Search results for: Kunal Mankodi

Authors: Kunal Mankodi, Sudhir Pandey

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This study aims to assess the factors that play a role in setting up and running a social enterprise driven towards sustainability at the intersection of energy, environment, and poverty alleviation. According to the theory of sustainability-oriented innovation (SOI), conventional organisations adapt their processes to focus on sustainability-oriented innovations. On the other hand, social enterprises that are purpose-driven are also influenced by the context of innovation, which need due attention. This paper presents an account of innovation at Oorja - an Indian social enterprise operating with a farming-as-a-service business model. It aims to illustrate the contexts in which the innovative solutions were developed to work at an intersection between agriculture and clean energy, thereby allowing small farmers access to efficient solutions in the agriculture cycle. Primary data was collected through in-depth interviews, and secondary data was collected from company sources. The study finds that in the case of a social enterprise, the definition of innovation assumes a wider scope by going beyond the introduction of a new product/service. The context of innovation for social enterprise is affected by organisational factors such as organisation’s philosophical mindset, behaviour towards innovation, organisation’s capabilities, regulatory environment, and customer receptiveness. Additionally, the study also finds that the context of innovation for a social enterprise is affected by its organizational structure. A majority of these organizational factors are, in turn, affected by individual (Founder’s) factors such as the founder’s formative years, education, direct exposure to relevant issues, complementary skills of co-founders, and a common calling.

Keywords: context of innovation, social enterprise, sustainability oriented innovations, emerging markets, agriculture

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Authors: Hireni Mankodi

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The textile preforms for thermoplastic composite play a key role in providing the mechanical properties and gives the idea about preparing combination of yarn from Glass, Basalt, Carbon as reinforcement and PP, PET, Nylon as thermoplastic matrix at yarn stage for preforms to improve the quality and performance of laminates. The main objectives of this work are to develop the hybrid yarn using different yarn manufacturing process and prepare different performs using hybrid yarns. It has been observed that the glass/pp combination give homogeneous distribution in yarn. The proportion varied to optimize the glass/pp composition. The different preform has been prepared with combination of hybrid yarn, PP, glass combination. Further studies will investigate the effect of glass content in fabric, effect of weave, warps and filling density, number of layer plays significant role in deciding mechanical properties of thermoplastic laminates.

Keywords: thermoplastic, preform, laminates, hybrid yarn, glass

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Authors: Hireni R. Mankodi, D. J. Chudasama

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The textile preforms play a key role in providing the mechanical properties and gives the idea about selection parameter of preforms to improve the quality and performance of laminates. The main objectives of this work are to study the effect of non-crimp fabric preform structure in final properties of laminates. It has been observed that the multi-axial preform give better mechanical properties of laminates as compared to woven and biaxial fabrics. This study investigated the effect of different non-crimp glass preform structure on tensile strength, bending and compression properties of glass laminates. The different woven, bi-axial and multi-axial fabrics with similar GSM used to manufacture the laminates using polyester resin. The structural and mechanical properties of preform and laminates were studied using standard methods. It has been observed that the glass fabric geometry, including type of weaves, warps and filling density and number of layer plays significant role in deciding mechanical properties of laminates.

Keywords: preform, non-crimp structure, laminates, bi-axial, multiaxial

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Authors: Kunal Tongaria, Abhishek Mangal, S. Mandal, Devendra Mohan

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The carbonation of concrete is a phenomenon which is a function of various interdependent parameters. Therefore, in spite of numerous literature and database, the useful generalization is not an easy task. These interdependent parameters can be grouped under the category of internal and external factors. This paper focuses on the internal parameters which govern and increase the probability of the ingress of deleterious substances into concrete. The mechanism of effects of internal parameters such as microstructure for with and without supplementary cementing materials (SCM), water/binder ratio, the age of concrete etc. has been discussed. This is followed by the comparison of various proposed mathematical models for the deterioration of concrete. Based on existing laboratory experiments as well as field results, this paper concludes the present understanding of mechanism, modeling and future research needs in this field.

