180 research outputs found
Crystal structure of the Eg5 - K858 complex and implications for structure-based design of thiadiazole-containing inhibitors
No full textThe thiadiazole scaffold is an important core moiety in a variety of clinical drug candidates targeting a range of diseases. For example, the 2,4,5-substituted 1,3,4-thiadiazole scaffold is present in a lead compound and at least two clinical candidates targeting the human motor protein Eg5, against neoplastic diseases. An inhibitor named K858 has in vivo activity in various mouse xenografts whereas the clinical candidates (S)-ARRY-520 and (R)-Litronesib have entered clinical trials with the former one in phase III clinical trials either alone or in combination with a proteasome inhibitor against relapsed/refractory multiple myeloma. Astonishingly, structural data are lacking for all thiadiazole-containing Eg5 inhibitors. Here we report the structure determination of two crystal forms of the ternary Eg5-ADP-K858 complex, locking the motor in the so-called final inhibitor bound state, thus blocking ADP release, a crucial stage for Eg5 activity. K858 acts at the established allosteric inhibitor-binding pocket formed of helix α2, loop L5 and helix α3. The structure of the complex has far reaching consequences for thiadiazole containing Eg5 inhibitors. For example, we could rationalise the structure-activity relationship in the crucial 5-position of the thiadiazole scaffold and the complex will serve in the future as a basis for strucutre-based drug design
Development of collagen scaffold with internal channels via indirect rapid prototyping
No full text202 p.The author would like to take this opportunity to acknowledge the contribution of anumber of people for this project. The realization of the project would not have beenpossible without the advice and assistance from them.The author wishes to express her sincere gratitude and appreciation to A/P Chua CheeKai, A/P Leong Kah Fai and Dr. Margam Chandrasekaran, for their invaluable adviceand motivation throughout the project. Appreciation is also extended to As/P AlastairCampbell Ritchie from the School of Mechanical and Aerospace Engineering, NTU,and Mr Timothy Tan and Dr Peter Lee from DNA Center, NIE, for their guidance inthe project. Heartfelt thanks to Ms Hu Quijun, from SIMTech for her guidance andsupport.DOCTOR OF PHILOSOPHY (MAE
Performance of a self-correlating synchronization and detection scheme for IR-UWB in multi-user multipath environments
No full textOwing to the very low duty cycle of impulse like ultra wideband signals, timing acquisition with acceptable accuracy and complexity has been a constant topic of research. Most acquisition techniques can be broadly classified under two categories: Training based algorithms, which require a specific training sequence at the start of communication and - Blind Acquisition, which relies on the correlation between successive data symbols transmitted and cyclostationarity of the transmitted signal. Amidst algorithms which use a clean template or a noiseless reference, a recent class of techniques named 'Timing based on Dirty Templates' (TDT) has been proposed.
These algorithms rely on the correlation of two adjacent portions of the noisy received signal. One portion of the noisy received signal acts as a template for the other, thus improving the synchronization speeds and accuracy by making the acquisition independent of training sequences. A novel blind TDT algorithm, which we refer to as Agrawal Blind Synchronization scheme (ABS), was proposed for IR-UWB signals. Based on the design of the time hopping code, significant improvements in acquisition speeds have been demonstrated using the ABS scheme, compared to existing blind acquisition schemes.
The objective of this thesis is to analyze the performance capabilities of the selfcorrelating ABS scheme in multi-user multipath environments. Adopting the best performing time hopping pattern, we investigate the effect of multiple interferers on absolute timing error, under various SNR scenarios as well as multiple symbols used for timing acquisition. Link performance is evaluated through bit-error-rate (BER) analysis under various system conditions. Since we use differential methods for timing acquisition as well as symbol detection, significant energy capture can be achieved in a dense multipath scenario due to self-Raking. We also propose modifications to conventional differential detectors to avoid self-Raking of interfering pulses. As a comparison to differential detectors, the detection performance of an ideal Rake receiver was tested with the ABS scheme. Our results indicate that the timing error performance the ABS scheme and thus the BER performance of the detection phase deteriorate notably with increase in the number of users in the system. The effective number of interferers is the limiting factor in both absolute timing error and BER performance. In differential detection, the effect of interference is so large it dominates over the effect of timing errors. The use of the ABS scheme is advantageous when Rake receivers are used, since timing error has a drastic effect of degrading the BER performance. The improvements of using ABS scheme in multi-user multi-path environments become more prominent in the case of ideal Rake reception, as compared to differential detection.M.S.Includes bibliographical references (p. 63-66)
Concept Based Author Recommender System for CiteSeer
