Search results for: Anukul K. Thakur

Authors: Satendra Pal Singh, Dalip Kr. Kakru, Jyoti Mishra, Rajesh Thakur, Tarana Sarwat

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COVID-19 is still an intrigue as far as morbidity or mortality is concerned. The rate of recovery varies from person to person, & it depends upon the accessibility of the healthcare system and the roles played by the physicians and caregivers. It is envisaged that with the passage of time, people would become immune to this virus, and those who are vulnerable would sustain themselves with the help of vaccines. The proposed study deals with the severeness of COVID-19 is associated with some specific biomarkers linked to correlate age and gender. We will be assessing the overall homeostasis of the persons who were affected by the coronavirus infection and also of those who recovered from it. Some people show more severe effects, while others show very mild symptoms, however, they show low CT values. Thus far, it is unclear why the new strain of Covid has different effects on different people in terms of age, gender, and ABO blood typing. According to data, the fatality rate with heart disease was 10.5 percent, 7.3 percent were diabetic, and 6 percent who are already infected from other comorbidities. However, some COVID-19 cases are worse than others & it is not fully explainable as of date. Overall data show that the ABO blood group is effective or prone to the risk of SARS-COV2 infection, while another study also shows the phenotypic effects of the blood group related to covid. It is an accepted fact that females have more strong immune systems than males, which may be related to the fact that females have two ‘X’ chromosomes, which might contain a more effective immunity booster gene on the X chromosome, and are capable to protect the female. Also specific sex hormones also induce a better immune response in a specific gender. This calls for in-depth analysis to be able to gain insight into this dilemma. COVID-19 is still not fully characterized, and thus we are not very familiar with its biology, mode of infection, susceptibility, and overall viral load in the human body. How many virus particles are needed to infect a person? How, then, comorbidity contribute to coronavirus infection? Since the emergence of this virus in 2020, a large number of papers have been published, and seemingly, vaccines have been prepared. But still, a large number of questions remain unanswered. The proneness of humans for infection by covid-19 needs to be established to be able to develop a better strategy to fight this virus. Our study will be on the Impact of demography on the Severity of covid-19 infection & at the same time, will look into gender-specific sensitivity of Covid-19 and the Operational variation of different biochemical markers in Covid-19 positive patients. Besides, we will be studying the co-relation, if any, of COVID severity & ABO Blood group type and the occurrence of the most common blood group type amongst positive patience.

Keywords: coronavirus, ABO blood group, age, gender

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Authors: Ila Thakur, Atul Srivastava, Shyamprasad Karagadde

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The phenomenon of double-diffusive convection is driven by density gradients created by two different components (e.g., temperature and concentration) having different molecular diffusivities. The evolution of horizontal double-diffusive layers (DDLs) is one of the outcomes of double-diffusive convection occurring in a laterally/vertically cooled rectangular cavity having a pre-existing vertically stable composition field. The present work mainly focuses on different characteristics of the formation and merging of double-diffusive layers by imposing lateral/vertical thermal gradients in a vertically stable compositional field. A CFD-based twodimensional fluent model has been developed for the investigation of the aforesaid phenomena. The configuration containing vertical thermal gradients shows the evolution and merging of DDLs, where, elements from the same horizontal plane move vertically and mix with surroundings, creating a horizontal layer. In the configuration of lateral thermal gradients, a specially oriented convective roll was found inside each DDL and each roll was driven by the competing density change due to the already existing composition field and imposed thermal field. When the thermal boundary layer near the vertical wall penetrates the salinity interface, it can disrupt the compositional interface and can lead to layer merging. Different analytical scales were quantified and compared for both configurations. Various combinations of solutal and thermal Rayleigh numbers were investigated to get three different regimes, namely; stagnant regime, layered regime and unicellular regime. For a particular solutal Rayleigh number, a layered structure can originate only for a range of thermal Rayleigh numbers. Lower thermal Rayleigh numbers correspond to a diffusion-dominated stagnant regime. Very high thermal Rayleigh corresponds to a unicellular regime with high convective mixing. Different plots identifying these three regimes, number, thickness and time of existence of DDLs have been studied and plotted. For a given solutal Rayleigh number, an increase in thermal Rayleigh number increases the width but decreases both the number and time of existence of DDLs in the fluid domain. Sudden peaks in the velocity and heat transfer coefficient have also been observed and discussed at the time of merging. The present study is expected to be useful in correlating the double-diffusive convection in many large-scale applications including oceanography, metallurgy, geology, etc. The model has also been developed for three-dimensional geometry, but the results were quite similar to that of 2-D simulations.