Keywords: carbonation, diffusion coefficient, microstructure of concrete, reinforced concrete

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Authors: Kunal Das, Priya Sengupta, Abhishek K. Singh

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Pin assignment, scheduling, routing and error detection for arbitrary biochemical protocols in Digital Microfluidic Biochip have been reported in this paper. The research work is concentrating on pin assignment for 2 or 3 droplets routing in the arbitrary biochemical protocol, scheduling and routing in m × n biochip. The volumetric error arises due to droplet split in the biochip. The volumetric error detection is also addressed using biochip AND logic gate which is known as microfluidic AND or mAND gate. The algorithm for pin assignment for m × n biochip required m+n-1 numbers of pins. The basic principle of this algorithm is that no same pin will be allowed to be placed in the same column, same row and diagonal and adjacent cells. The same pin should be placed a distance apart such that interference becomes less. A case study also reported in this paper.

Keywords: digital microfludic biochip, cross-contamination, pin assignment, microfluidic AND gate

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Authors: Abhishek Mangal, Kunal Tongaria, S. Mandal, Devendra Mohan

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Carbonation of reinforced concrete structures has emerged as one of the major challenges for Civil engineers across the world. With increasing emissions from various activities, carbon dioxide concentration in the atmosphere has been eve rising, enhancing its penetration in porous concrete, reaching steel bars and ultimately leading to premature failure. Several literatures have been published dealing with the various interdependent variables related to carbonation. However, with innumerable variability a generalization of these data proves to be a troublesome task. This paper looks into this carbonation anomaly in concrete structures caused by various external variables such as relative humidity, concentration of CO2, curing period and ambient temperature. Significant discussions and comparisons have been presented on the basis of various studies conducted with an aim to predict the depth of carbonation as a function of these multidimensional parameters using various numerical and statistical modelling techniques.

Keywords: carbonation, curing, exposure conditions, relative humidity

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Authors: Kunal Shah, Swati Patel

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Many real world problems involve data which can be considered as multi-label data streams. Efficient methods exist for multi-label classification in non streaming scenarios. However, learning in evolving streaming scenarios is more challenging, as the learners must be able to adapt to change using limited time and memory. Classification is used to predict class of unseen instance as accurate as possible. Multi label classification is a variant of single label classification where set of labels associated with single instance. Multi label classification is used by modern applications, such as text classification, functional genomics, image classification, music categorization etc. This paper introduces the task of multi-label classification, methods for multi-label classification and evolution measure for multi-label classification. Also, comparative analysis of multi label classification methods on the basis of theoretical study, and then on the basis of simulation was done on various data sets.

Keywords: binary relevance, concept drift, data stream mining, MLSC, multiple window with buffer

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Authors: Sukhleen Bindra Narang, Dalveer Kaur, Kunal Pubby

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Dielectric ceramic samples in the BaO-Re2O3-TiO2 ternary system were synthesized with structural formula Ba2-xRe4+2x/3Ti8O24 where Re= rare earth metal and Re= Sm and La where x varies from 0.0 to 0.6 with step size 0.1. Polycrystalline samples were prepared by the conventional solid state reaction technique. The dielectric, electrical and impedance analysis of all the samples in the frequency range 1KHz- 1MHz at room temperature (25°C) have been done to get the understanding of electrical conduction and dielectric relaxation and their correlation. Dielectric response of the samples at lower frequencies shows dielectric dispersion while at higher frequencies it shows dielectric relaxation. The ac conductivity is well fitted by the Jonscher law (σac = σdc+Aωn). The spectroscopic data in the impedance plane confirms the existence of grain contribution to the relaxation. All the properties are found out to be function of frequency as well as the amount of substitution.

Keywords: dielectric ceramics, dielectric constant, loss tangent, AC conductivity, impedance spectroscopy

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Authors: Kunal Ahluwalia, Ampara Aramcharoen, Chan Wai Luen, Swee Hock Yeo

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The different process engineering applications of vibratory finishing technology have led to its versatile use in the development of aviation components. The most noteworthy applications of vibratory finishing include deburring and imparting the required surface finish. In this paper, vibratory finishing has been used to study its effectiveness in removal of laser shock peened (LSP) layers from Titanium workpieces. A vibratory trough operating at a frequency of 25 Hz, amplitude 3.5 mm and titanium specimens (Ti-6Al-4V, Grade 5) of dimensions 50 x 50 x 10 mm³ were utilized for the experiments. A vibrating fixture operating at 200 Hz was used to provide vibration to the test piece and was immersed in the vibratory trough. It was evident that there is an increase in efficiency of removal of the complex featured layer and smoother surface finish with the introduction of the vibrating fixture in the vibratory finishing setup as compared to the conventional vibratory finishing setup wherein the fixture is not vibrating.

