Search results for: binding kinetics

Authors: Amir Zeb, Shailima Rampogu, Minky Son, Ayoung Baek, Sang H. Yoon, Keun W. Lee

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Neurotoxic insults activate calpain, which in turn produces truncated p25 from p35. p25 forms hyperactivated Cdk5/p25 complex, and thereby induces severe neuropathological aberrations including hyperphosphorylated tau, neuroinflammation, apoptosis, and neuronal death. Inhibition of Cdk5/p25 complex alleviates aberrant phosphorylation of tau to mitigate AD pathology. PHA-793887 and Roscovitine have been investigated as selective inhibitors of Cdk5/p25 with IC50 values 5nM and 160nM, respectively, but their mechanistic studies remain unknown. Herein, computational simulations have explored the binding mode and interaction mechanism of PHA-793887 and Roscovitine with Cdk5/p25. Docking results suggested that PHA-793887 and Rsocovitine have occupied the ATP-binding site of Cdk5 and obtained highest docking (GOLD) score of 66.54 and 84.03, respectively. Furthermore, molecular dynamics (MD) simulation demonstrated that PHA-793887 and Roscovitine established stable RMSD of 1.09 Å and 1.48 Å with Cdk5/p25, respectively. Profiling of polar interactions suggested that each inhibitor formed hydrogen bonds (H-bond) with catalytic residues of Cdk5 and could remain stable throughout the molecular dynamics simulation. Additionally, binding free energy calculation by molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) suggested that PHA-793887 and Roscovitine had lowest binding free energies of -150.05 kJ/mol and -113.14 kJ/mol, respectively with Cdk5/p25. Free energy decomposition demonstrated that polar energy by H-bond between the Glu81 of Cdk5 and PHA-793887 is the essential factor to make PHA-793887 highly selective towards Cdk5/p25. Overall, this study provided substantial evidences to explore mechanistic interactions of the selective inhibitors of Cdk5/p25 and could be used as fundamental considerations in the development of structure-based selective inhibitors of Cdk5/p25.

Keywords: Cdk5/p25 inhibition, molecular modeling of Cdk5/p25, PHA-793887 and roscovitine, selective inhibition of Cdk5/p25

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Authors: Ben Otange, Wolfgang Parak, Florian Schulz, Michael Alexander Rubhausen

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The feasibility of extending the usage of molecular imprinting technique in complex biomolecules is demonstrated in this research. This technique is promising in diverse applications in areas such as drug delivery, diagnosis of diseases, catalysts, and impurities detection as well as treatment of various complications. While molecularly imprinted polymers MIP remain robust in the synthesis of molecules with remarkable binding sites that have high affinities to specific molecules of interest, extending the usage to complex biomolecules remains futile. This work reports on the successful synthesis of MIP from complex proteins: BSA, Transferrin, and MUC1. We show in this research that despite the heterogeneous binding sites and higher conformational flexibility of the chosen proteins, relying on their respective epitopes and motifs rather than the whole template produces highly sensitive and selective MIPs for specific molecular binding. Introduction: Proteins are vital in most biological processes, ranging from cell structure and structural integrity to complex functions such as transport and immunity in biological systems. Unlike other imprinting templates, proteins have heterogeneous binding sites in their complex long-chain structure, which makes their imprinting to be marred by challenges. In addressing this challenge, our attention is inclined toward the targeted delivery, which will use molecular imprinting on the particle surface so that these particles may recognize overexpressed proteins on the target cells. Our goal is thus to make surfaces of nanoparticles that specifically bind to the target cells. Results and Discussions: Using epitopes of BSA and MUC1 proteins and motifs with conserved receptors of transferrin as the respective templates for MIPs, significant improvement in the MIP sensitivity to the binding of complex protein templates was noted. Through the Fluorescence Correlation Spectroscopy FCS measurements on the size of protein corona after incubation of the synthesized nanoparticles with proteins, we noted a high affinity of MIPs to the binding of their respective complex proteins. In addition, quantitative analysis of hard corona using SDS-PAGE showed that only a specific protein was strongly bound on the respective MIPs when incubated with similar concentrations of the protein mixture. Conclusion: Our findings have shown that the merits of MIPs can be extended to complex molecules of higher biomolecular mass. As such, the unique merits of the technique, including high sensitivity and selectivity, relative ease of synthesis, production of materials with higher physical robustness, and higher stability, can be extended to more templates that were previously not suitable candidates despite their abundance and usage within the body.