No full textThe information explosion in today's electronic world has created the need for information filtering techniques that help users filter out extraneous content to identify the right information they need to make important decisions. Recommender systems are one approach to this problem, based on presenting potential items of interest to a user rather than requiring the user to go looking for them. In this paper we propose a recommender system that recommends research papers of potential interest to the author from the CiteSeer database. For each author participating in the study, we create a user profile based on their previously published papers. Based on similarities between the user profile and profiles for documents in the collection, additional papers are recommended to the author. We introduce a novel way of representing the user profiles as tree of concepts and an algorithm for computing the similarity between the user profiles and document profiles using a tree-edit distance measure. Experiments with a group of volunteers show that our tree based algorithm provides better recommendations than a traditional vector-space model based technique
In Vitro Evaluation of Smart Pellets as Intelligent Drug Delivery Systems
No full textIn Vitro Evaluation of Smart Pellets as Intelligent Drug Delivery Systems
Mohammad F. Bayan, Balakumar Chandrasekaran, Rahaf M. Allan and Weaam A. Khalaf
Faculty of Pharmacy, Philadelphia University, P.O. Box 1, Amman 19392, Jordan
Email: [email protected]
Introduction
The small intestine is where most conventional oral formulations are mostly absorbed. This restricts their usage in the treatment of several colon disorders since the medicine must act topically at the site of inflammation. This opened the door for the development of an intelligent colonic drug delivery system, which enhanced therapeutic effectiveness, decreased dosing frequency and potential side effects, and increased patient acceptance—particularly in situations where enemas or other topical preparations might not be sufficient to treat inflammation alone. This study's primary goal was to develop a smart medication delivery system based on pH-sensitive polymeric formulations made using a free-radical bulk polymerization technique. In the formulations, 5-amino salicylic acid was used as a model drug and Capmul MCM C8 was added to increase bioavailability. The in vitro swelling and release evaluation showed that the developed system may be able to delay drug release under conditions that mimic the stomach and small intestine while triggering it under conditions that mimic the colon, indicating its potential usefulness as a smart colonic drug delivery system.
Materials and Methods
Hydroxyethyl methacrylate (HEMA), Methacrylic acid (MAA), Dimethylaminoethyl methacrylate (DMAEMA), 5-amino salicylic acid, ethylene glycol dimethacrylate (EGDMA), disodium hydrogen phosphate dodecahydrate, azobisisobutyronitrile (AIBN), potassium chloride, sodium chloride, potassium dihydrogen phosphate, BRAND® stopcock grease, sodium dodecyl sulphate, and sodium hydroxide were purchased from Sigma-Aldrich. Capmul® MCM C8 was purchased from ABITEC. Hydrochloric acid (37%) was purchased from Biosolve Chimie.
Preparation of Intelligent Pellets: Nine pellet formulations based on HEMA, MAA, and/or DMAEMA monomers were prepared utilizing a free-radical thermal bulk polymerization technique [1]. The pellets were loaded with 5-amino salicylic acid and capmul MCM C8 as a dissolution enhancer and model drug, respectively. Pellets' Swelling Studies: The pellets' in vitro swelling behavior was examined in a biobase thermostatic shaking water bath SWB-A at 37 °C in buffers with equal ionic strengths at pH 1.2 and pH 7.4. The equilibrium swelling ratio and swelling behavior were examined as previously described by Bayan et al [2]. Pellets' Release Studies: The in vitro release of the model drug (5-amino salicylic acid) was examined using a modified Heelan and Corrigan method in a biobase thermostatic shaking water bath SWB-A working at 100 rounds per minute and 37 °C in buffers of equivalent ionic strength, at pH 1.2 and pH 7.4 [3]. After fitting the first 60% of the release data to the Korsmeyer-Peppas model, the release rate and mechanism of the medication were studied. The two-way analysis of variance test and Tukey's multiple comparison test (n = 3, p 0.05) were used to statistically examine all of the data. The graphics and statistical analyses were created using the GraphPad Prism software, version 9.4.0.
Results and Discussions
Figures 1-2 show the in vitro swelling profile and equilibrium swelling ratio of the pellets at each pH. When comparing the swelling profiles of HEMA-co-MAA pellets at pH 7.4 and pH 1.2, a significantly higher swelling was observed at pH 7.4. This may be attributed to the fact that these polymers' anionic pendant groups (MAA) were more ionized in the simulated intestinal fluid than in the simulated gastric fluid, resulting in stronger electrostatic interactions and increased swelling. At pH 1.2 compared to pH 7.4, the swelling profile for the HEMA-co-DMAEMA pellets was much higher. This may be related to the fact that these polymers' cationic pendant group (DMAEMA) were more ionized in the simulated gastric fluid than in the simulated intestinal fluid. Figures 3-4 display the in vitro release profiles of the produced pellets at each pH. In comparison to the HEMA-co-DMAEMA based pellets (F7-F9), the HEMA and HEMA-co-MAA based pellets (F1-F6) showed a greater ability to delay the release of the model drug at pH 1.2. When compared to the other formulations, the HEMA-co-MAA-based Pellets (F3-F6) showed a greater release rate at pH 7.4. With a cumulative release of almost 75% after 12 hours, F4 had the largest cumulative drug release at pH 7.4. After five hours at pH 1.2, this formulation attained a cumulative release of about 25%. An n value more than 0.5 and less than 1 was obtained for all pellets at pH 7.4 and for F7-F9 at pH 1.2, indicating an anomalous mechanism of drug release. This implies that diffusion and polymer swelling control the drug release in these formulations. At pH 1.2, F1–F6 pellets exhibited a n value lower than 0.5, indicating a Fickian diffusion mechanism.