Keywords: laser shock peening, material removal, surface roughness, vibrating fixture, vibratory finishing

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Authors: Nihal Murali, Kunal Gupta, Surekha Bhanot

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Training of artificial neural networks (ANNs) using reinforcement learning (RL) techniques is being widely discussed in the robot learning literature. The high model complexity of ANNs along with the model-free nature of RL algorithms provides a desirable combination for many robotics applications. There is a huge need for algorithms that generalize using raw sensory inputs, such as vision, without any hand-engineered features or domain heuristics. In this paper, the standard control problem of line following robot was used as a test-bed, and an ANN controller for the robot was trained on images from a live video feed using Q-learning. A virtual agent was first trained in simulation environment and then deployed onto a robot’s hardware. The robot successfully learns to traverse a wide range of curves and displays excellent generalization ability. Qualitative analysis of the evolution of policies, performance and weights of the network provide insights into the nature and convergence of the learning algorithm.

Keywords: artificial neural networks, q-learning, reinforcement learning, robot learning

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Authors: Kunal Krishna Das, Eddie S. S. Lam

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Preplaced Aggregate Concrete (PAC) is produced by first placing the coarse aggregate into the formwork, followed by injection of grout to fill in the voids in between the coarse aggregates. In this study, tests were carried out to determine the effects of supplementary cementitious materials on the properties of PAC. Cement was partially replaced by ground granulated blast furnace slag (GGBS) and silica fume (SF) at different proportions. Grout properties were determined by the flow cone test and compressive strength test. Grout proportion was optimized statistically. It was applied to form PAC. Hardened properties of PAC, comprising compressive strength, splitting tensile strength, chloride-ion penetration and drying shrinkage, were evaluated. GGBS enhanced the flowability of the grout, whereas SF enhanced the strength of PAC. Both GGBS and SF improved the resistance to chloride-ion penetration with the drawback of increased drying shrinkage. Nevertheless, drying shrinkage was within the range to be classified as low shrinkage concrete.

Keywords: factorial design, ground granulated blast furnace slag, preplaced aggregate concrete, silica fume

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Authors: Kunal D. Bhagat, Truong V. Vu, John C. Wells, Hideyuki Takakura, Yu Kawano, Fumio Ogawa

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Hollow germanium alloy quasi-spheres of diameters 1 to 2 mm with a relatively smooth inner and outer surface have been produced. The germanium was first melted at around 1273 K and then exuded from a coaxial nozzle into an inert atmosphere by argon gas supplied to the inner nozzle. The falling spheres were cooled by water spray and collected in a bucket. The spheres had a horn type of structure on the outer surface, which might be caused by volume expansion induced by the density difference between solid and gas phase. The frequency of the sphere formation was determined from the videos to be about 133 Hz. The outer diameter varied in the range of 1.3 to 1.8 mm with a wall thickness in the range of 0.2 to 0.5 mm. Solid silicon spheres are used for spherical silicon solar cells (S₃CS), which have various attractive features. Hollow S₃CS promise substantially higher energy conversion efficiency if their wall thickness can be kept to 0.1–0.2 mm and the inner surface can be passivated. Our production of hollow germanium spheres is a significant step towards the production of hollow S₃CS with, we hope, higher efficiency and lower material cost than solid S₃CS.

Keywords: hollow spheres, semiconductor, compound jet, dropping method

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Authors: Debalina Datta, Pratyaypratim Datta, Kunal Kanti Majumdar

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Introduction: In India 8.1% of total population is elderly. The standard of living and meaningfulness of life are indirectly measured by assessing quality of life of elderly. So, it is important to improve quality of life. Quality of life is an individual’s understanding of his/ her life situation with respect to his/ her values and cultural context as well as in relation to his/her goals, expectations and concerns. The present study was planned to assess the quality of life of geriatric people in urban West Bengal, India. Materials and methods: It was a community based cross sectional observational study conducted among people aged 60 years and above in Kolkata and Sonarpur region of West Bengal, India. Data collection was done by house to house visit using Quality of Life- BREF questionnaire (WHOQOL-BERF) developed by WHO. Analysis of quality of life of physical, psychological, social relationship and environmental domain was done using SPSS (version 16.0). Results: Transformed score (0-100 scale) was used for each domain. Mean of physical, psychological, social relationship and environmental domain were found to be 42.25, 40.84, 39.62 and 48.36 respectively. There was no significant difference in score between Kolkata and Sonarpur people in any domain except social relationship domain, where people living at Sonarpur scored significantly better. Conclusion: Rehabilitation of old age people can be done by improving their quality of life. Social interaction with people of all ages, allowing them to take important family decision, engaging them in different social activities can help a lot.

