it has a sustained (constant) p53 response, or there are oscillations in p53 concentration. The claimed dosage strategy achieves the p53 response in the first case. However, for the induction of oscillations, it is shown through bifurcation analysis that to achieve oscillating behavior of p53 inhibition of Mdm2 is not enough, rather antirepression of the p53-Mdm2 complex is also needed which leads to the need of a new drug design paradigm.
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•We investigated the cellular mechanism of action of drug nutlin.•integrated model of (Hunziker (2010) and Puszynski (2014)) to repress the p53-Mdm2.•To perceive the drug dosage design for Nutlin to revive the function of the p53
We assessed the difference in hospital based and early clinical outcomes between the direct anterior approach and the posterior approach in patients who undergo total hip arthroplasty (THA).
The ...outcome was assessed in 448 (203 males, 245 females) consecutive patients undergoing unilateral primary THA after the implementation of an 'Enhanced Recovery' pathway. In all, 265 patients (mean age: 71 years (49 to 89); 117 males and 148 females) had surgery using the direct anterior approach (DAA) and 183 patients (mean age: 70 years (26 to 100); 86 males and 97 females) using a posterior approach. The groups were compared for age, gender, American Society of Anesthesiologists grade, body mass index, the side of the operation, pre-operative Oxford Hip Score (OHS) and attendance at 'Joint school'. Mean follow-up was 18.1 months (one to 50).
There was no significant difference in mean length of stay (p = 0.07), pain scores on the day of surgery, the first, second and third post-operative days (p = 0.36, 0.23, 0.25 and 0.59, respectively), the day of mobilisation (p = 0.12), the mean OHS at six and 24 months (p = 0.08, and 0.29, respectively), the incidence of infection (p = 1.0), dislocation (p = 1.0), re-operation (p = 0.21) or 28 days' re-admission (p = 0.06). Significantly more patients in the DAA group achieved a planned discharge target of three days post-operatively (68% vs 56%, p = 0.007). The rate of periprosthetic femoral fractures was significantly higher in the DAA group (p = 0.04).
We conclude that there is no difference in clinical outcomes between the DAA and the posterior approach in patients undergoing THA when an 'Enhanced Recovery' pathway is used. However, a significantly higher rate of periprosthetic femoral fractures remains a concern with the DAA, even in experienced hands.
Our results show that the DAA for THA is not superior to posterior approach when 'Enhanced Recovery' pathway is used. Cite this article: Bone Joint J 2016;98-B:754-60.
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