Conclusions
The in vitro swelling and release investigations showed that F4 may be able to postpone the drug release while it is present in the stomach and small intestine, while triggering its release in the colon. This makes it promising to achieve a colonic-specific delivery for the potential treatment of colon-associated diseases, such as inflammatory bowel diseases. Further work is required to evaluate the in vivo behavior, biocompatibility, and safety of this system.
References
Bayan MF, Salem MS, Bayan RF. Development and In Vitro Evaluation of a Large-Intestinal Drug Delivery System. Research Journal of Pharmacy and Technology. 2022, 15(1):35-9.
Bayan MF, Marji SM, Salem MS, Begum MY, Chidambaram K, Chandrasekaran B. Development of Polymeric-Based Formulation as Potential Smart Colonic Drug Delivery System. Polymers. 2022, 14(17):3697.
Obaidat RM, Tashtoush BM, Bayan MF, T Al Bustami R, Alnaief M. Drying using supercritical fluid technology as a potential method for preparation of chitosan aerogel microparticles. Aaps Pharmscitech. 2015, 16(6):1235-44
TAG: trip-boxes for automatic event generation
No full textThe increased use of location-aware mobile devices has given rise to a need to trigger actions at certain geographic locations. For example, when conducting outdoor vehicular experiments, data frequently needs to be collected within one geographic region. The data collection can be initiated manually, however, it is a tedious process and prone to manual errors. Our framework is designed to use Global Positioning System location updates to automatically trigger actions upon entering and leaving these geographic zones. We mark these zones using trip-boxes, a rectangular box enclosing a geographical area with its orientation towards geographic north and east direction, which can be defined in Google Earth and exported into the trip-box system. The system also uses guard intervals to prevent repeated triggering of trip-boxes due to GPS oscillations. In our evaluation, we experimentally determine the chances of skipping the Trip-Box for a given speed, sampling rate of GPS and the length and the width parameters of the Trip-Box. We conducted experiments for finding a suitable width of the Trip-Box for speeds between 0 - 80mph and by varying sampling intervals from 1 - 5Hz. We also determine the guard flags based on distance traveled and elapsed time calculated after crossing the boundary of the Trip-Box to prevent the repeated triggering of same events. Evaluating experiments using a GPS with 5Hz sampling rate and a standard deviation of 7.5m for a 95 percent accuracy, our results show that on crossing a Trip-Box of width 2m and length 28m is 95 percent reliable when the object moves with a speed less than or equal 20mph.M.S.Includes abstractVitaIncludes bibliographical referencesby Janani Chandrasekara
Direct inference of location-related context from wireless signal strength
No full textIn this dissertation we derive location-related context likemobility-states, co-mobility, speed and decelerations directly from the wireless signal strength information. The key insight is that the time-series of signal strength is robust to environmental factors that typically negatively affect the RSS-based localization systems. Therefore, inferring these physical properties directly from the time-series of wireless signal strength is more accurate than deriving them from location estimates. We apply correlation and time warping algorithms to the time series of wireless signals
to infer these properties. Our trace-driven experimental approach shows that our inference techniques can work with minimal infrastructure, are computationally efficient, requires no explicit user participation and can produce higher accuracies than location-based systems. We have also experimentally identified the factors that limit the accuracy of indoor localization and
have proved the existing assumptions behind theoretical lower bounds of indoor localization
incorrect. Our results will enable new context aware applications, because accurate estimates of comobility
and speed offer a richer set of primitives available to applications. Such applications can derive user mobility states like walking, running, driving or social states, such as if a user is in a meeting or alone.Ph.D.Includes bibliographical referencesIncludes vitaby Gayathri Chandrasekara
Shoulder pain in manual wheelchair users: towards a multi-disciplinary solution for a multi-faceted problem
No full textIt is estimated that there are over 2 million manual wheelchair users in the United States. Up to 70% of manual wheelchair users report upper limb pain, which is mainly manifested in the shoulder and wrist. Shoulder pain in wheelchair users is linked to difficulty performing activities of daily living, decreased physical activity and decreased quality of life.