Keywords: quality of life, elderly, Urban West Bengal, India

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Authors: Ziad Abdeldayem, Jakub Markiewicz, Kunal Kansara, Laura Edwards

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Airborne Laser Scanning (ALS) is one of the main technologies for generating high-resolution digital terrain models (DTMs). DTMs are crucial to several applications, such as topographic mapping, flood zone delineation, geographic information systems (GIS), hydrological modelling, spatial analysis, etc. Laser scanning system generates irregularly spaced three-dimensional cloud of points. Raw ALS data are mainly ground points (that represent the bare earth) and non-ground points (that represent buildings, trees, cars, etc.). Removing all the non-ground points from the raw data is referred to as filtering. Filtering heavily forested areas is considered a difficult and challenging task as the canopy stops laser pulses from reaching the terrain surface. This research presents an approach for removing non-ground points from raw ALS data in densely forested areas. Smoothing splines are exploited to interpolate and fit the noisy ALS data. The presented filter utilizes a weight function to allocate weights for each point of the data. Furthermore, unlike most of the methods, the presented filtering algorithm is designed to be automatic. Three different forested areas in the United Kingdom are used to assess the performance of the algorithm. The results show that the generated DTMs from the filtered data are accurate (when compared against reference terrain data) and the performance of the method is stable for all the heavily forested data samples. The average root mean square error (RMSE) value is 0.35 m.

Keywords: airborne laser scanning, digital terrain models, filtering, forested areas

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Authors: Sanchita Abrol, Kunal Rana, Ankit Dhir, S. K. Gupta

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According to N.R.E.L.’s findings, 700 crore gallons of petrol is used annually to run the air conditioners of passenger vehicles (nearly 6% of total fuel consumption in the USA). Beyond fuel use, the Environmental Protection Agency reported that refrigerant leaks from auto air conditioning units add an additional 5 crore metric tons of carbon emissions to the atmosphere each year. The objective of our project is to deal with this vital issue by carefully modifying the interiors of a car thereby increasing its mileage and the efficiency of its engine. This would consequently result in a decrease in tail emission and generated pollution along with improved car performance. An automatic mechanism, deployed between the front and the rear seats, consisting of transparent thermal insulating sheet/curtain, would roll down as per the requirement of the driver in order to optimize the volume for effective air conditioning, when travelling alone or with a person. The reduction in effective volume will yield favourable results. Even on a mild sunny day, the temperature inside a parked car can quickly spike to life-threatening levels. For a stationary parked car, insulation would be provided beneath its metal body so as to reduce the rate of heat transfer and increase the transmissivity. As a result, the car would not require a large amount of air conditioning for maintaining lower temperature, which would provide us similar benefits. Authors established the feasibility studies, system engineering and primarily theoretical and experimental results confirming the idea and motivation to fabricate and test the actual product.

Keywords: automation, car, cooling insulating curtains, heat optimization, insulation, reduction in tail emission, mileage

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Authors: Kunal K. S., Shwetashri K. R., Keerthan G., Ajinkya R.

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Background: Normal pressure hydrocephalus is a condition caused by abnormal accumulation of cerebrospinal fluid (CSF) within the brain resulting in enlarged cerebral ventricles due to a disruption of CSF formation, absorption, or flow. Over the course of time, ventriculoperitoneal shunt under general anesthesia has become a standard of care. Yet only a finite number of centers have started the inclusion of regional anesthesia techniques for the such patient cohort. Stem Case: We report a case of a 75-year-old male with underlying aortic sclerosis and cardiomyopathy who presented with complaints of confusion, forgetfulness, and difficulty in walking. Neuro-imaging studies revealed disproportionally enlarged subarachnoid space hydrocephalus (DESH). The baseline blood pressure was 116/67 mmHg with a heart rate of 106 beats/min and SpO2 of 96% on room air. The patient underwent smooth induction followed by sonographically guided superficial cervical plexus block and transverse abdominis plane block. Intraoperative pain indices were monitored with Analgesia nociceptive index monitor (ANI, MdolorisTM) and surgical plethysmographic index (SPI, GE Healthcare, Helsinki, FinlandTM). These remained stable during the application of the block and the entire surgical duration. No significant hemodynamic response was observed during the tunneling of the skin by the surgeon. The patient underwent a smooth recovery and emergence. Conclusion: Our decision to incorporate peripheral nerve blockade in conjunction with general anesthesia resulted in opioid-sparing anesthesia and decreased post-operative analgesic requirement by the patient. This blockade was successful in suppressing intraoperative stress responses. Our patient recovered adequately and underwent an uncomplicated post-operative stay.