Keywords: double diffusive layers, natural convection, Rayleigh number, thermal gradients, compositional gradients

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Authors: Bhavneet Bharti, Prahbhjot Malhi, Vandana Thakur

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Introduction: Children of the urban migrant laborers have great difficulty in accessing government programs which are otherwise routinely available in rural settings. These include programs for child care, nutrition, health and education. There are major communicative fault-lines preventing advocacy for these marginalized children. The overarching aim of this study was to investigate the role of an innovative strategy of children’s drawings in supporting communication between children, social workers, pediatricians and other child advocates to fulfil their fundamental child rights. Materials and Methods: The data was collected over a period of one-year April 2015 to April 2016 during the routine visits by the members of the Social Pediatrics team including a social worker, pediatricians and an artist to the makeshift colony of migrant laborers. Once a week a drawing session was organized where the children including adolescents were asked to any drawing and provide a narrative thereafter. 5-30 children attended these weekly sessions for one year. All these drawings were then classified into various themes and exhibited on 16th April 2016 in the Govt. College of Art Museum. The forum was used for advocacy of Child Rights of these underprivileged children to Secretary social welfare. Results: Mean (SD) age of children in present observational study was 8.5 (2.5) years, with 60% of the boys. Majority of children demonstrated themes which were local and contextualized to their daily needs, threats and festivals which clearly underscored their fundamental right to basic services and equality of opportunities to achieve their full development Drawings of tap with flowing water, queues of people collecting water from hand pumps reflect the local problem of water availability for these children. Young children talking about fear of rape and murder following their drawings indicate the looming threat of potential abuse and neglect. Besides reality driven drawing, children also echoed supernatural beliefs, dangers and festivities in their drawings. Anyone who watched these children at work with art materials was able to see the intense level of absorption, clearly indicating the enjoyment they received, making it a meaningful activity. Indeed, this self-advocacy through art exhibition led to the successful establishment of mobile Anganwadi (A social safety net programme of the government) in their area of stay. Conclusions: This observational study is an example of how children were able to do self-advocacy to protect their rights. Of particular importance, these drawings address how psychologists and other child advocates can ensure in a child-centered manner that the voice of children is heard and represented in all assessments of their well-being and future care options.

Keywords: child advocacy, children drawings, child rights, marginalized children

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Authors: Shailaja Thakur

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Managerial literature abounds with discussions on business strategies, success stories as well as cases of failure, which provide an indication of the parameters that should be considered in gauging the dynamism of an entrepreneur. Neoclassical economics has reduced entrepreneurship to a mere factor of production, driven solely by the profit motive, thus stripping him of all creativity and restricting his decision making to mechanical calculations. His ‘dynamism’ is gauged simply by the amount of profits he earns, marginalizing any discussion on the means that he employs to attain this objective. With theoretical backing, we have developed an Index of Entrepreneurial Dynamism (IED) giving weights to the different moves that the entrepreneur makes during his business journey. Strategies such as changes in product lines, markets and technology are gauged as very important (weighting of 4); while adaptations in terms of technology, raw materials used, upgradations in skill set are given a slightly lesser weight of 3. Use of formal market analysis, diversification in related products are considered moderately important (weight of 2) and being a first generation entrepreneur, employing managers and having plans to diversify are taken to be only slightly important business strategies (weight of 1). The maximum that an entrepreneur can score on this index is 53. A semi-structured questionnaire is employed to solicit the responses from the entrepreneurs on the various strategies that have been employed by them during the course of their business. Binary as well as graded responses are obtained, weighted and summed up to give the IED. This index was tested on about 150 tribal entrepreneurs in Mizoram, a state of India and was found to be highly effective in gauging their dynamism. This index has universal acceptability but is devoid of the socio-cultural context, which is very central to the success and performance of the entrepreneurs. We hypothesize that a society that respects risk taking takes failures in its stride, glorifies entrepreneurial role models, promotes merit and achievement is one that has a conducive socio- cultural environment for entrepreneurship. For obtaining an idea about the social acceptability, we are putting forth questions related to the social acceptability of business to another set of respondents from different walks of life- bureaucracy, academia, and other professional fields. Similar weighting technique is employed, and index is generated. This index is used for discounting the IED of the respondent entrepreneurs from that region/ society. This methodology is being tested for a sample of entrepreneurs from two very different socio- cultural milieus- a tribal society and a ‘mainstream’ society- with the hypothesis that the entrepreneurs in the tribal milieu might be showing a higher level of dynamism than their counterparts in other regions. An entrepreneur who scores high on IED and belongs to society and culture that holds entrepreneurship in high esteem, might not be in reality as dynamic as a person who shows similar dynamism in a relatively discouraging or even an outright hostile environment.