The main focus of this dissertation is to identify biomarkers from wheelchair propulsion data that are potentially related to shoulder pain in manual wheelchair users. Three biomarkers that distinguish between manual wheelchair users with and without shoulder pain are identified. The acceptability of the identified biomarkers are subjected to hypothesis testing using data collected from a sample of 30 experienced adult manual wheelchair users with and without shoulder pain. The results and their implications will be discussed. In this dissertation we will also discuss the interpretation and the physical significance of each of the results, a summary of limitations for the approaches adopted, and suggestions on the future course of research to address these limitations.
While the past two decades of research on shoulder pain and wheelchair propulsion has led to the development of important clinical guidelines, it has failed to identify specific biomarkers that may be related to shoulder pain in manual wheelchair users. This could be in part due to employing a binary approach by focusing on just (1) the pure bio-mechanical aspects, and (2) wheelchair design aspects (ergonomics). The originality of this dissertation is in the adoption of a multidisciplinary approach. Methodologies integrating theories and analyses from fields related to human movement science such as human motor control theory, non-linear dynamics and human factors (occupational ergonomics) are adopted to identify potential biomarkers that relate to shoulder pain in manual wheelchair users.
This dissertation concludes with preliminary results from a prototype wearable device, custom developed for manual wheelchair users. Wheelchair propulsion data obtained from the device will be benchmarked with data from the currently available technologies for tracking manual wheelchair propulsion (SMARTWheel and motion capture). This dissertation also proposes a framework for incorporating the research findings into the custom developed wearable technology for home-based rehabilitation training purposes.Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2017-12-01The student, Chandrasekaran Jayaraman, accepted the attached license on 2015-11-13 at 12:03.The student, Chandrasekaran Jayaraman, submitted this Dissertation for approval on 2015-11-13 at 14:43.This Dissertation was approved for publication on 2015-11-17 at 16:18.DSpace SAF Submission Ingestion Package generated from Vireo submission #8782 on 2016-03-02 at 14:13:03Made available in DSpace on 2016-03-02T21:06:28Z (GMT). No. of bitstreams: 2
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Serine protease identification (in vitro) and molecular structure predictions (in silico) from a phytopathogenic fungus, Alternaria solani
No full textCitation: Chandrasekaran, M., Chandrasekar, R., Sa, T., & Sathiyabama, M. (2014). Serine
protease identification (in vitro) and molecular structure predictions (in silico) from a
phytopathogenic fungus, Alternaria solani. Retrieved from http://krex.ksu.eduSerine proteases generally share a relatively high degree of sequence identity and play a major role in the diversity of biological processes. Here we focus on three-dimensional molecular architecture of serine proteases from Alernaria solani. The difference in flexibility of active binding pockets and electrostatic surface potential distribution of serine proteases in comparison with other fungal species is reported in this study. In this study we have purified a serine protease from the early blight pathogen, Alernaria solani. MALDI-TOF-MS/MS analysis revealed that protease produced by A. solani belongs to alkaline serine proteases. AsP is made up of 403 amino acid residues with molecular weight of 42.1kDa (Isoelectric point (pI)-6.51) and molecular formula C[subscript 1859]H[subscript 2930]N[subscript 516]O[subscript 595]S[subscript 4]. The follow-up research on the molecular structure prediction is used for assessing the quality of A. solani Protease (AsP). The AsP protein structure model was built based on its comparative homology with serine protease using the program, MODELER. AsP had 16 β-sheets and 10 α-helices, with Ser[superscript 350] (G347-G357), Asp[superscript 158] (D158-H169) and His[superscript 193] (H193-G203) in separate turn/coil structures. Biological metal binding region situated near the 6th-helix and His[superscript 193] residue is responsible for metal binding site. In addition, the calcium ion is coordinated by the carboxyl groups of Lys[superscript 84], Ile[superscript 85], Lys[superscript 86], Asp[superscript 87], Phe[superscript 88], Ala[superscript 89], Ala[superscript 90] (K84-A90) for first calcium (Ca[superscript 2+]) binding site and carbonyl oxygen atom of Lys[superscript 244], Gly[superscript 245], Arg[superscript 246], Thr[superscript 247], Lys[superscript 248], Lys[superscript 249], and Ala[superscript 250] (K244–A250), for second Ca[superscript 2+] binding site. Moreover, Ramachandran plot analysis of protein residues falling into most favored secondary structures were determined (83.3%). The predicted molecular 3D structural model was further verified using PROCHECK, ERRAT and VADAR servers to confirm the geometry and stereo-chemical parameters of the molecular structural design. The functional analysis of AsP 3D molecular structure predictions familiar in the current study may provide a new perspective in the understanding and identification of antifungal protease inhibitor designing
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