Keywords: desh, NPH, VP shunt, cervical plexus block, transversus abdominis plane block

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Authors: Garima Singh, Kunal Malhotra

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Objective: The expansion of telehealth has been instrumental in increasing access to medical services, especially for underserved and rural communities. In 2020, 14 million patients received virtual care through telemedicine and the global telemedicine market is expected to reach up to $185 million by 2023. It provides a platform and allows a patient to receive primary care as well as specialized care using technology and the comfort of their homes. Telemedicine was particularly useful during COVID-pandemic and the number of telehealth visits increased by 5000% during that time. It continues to serve as a significant resource for patients seeking care and to bridge the gap between the disease and the treatment. Method: As per APA (American Psychiatric Association), Telemedicine is the process of providing health care from a distance through technology. It is a subset of telemedicine, and can involve providing a range of services, including evaluations, therapy, patient education and medication management. It can involve direct interaction between a physician and the patient. It also encompasses supporting primary care providers with specialist consultation and expertise. It can also involve recording medical information (images, videos, etc.) and sending this to a distant site for later review. Results: In our organization, we are using telepsychiatry and serving 25 counties and approximately 1.4 million people. We provide multiple services, including inpatient, outpatient, crisis intervention, Rehab facility, autism services, case management, community treatment and multiple other modalities. With project ECHO (Extension for Community Healthcare Outcomes) it has been used to advise and assist primary care providers in treating mental health. It empowers primary care providers to treat patients in their own community by sharing knowledge. Conclusion: Telemedicine has shown to be a great medium in meeting patients’ needs and accessible mental health. It has been shown to improve access to care in both urban and rural settings by bringing care to a patient and reducing barriers like transportation, financial stress and resources. Telemedicine is also helping with reducing ER visits, integrating primary care and improving the continuity of care and follow-up. There has been substantial evidence and research about its effectiveness and its usage.

Keywords: telehealth, telemedicine, access to care, medical technology

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Authors: Kunal Bhardwaj, Christine Browne

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With the increase in global awareness of the environmental impacts of plastic-based products, there has been a massive drive to reduce our use of these products. Use of plastic-based substrates in electronic circuits has been a matter of concern recently. Plastics provide a very smooth and cheap surface for printing high-performance electronics due to their non-permeability to ink and easy mouldability. In this research, we explore the use of nano cellulose (NC) films in electronics as they provide an advantage of being 100% recyclable and eco-friendly. The main hindrance in the mass adoption of NC film as a substitute for plastic is its higher surface roughness which leads to ink penetration, and dispersion in the channels on the film. This research was conducted to tune the RMS roughness of NC films to a range where they can replace plastics in electronics(310-470nm). We studied the dependence of the surface roughness of the NC film on the following tunable aspects: 1) composition by weight of the NC suspension that is sprayed on a silicon wafer 2) the width and the depth of the channels on the silicon wafer used as a base. Various silicon wafers with channel depths ranging from 6 to 18 um and channel widths ranging from 5 to 500um were used as a base. Spray coating method for NC film production was used and two solutions namely, 1.5wt% NC and a 50-50 NC-CNC (cellulose nanocrystal) mixture in distilled water, were sprayed through a Wagner sprayer system model 117 at an angle of 90 degrees. The silicon wafer was kept on a conveyor moving at a velocity of 1.3+-0.1 cm/sec. Once the suspension was uniformly sprayed, the mould was left to dry in an oven at 50°C overnight. The images of the films were taken with the help of an optical profilometer, Olympus OLS 5000. These images were converted into a ‘.lext’ format and analyzed using Gwyddion, a data and image analysis software. Lowest measured RMS roughness of 291nm was with a 50-50 CNC-NC mixture, sprayed on a silicon wafer with a channel width of 5 µm and a channel depth of 12 µm. Surface roughness values of 320+-17nm were achieved at lower (5 to 10 µm) channel widths on a silicon wafer. This research opened the possibility of the usage of 100% recyclable NC films with an additive (50% CNC) in high-performance electronics. Possibility of using additives like Carboxymethyl Cellulose (CMC) is also being explored due to the hypothesis that CMC would reduce friction amongst fibers, which in turn would lead to better conformations amongst the NC fibers. CMC addition would thus be able to help tune the surface roughness of the NC film to an even greater extent in future.