Keywords: index of entrepreneurial dynamism, India, social acceptability, tribal entrepreneurs

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Authors: Amiya Kumar Thakur, Dinesh Ganvir, Prem Pal Bansal

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Industrial by product utilization has been encouraged due to environment and economic factors. Since electric arc furnace slag aggregate is a by-product of steel industry and its storage is a major concern hence it can be used as a replacement of natural aggregate as its physical and mechanical property are comparable or better than the natural aggregates. The present study investigates the effect of partial and full replacement of natural coarse aggregate with coarse EAF slag aggregate and partial replacement of cement with ground granulated blast furnace slag (GGBFS) on the mechanical and durability properties of roller compacted concrete pavement (RCCP).The replacement level of EAF slag aggregate were at five levels (i.e. 0% ,25% ,50%,75% & 100%) and of GGBFS was (0 % & 30%).The EAF slag aggregate was stabilized by exposing to outdoor condition for several years and the volumetric expansion test using steam exposure device was done to check volume stability. Soil compaction method was used for mix proportioning of RCCP. The fresh properties of RCCP investigated were fresh density and modified vebe test was done to measure the consistency of concrete. For investigating the mechanical properties various tests were done at 7 and 28 days (i.e. Compressive strength, split tensile strength, flexure strength modulus of elasticity) and also non-destructive testing was done at 28 days (i.e. Ultra pulse velocity test (UPV) & rebound hammer test). The durability test done at 28 days were water absorption, skid resistance & abrasion resistance. The results showed that with the increase in slag aggregate percentage there was an increase in the fresh density of concrete and also slight increase in the vebe time but with the 30 % GGBFS replacement the vebe time decreased and the fresh density was comparable to 0% GGBFS mix. The compressive strength, split tensile strength, flexure strength & modulus of elasticity increased with the increase in slag aggregate percentage in concrete when compared to control mix. But with the 30 % GGBFS replacement there was slight decrease in mechanical properties when compared to 100 % cement concrete. In UPV test and rebound hammer test all the mixes showed excellent quality of concrete. With the increase in slag aggregate percentage in concrete there was an increase in water absorption, skid resistance and abrasion resistance but with the 30 % GGBFS percentage the skid resistance, water absorption and abrasion resistance decreased when compared to 100 % cement concrete. From the study it was found that the mix containing 30 % GGBFS with different percentages of EAF slag aggregate were having comparable results for all the mechanical and durability property when compared to 100 % cement mixes. Hence 30 % GGBFS can be used as cement replacement with 100 % EAF slag aggregate as natural coarse aggregate replacement.

Keywords: durability properties, electric arc furnace slag aggregate, GGBFS, mechanical properties, roller compacted concrete pavement, soil compaction method

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Authors: Shivani Thakur, Jasmin Dominguez Cervantes, Ahmed Zabiba, Fatima Zabiba, Sandhini Agarwal, Kamalpreet Kaur, Hussein Maatouk, Shae Chand, Omar Madriz, Tiffany Huang, Saloni Bansal