Keywords: nano cellulose films, electronic circuits, nanocrystals and surface roughness

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Authors: Kunal Garg, Louise Theusen Hermansan, Kanoktip Puttaraska, Oliver Hendricks, Heidi Pirttinen, Leona Gilbert

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The Germ Theory (one infectious determinant is equal to one disease) has unarguably evolved our capability to diagnose and treat infectious diseases over the years. Nevertheless, the advent of technology, climate change, and volatile human behavior has brought about drastic changes in our environment, leading us to question the relevance of the Germ Theory in our day, i.e. will vector-borne disease (VBD) sufferers produce multiple immune responses when tested for multiple microbes? Vector diseased patients producing multiple immune responses to different microbes would evidently suggest human polymicrobial infections (HPI). Ongoing diagnostic tools are exceedingly unequipped with the current research findings that would aid in diagnosing patients for polymicrobial infections. This shortcoming has caused misdiagnosis at very high rates, consequently diminishing the patient’s quality of life due to inadequate treatment. Equipped with the state-of-art scientific knowledge, PolyScan intends to address the pitfalls in current VBD diagnostics. PolyScan is a multiplex and multifunctional enzyme linked Immunosorbent assay (ELISA) platform that can test for numerous VBD microbes and allow simultaneous screening for multiple types of antibodies. To validate PolyScan, Lyme Borreliosis (LB) and spondyloarthritis (SpA) patient groups (n = 54 each) were tested for Borrelia burgdorferi, Borrelia burgdorferi Round Body (RB), Borrelia afzelii, Borrelia garinii, and Ehrlichia chaffeensis against IgM and IgG antibodies. LB serum samples were obtained from Germany and SpA serum samples were obtained from Denmark under relevant ethical approvals. The SpA group represented chronic LB stage because reactive arthritis (SpA subtype) in the form of Lyme arthritis links to LB. It was hypothesized that patients from both the groups will produce multiple immune responses that as a consequence would evidently suggest HPI. It was also hypothesized that the multiple immune response proportion in SpA patient group would be significantly larger when compared to the LB patient group across both antibodies. It was observed that 26% LB patients and 57% SpA patients produced multiple immune responses in contrast to 33% LB patients and 30% SpA patients that produced solitary immune responses when tested against IgM. Similarly, 52% LB patients and an astounding 73% SpA patients produced multiple immune responses in contrast to 30% LB patients and 8% SpA patients that produced solitary immune responses when tested against IgG. Interestingly, IgM immune dysfunction in both the patient groups was also recorded. Atypically, 6% of the unresponsive 18% LB with IgG antibody was recorded producing multiple immune responses with the IgM antibody. Similarly, 12% of the unresponsive 19% SpA with IgG antibody was recorded producing multiple immune responses with the IgM antibody. Thus, results not only supported hypothesis but also suggested that IgM may atypically prevail longer than IgG. The PolyScan concept will aid clinicians to detect patients for early, persistent, late, polymicrobial, & immune dysfunction conditions linked to different VBD. PolyScan provides a paradigm shift for the VBD diagnostic industry to follow that will drastically shorten patient’s time to receive adequate treatment.

Keywords: diagnostics, immune dysfunction, polymicrobial, TICK-TAG

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Authors: Ram Sharma, Esha Chatterjee, Santosh Kumar Guru, Kunal Nepali

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A tractable anti-lung cancer agent was identified via the installation of a Ring C expanded synthetic analogue of the alkaloid vasicinone [7,8,9,10-tetrahydroazepino[2,1-b] quinazolin-12(6H)-one (TAZQ)] as a surface recognition part in the HDAC inhibitory three-component model. Noteworthy to mention that the candidature of TAZQ was deemed suitable for accommodation in HDAC inhibitory pharmacophore as per the results of the fragment recruitment process conducted by our laboratory. TAZQ was pinpointed through the fragment screening program as a synthetically flexible fragment endowed with some moderate cell growth inhibitory activity against the lung cancer cell lines, and it was anticipated that the use of the aforementioned fragment to generate hydroxamic acid functionality (zinc-binding motif) bearing HDAC inhibitors would boost the antitumor efficacy of TAZQ. Consistent with our aim of applying epigenetic targets to the treatment of lung cancer, a strikingly potent anti-lung cancer scaffold (compound 6) was pinpointed through a series of in-vitro experiments. Notably, the compounds manifested a magnificent activity profile against KRAS and EGFR mutant lung cancer cell lines (IC50 = 0.80 - 0.96 µM), and the effects were found to be mediated through preferential HDAC6 inhibition (IC50 = 12.9 nM). In addition to HDAC6 inhibition, the compounds also elicited HDAC1 and HDAC3 inhibitory activity with an IC50 value of 49.9 nM and 68.5 nM, respectively. The HDAC inhibitory ability of compound 6 was also confirmed from the results of the western blot experiment that revealed its potential to decrease the expression levels of HDAC isoforms (HDAC1, HDAC3, and HDAC6). Noteworthy to mention that complete downregulation of the HDAC6 isoform was exerted by compound 6 at 0.5 and 1 µM. Moreover, in another western blot experiment, treatment with hydroxamic acid 6 led to upregulation of H3 acK9 and α-Tubulin acK40 levels, ascertaining its inhibitory activity toward both the class I HDACs and Class II B HDACs. The results of other assays were also encouraging as treatment with compound 6 led to the suppression of the colony formation ability of A549 cells, induction of apoptosis, and increase in autophagic flux. In silico studies led us to rationalize the results of the experimental assay, and some key interactions of compound 6 with the amino acid residues of HDAC isoforms were identified. In light of the impressive activity spectrum of compound 6, a pH-responsive nanocarrier (hyaluronic acid-compound 6 nanoparticles) was prepared. The dialysis bag approach was used for the assessment of the nanoparticles under both normal and acidic circumstances, and the pH-sensitive nature of hyaluronic acid-compound 6 nanoparticles was confirmed. Delightfully, the nanoformulation was devoid of cytotoxicity against the L929 mouse fibroblast cells (normal settings) and exhibited selective cytotoxicity towards the A549 lung cancer cell lines. In a nutshell, compound 6 appears to be a promising adduct, and a detailed investigation of this compound might yield a therapeutic for the treatment of lung cancer.

Keywords: HDAC inhibitors, lung cancer, scaffold, hyaluronic acid, nanoparticles

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Authors: Amandeep Thakur, Yi-Hsuan Chu, Chun-Hsu Pan, Kunal Nepali

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The transfer of ADP-ribose residues onto target substrates from nicotinamide adenine dinucleotide (NAD) (PARylation) is catalyzed by Poly (ADP-ribose) polymerases (PARPs). Amongst the PARP family members, the DNA damage response in cancer is majorly regulated by PARP1 and PARP2. The blockade of DNA repair by PARP inhibitors leads to the progression of DNA single-strand breaks (induced by some triggering factors) to double-strand breaks. Notably, PARP inhibitors are remarkably effective in cancers with defective homologous recombination repair (HRR). In particular, cancer cells with BRCA mutations are responsive to therapy with PARP inhibitors. The aforementioned requirement for PARP inhibitors to be effective confers a narrow activity spectrum to PARP inhibitors, which hinders their clinical applicability. Thus, the quest to expand the application horizons of PARP inhibitors beyond BRCA mutations is the need of the hour. Literature precedents reveal that HDAC inhibition induces BRCAness in cancer cells and can broaden the therapeutic scope of PARP inhibitors. Driven by such disclosures, dual inhibitors targeting both PARP and HDAC enzymes were designed by our research group to extend the efficacy of PARP inhibitors beyond BRCA-mutated cancers to cancers with induced BRCAness. The design strategy involved the installation of Veliparib, an investigational PARP inhibitor, as a surface recognition part in the HDAC inhibitor pharmacophore model. The chemical architecture of veliparib was deemed appropriate as a starting point for the generation of dual inhibitors by virtue of its size and structural flexibility. A validatory docking study was conducted at the outset to predict the binding mode of the designed dual modulatory chemical architectures. Subsequently, the designed chemical architectures were synthesized via a multistep synthetic route and evaluated for antitumor efficacy. Delightfully, one compound manifested impressive anti-leukemic effects (HL-60 cell lines) mediated via dual inhibition of PARP and class I HDACs. The outcome of the western blot analysis revealed that the compound could downregulate the expression levels of PARP1 and PARP2 and the HDAC isoforms (HDAC1, 2, and 3). Also, the dual PARP-HDAC inhibitor upregulated the protein expression of the acetyl histone H3, confirming its abrogation potential for class I HDACs. In addition, the dual modulator could arrest the cell cycle at the G0/G1 phase and induce autophagy. Further, polymer-based nanoformulation of the dual inhibitor was furnished to afford targeted delivery of the dual inhibitor at the cancer site. Transmission electron microscopy (TEM) results indicate that the nanoparticles were monodispersed and spherical. Moreover, the polymeric nanoformulation exhibited an appropriate particle size. Delightfully, pH-sensitive behavior was manifested by the polymeric nanoformulation that led to selective antitumor effects towards the HL-60 cell lines. In light of the magnificent anti-leukemic profile of the identified dual PARP-HDAC inhibitor, in-vivo studies (pharmacokinetics and pharmacodynamics) are currently being conducted. Notably, the optimistic findings of the aforementioned study have spurred our research group to initiate several medicinal chemistry campaigns to create bifunctional small molecule inhibitors addressing PARP as the primary target.