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Contraceptives are an effective public health achievement, allowing for family planning and reducing the risk of sexually transmitted diseases (STDs). California’s rural Central Valley has high rates of teenage pregnancy and STDs. Factors affecting contraceptive usage here may include religious concerns, financial issues, and regional variations in the accessibility and availability of contraceptives. The increasing population and diversity of the Central Valley make the understanding of the determinants of unintended pregnancy and STDs increasingly nuanced. Patients in California’s Central Valley were surveyed at 6 surgical clinics to assess attitudes toward contraceptives. The questionnaire consisted of demographics and 14 Likert-scale statements investigating patients’ feelings regarding contraceptives. Parametric and non-parametric analysis was performed on the Likert statements. A correlation matrix for the Likert-scale statements was used to evaluate the strength of the relationship between each question. 76 patients aged 18-75 years completed the questionnaire. 90% of the participants were female, 76% Hispanic, 36% married, 44% with an income range between 30-60K, and 83% were between childbearing ages. 60% of participants stated they are currently using or had used some type of contraceptive. 25% of participants had at least one unplanned pregnancy. The most common type of contraceptives used were oral contraceptives(28%) and condoms(38%). The top reasons for patients’ contraceptive usage were: prevention of pregnancy (72%), safe sex/prevention of STDs (32%), and regulation of menstrual cycle (19%). Further analysis of Likert responses revealed that contraception usage increased due to approval of contraceptives (x̄=3.98, σ =1.02); partner approval of contraceptives (x̄=3.875, σ =1.16); and reduced anxiety about pregnancy (x̄=3.875, σ =1.23). Younger females (18-34 years old) agreed more with the statement that the cost of contraceptive supplies is too expensive than older females (35-75 years old), (x̄=3.2, σ = 1.4 vs x̄=2.8, σ =1.3, p<0.05). Younger females (44%) were also more likely to use short-acting contraceptive methods (oral and male condoms) compared to older females (64%) who use long-acting methods (implants/ intrauterine devices). 51% of Hispanic females were using some type of contraceptive. Of those Hispanic females who do not use contraceptives, 33% stated having no children, and all plan to have at least one child in the future. 35% of participants had a bachelor's degree. Those with bachelor’s degrees were more likely to use contraceptives, 58% vs 51%, p<0.05, and less likely to have unplanned pregnancy, 50% vs. 12%, p<0.01. There is increasing use and awareness among patients in rural settings concerning contraceptives. Our finding shows that younger women and women with higher educational attainment tend to have more positive attitudes towards the use of contraceptives. This work gives physicians an understanding of patients’ concerns about contraceptive methods and offers insight into culturally competent intervention programs that respect individual values.

Keywords: contraceptives, public health, rural california, women of child baring age

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Authors: Ashish Thakur

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This technical paper was written in view of focusing the biomaterials and its various applications in modern industries. Author tires to elaborate not only the medical, infect plenty of application in other industries. The scope of the research area covers the wide range of physical, biological and chemical sciences that underpin the design of biomaterials and the clinical disciplines in which they are used. A biomaterial is now defined as a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure. Biomaterials are invariably in contact with living tissues. Thus, interactions between the surface of a synthetic material and biological environment must be well understood. This paper reviews the benefits and challenges associated with surface modification of the metals in biomedical applications. The paper also elaborates how the surface characteristics of metallic biomaterials, such as surface chemistry, topography, surface charge, and wettability, influence the protein adsorption and subsequent cell behavior in terms of adhesion, proliferation, and differentiation at the biomaterial–tissue interface. The chapter also highlights various techniques required for surface modification and coating of metallic biomaterials, including physicochemical and biochemical surface treatments and calcium phosphate and oxide coatings. In this review, the attention is focused on the biomaterial-associated infections, from which the need for anti-infective biomaterials originates. Biomaterial-associated infections differ markedly for epidemiology, aetiology and severity, depending mainly on the anatomic site, on the time of biomaterial application, and on the depth of the tissues harbouring the prosthesis. Here, the diversity and complexity of the different scenarios where medical devices are currently utilised are explored, providing an overview of the emblematic applicative fields and of the requirements for anti-infective biomaterials. In addition to this, chapter introduces nanomedicine and the use of both natural and synthetic polymeric biomaterials, focuses on specific current polymeric nanomedicine applications and research, and concludes with the challenges of nanomedicine research. Infection is currently regarded as the most severe and devastating complication associated to the use of biomaterials. Osteoporosis is a worldwide disease with a very high prevalence in humans older than 50. The main clinical consequences are bone fractures, which often lead to patient disability or even death. A number of commercial biomaterials are currently used to treat osteoporotic bone fractures, but most of these have not been specifically designed for that purpose. Many drug- or cell-loaded biomaterials have been proposed in research laboratories, but very few have received approval for commercial use. Polymeric nanomaterial-based therapeutics plays a key role in the field of medicine in treatment areas such as drug delivery, tissue engineering, cancer, diabetes, and neurodegenerative diseases. Advantages in the use of polymers over other materials for nanomedicine include increased functionality, design flexibility, improved processability, and, in some cases, biocompatibility.