Keywords: PARP inhibitors, HDAC inhibitors, BRCA mutations, leukemia

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Authors: Kelsi Hagerty, Ami Rosen, Aaliyah Heyward, Nadia Ali, Emily Brown, Erin Demo, Yue Guan, Modele Ogunniyi, Brianna McDaniels, Alanna Morris, Kunal Bhatt

Abstract:

Hereditary transthyretin amyloidosis (hATTR) is a progressive, multi-systemic, and life-threatening disease caused by a disruption in the TTR protein that delivers thyroxine and retinol to the liver. This disruption causes the protein to misfold into amyloid fibrils, leading to the accumulation of the amyloid fibrils in the heart, nerves, and GI tract. Over 130 variants in the TTR gene are known to cause hATTR. The Val122Ile variant is the most common in the United States and is seen almost exclusively in people of African descent. TTR variants are inherited in an autosomal dominant fashion and have incomplete penetrance and variable expressivity. Individuals with hATTR may exhibit symptoms from as early as 30 years to as late as 80 years of age. hATTR is characterized by a wide range of clinical symptoms such as cardiomyopathy, neuropathy, carpal tunnel syndrome, and GI complications. Without treatment, hATTR leads to progressive disease and can ultimately lead to heart failure. hATTR disproportionately affects individuals of African descent; the estimated prevalence of hATTR among Black individuals in the US is 3.4%. Unfortunately, hATTR is often underdiagnosed and misdiagnosed because many symptoms of the disease overlap with other cardiac conditions. Due to the progressive nature of the disease, multi-systemic manifestations that can lead to a shortened lifespan, and the availability of free genetic testing and promising FDA-approved therapies that enhance treatability, early identification of individuals with a pathogenic hATTR variant is important, as this can significantly impact medical management for patients and their relatives. Furthermore, recent literature suggests that TTR genetic testing should be performed in all patients with suspicion of TTR-related cardiomyopathy, regardless of age, and that follow-up with genetic counseling services is recommended. Relatives of patients with hATTR benefit from genetic testing because testing can identify carriers early and allow relatives to receive regular screening and management. Despite the striking prevalence of hATTR among Black individuals, hATTR remains underdiagnosed in this patient population, and germline genetic testing for hATTR in Black individuals seems to be underrepresented, though the reasons for this have not yet been brought to light. Historically, Black patients experience a number of barriers to seeking healthcare that has been hypothesized to perpetuate the underdiagnosis of hATTR, such as lack of access and mistrust of healthcare professionals. Prior research has described a myriad of factors that shape an individual’s decision about whether to pursue presymptomatic genetic testing for a familial pathogenic variant, such as family closeness and communication, family dynamics, and a desire to inform other family members about potential health risks. This study explores these factors through 10 in-depth interviews with patients with hATTR about what factors may be contributing to the underdiagnosis of hATTR in the Black population. Participants were selected from the Emory University Amyloidosis clinic based on having a molecular diagnosis of hATTR. Interviews were recorded and transcribed verbatim, then coded using MAXQDA software. Thematic analysis was completed to draw commonalities between participants. Upon preliminary analysis, several themes have emerged. Barriers identified include i) Misdiagnosis and a prolonged diagnostic odyssey, ii) Family communication and dynamics surrounding health issues, iii) Perceptions of healthcare and one’s own health risks, and iv) The need for more intimate provider-patient relationships and communication. Overall, this study gleaned valuable insight from members of the Black community about possible factors contributing to the underdiagnosis of hATTR, as well as potential solutions to go about resolving this issue.

Keywords: cardiac amyloidosis, heart failure, TTR, genetic testing

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