Keywords: nanomedicine, tissue, infections, biomaterials

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Authors: B. K. Kanungo, Monika Thakur, Minati Baral

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8-hydroxyquinoline, (8HQ), experiences a renaissance due to its utility as a building block in metallosupramolecular chemistry and its versatile use of its derivatives in various fields of analytical chemistry, materials science, and pharmaceutics. It forms stable complexes with a variety of metal ions. Assembly of more than one such unit to form a polydentate chelator enhances its coordinating ability and the related properties due to the chelate effect resulting in high stability constant. Keeping in view the above, a nonadentate chelator N-[3,5-bis(8-hydroxyquinoline-2-amido)cyclohexyl]-8-hydroxyquinoline-2-carboxamide, (TACH2OX), containing a central cis,cis-1,3,5-triaminocyclohexane appended to three 8-hydroxyquinoline at 2-position through amide linkage is developed, and its solution thermodynamics, photophysical and Density Functional Theory (DFT) studies were undertaken. The synthesis of TACH2OX was carried out by condensation of cis,cis-1,3,5-triaminocyclohexane, (TACH) with 8‐hydroxyquinoline‐2‐carboxylic acid. The brown colored solid has been fully characterized through melting point, infrared, nuclear magnetic resonance, electrospray ionization mass and electronic spectroscopy. In solution, TACH2OX forms protonated complexes below pH 3.4, which consecutively deprotonates to generate trinegative ion with the rise of pH. Nine protonation constants for the ligand were obtained that ranges between 2.26 to 7.28. The interaction of the chelator with two trivalent metal ion Fe3+ and Al3+ were studied in aqueous solution at 298 K. The metal-ligand formation constants (ML) obtained by potentiometric and spectrophotometric method agree with each other. The protonated and hydrolyzed species were also detected in the system. The in-silico studies of the ligand, as well as the complexes including their protonated and deprotonated species assessed by density functional theory technique, gave an accurate correlation with each observed properties such as the protonation constants, stability constants, infra-red, nmr, electronic absorption and emission spectral bands. The nature of electronic and emission spectral bands in terms of number and type were ascertained from time-dependent density functional theory study and the natural transition orbitals (NTO). The global reactivity indices parameters were used for comparison of the reactivity of the ligand and the complex molecules. The natural bonding orbital (NBO) analysis could successfully describe the structure and bonding of the metal-ligand complexes specifying the percentage of contribution in atomic orbitals in the creation of molecular orbitals. The obtained high value of metal-ligand formation constants indicates that the newly synthesized chelator is a very powerful synthetic chelator. The minimum energy molecular modeling structure of the ligand suggests that the ligand, TACH2OX, in a tripodal fashion firmly coordinates to the metal ion as hexa-coordinated chelate displaying distorted octahedral geometry by binding through three sets of N, O- donor atoms, present in each pendant arm of the central tris-cyclohexaneamine tripod.

Keywords: complexes, DFT, formation constant, TACH2OX

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Authors: Vasundhara Arora, Anupam Jhobta, Suresh Thakur, Sanjiv Sharma

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Aims and Objectives: Intracranial tuberculosis (TB) is one of the most devastating manifestations of TB and a challenging public health issue of considerable importance and magnitude world over. This study elaborates on the imaging spectrum of neurotuberculosis on magnetic resonance imaging (MRI) in 29 clinically suspected cases from a tertiary care hospital. Materials and Methods: The prospective hospital based evaluation of MR imaging features of neuro-tuberculosis in 29 clinically suspected cases was carried out in Department of Radio-diagnosis, Indira Gandhi Medical Hospital from July 2017 to August 2018. MR Images were obtained on a 1.5 T Magnetom Avanto machine and were analyzed to identify any abnormal meningeal enhancement or parenchymal lesions. Microbiological and Biochemical CSF analysis was performed in radio-logically suspected cases and the results were compared with the imaging data. Clinical follow up of the patients started on anti-tuberculous treatment was done to evaluate the response to treatment and clinical outcome. Results: Age range of patients in the study was between 1 year to 73 years. The mean age of presentation was 11.5 years. No significant difference in the distribution of cerebral tuberculosis was noted among the two genders. Imaging findings of neuro-tuberculosis obtained were varied and non specific ranging from lepto-meningeal enhancement, cerebritis to space occupying lesions such as tuberculomas and tubercular abscesses. Complications presenting as hydrocephalus (n= 7) and infarcts (n=9) was noted in few of these patients. 29 patients showed radiological suspicion of CNS tuberculosis with meningitis alone observed in 11 cases, tuberculomas alone were observed in 4 cases, meningitis with parenchymal tuberculomas in 11 cases. Tubercular abscess and cerebritis were observed in one case each. Tuberculous arachnoiditis was noted in one patient. Gene expert positivity was obtained in 11 out of 29 radiologically suspected patients; none of the patients showed culture positivity. Meningeal form of the disease alone showed higher positivity rate of gene Xpert (n=5) followed by combination of meningeal and parenchymal forms of disease (n=4). The parenchymal manifestation of disease alone showed least positivity rates (n= 3) with gene xpert testing. All 29 patients were started on anti tubercular treatment based on radiological suspicion of the disease with clinical improvement observed in 27 treated patients. Conclusions: In our study, higher incidence of neuro- tuberculosis was noted in paediatric population with predominance of the meningeal form of the disease. Gene Xpert positivity obtained was low due to paucibacillary nature of cerebrospinal fluid (CSF) with even lower positivity of CSF samples in parenchymal form of the manifestation. MRI showed high accuracy in detecting CNS lesions in neuro-tuberculosis. Hence, it can be concluded that MRI plays a crucial role in the diagnosis because of its inherent sensitivity and specificity and is an indispensible imaging modality. It caters to the need of early diagnosis owing to poor sensitivity of microbiological tests more so in the parenchymal manifestation of the disease.

Keywords: neurotuberculosis, tubercular abscess, tuberculoma, tuberculous meningitis

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Authors: Priyanka Sharma, Ranjita Das, Mohan C. Kalita, Debajit Thakur

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Background: Actinomycetes are the richest source of novel bioactive secondary metabolites such as antibiotics, enzymes and other therapeutically useful metabolites with diverse biological activities. The present study aims at the antimicrobial potential and genetic diversity of culturable Actinomycetes isolated from protected forest ecosystems of Assam which includes Kaziranga National Park (26°30˝-26°45˝N and 93°08˝-93°36˝E), Pobitora Wildlife Sanctuary (26º12˝-26º16˝N and 91º58˝-92º05˝E) and Gibbon Wildlife Sanctuary (26˚40˝-26˚45˝N and 94˚20˝-94˚25˝E) which are located in the North-eastern part of India. Northeast India is a part of the Indo-Burma mega biodiversity hotspot and most of the protected forests of this region are still unexplored for the isolation of effective antibiotic-producing Actinomycetes. Thus, there is tremendous possibility that these virgin forests could be a potential storehouse of novel microorganisms, particularly Actinomycetes, exhibiting diverse biological properties. Methodology: Soil samples were collected from different ecological niches of the protected forest ecosystems of Assam and Actinomycetes were isolated by serial dilution spread plate technique using five selective isolation media. Preliminary screening of Actinomycetes for an antimicrobial activity was done by spot inoculation method and the secondary screening by disc diffusion method against several test pathogens, including multidrug resistant Staphylococcus aureus (MRSA). The strains were further screened for the presence of antibiotic synthetic genes such as type I polyketide synthases (PKS-I), type II polyketide synthases (PKS-II) and non-ribosomal peptide synthetases (NRPS) genes. Genetic diversity of the Actinomycetes producing antimicrobial metabolites was analyzed through 16S rDNA-RFLP using Hinf1 restriction endonuclease. Results: Based on the phenotypic characterization, a total of 172 morphologically distinct Actinomycetes were isolated and screened for antimicrobial activity by spot inoculation method on agar medium. Among the strains tested, 102 (59.3%) strains showed activity against Gram-positive bacteria, 98 (56.97%) against Gram-negative bacteria, 92 (53.48%) against Candida albicans MTCC 227 and 130 (75.58%) strains showed activity against at least one of the test pathogens. Twelve Actinomycetes exhibited broad spectrum antimicrobial activity in the secondary screening. The taxonomic identification of these twelve strains by 16S rDNA sequencing revealed that Streptomyces was found to be the predominant genus. The PKS-I, PKS-II and NRPS genes detection indicated diverse bioactive products of these twelve Actinomycetes. Genetic diversity by 16S rDNA-RFLP indicated that Streptomyces was the dominant genus amongst the antimicrobial metabolite producing Actinomycetes. Conclusion: These findings imply that Actinomycetes from the protected forest ecosystems of Assam, India, are a potential source of bioactive secondary metabolites. These areas are as yet poorly studied and represent diverse and largely unscreened ecosystem for the isolation of potent Actinomycetes producing antimicrobial secondary metabolites. Detailed characterization of the bioactive Actinomycetes as well as purification and structure elucidation of the bioactive compounds from the potent Actinomycetes is the subject of ongoing investigation. Thus, to exploit Actinomycetes from such unexplored forest ecosystems is a way to develop bioactive products.

Keywords: Actinomycetes, antimicrobial activity, forest ecosystems, RFLP

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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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