Keywords: molecularly imprinted polymers, specific binding, drug delivery, high biomolecular mass-templates

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Authors: Abul B. M. M. K. Islam, Nuria Lopez-Bigas, Elizaveta V. Benevolenskaya

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RBP2 has shown to be important for cell differentiation control through epigenetic mechanism. The main aim of the present study is genome-wide location analysis of human RBP2 isoforms that differ in a histone-binding domain by ChIPseq. It is conceivable that the larger isoform (LI) of RBP2, which contains a specific H3K4me3 interacting domain, differs from the smaller isoform (SI) in genomic location, may account for the observed diversity in RBP2 function. To distinguish the two RBP2 isoforms, we used the fact that the SI lacks the C-terminal PHD domain and hence used the antibodies detecting both RBP2 isoforms (AI) through a common central domain, and the antibodies detecting only LI but not SI, through a C-terminal PHD domain. Overall our analysis suggests that RBP2 occupies about 77 nucleotides and binds GC rich motifs of active genes, does not bind to centromere, telomere, or enhancer regions, and binding sites are conserved compare to random. A striking difference between the only-SI and only-LI is that a large number of only-SI peaks are located in CpG islands and close to TSS compared to only-LI peaks. Enrichment analysis of the related genes indicates that several oncogenic pathways and metabolic pathways/processes are significantly enriched among only-SI/AI targets, but not LI/only-LI peak’s targets.

Keywords: bioinformatics, cancer, ChIP-seq, KDM5A

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Authors: Hongquan Zhang

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Inspired by endogenous protein motors, researchers have constructed various synthetic DNA motors based on the specificity and predictability of Watson-Crick base pairing. However, the application of DNA motors to signal amplification and biosensing is limited because of low mobility and difficulty in real-time monitoring of the walking process. The objective of our work was to construct a new type of DNA motor termed target-triggered DNA motors that can walk for hundreds of steps in response to a single target binding event. To improve the mobility and processivity of DNA motors, we used gold nanoparticles (AuNPs) as scaffolds to build high-density, three-dimensional tracks. Hundreds of track strands are conjugated to a single AuNP. To enable DNA motors to respond to specific protein and nucleic acid targets, we adapted the binding-induced DNA assembly into the design of the target-triggered DNA motors. In response to the binding of specific target molecules, DNA motors are activated to autonomously walk along AuNP, which is powered by a nicking endonuclease or DNAzyme-catalyzed cleavage of track strands. Each moving step restores the fluorescence of a dye molecule, enabling monitoring of the operation of DNA motors in real time. The motors can translate a single binding event into the generation of hundreds of oligonucleotides from a single nanoparticle. The motors have been applied to amplify the detection of proteins and nucleic acids in test tubes and live cells. The motors were able to detect low pM concentrations of specific protein and nucleic acid targets in homogeneous solutions without the need for separation. Target-triggered DNA motors are significant for broadening applications of DNA motors to molecular sensing, cell imagining, molecular interaction monitoring, and controlled delivery and release of therapeutics.

Keywords: biosensing, DNA motors, gold nanoparticles, signal amplification

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Authors: Jay Ananth

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The drug discovery process currently requires numerous years of clinical testing as well as money just for a single drug to earn FDA approval. For drugs that even make it this far in the process, there is a very slim chance of receiving FDA approval, resulting in detrimental hurdles to drug accessibility. To minimize these inefficiencies, numerous studies have implemented computational methods, although few computational investigations have focused on a crucial feature of drugs: lipophilicity. Lipophilicity is a physical attribute of a compound that measures its solubility in lipids and is a determinant of drug efficacy. This project leverages Artificial Intelligence to predict the impact of a drug’s lipophilicity on its performance by accounting for factors such as binding affinity and toxicity. The model predicted lipophilicity and binding affinity in the validation set with very high R² scores of 0.921 and 0.788, respectively, while also being applicable to a variety of target receptors. The results expressed a strong positive correlation between lipophilicity and both binding affinity and toxicity. The model helps in both drug development and discovery, providing every pharmaceutical company with recommended lipophilicity levels for drug candidates as well as a rapid assessment of early-stage drugs prior to any testing, eliminating significant amounts of time and resources currently restricting drug accessibility.

Keywords: drug discovery, lipophilicity, ligand-receptor interactions, machine learning, drug development

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Authors: Abdullah Khan, Per Redelius, Nicole Kringos

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The breaking and coalescence process in bitumen emulsion strongly influence the performance of the cold mix asphalt (CMA) and this phase separation process is affected by the physio-chemical changes happening at the bitumen/water interface. In this paper, coalescence experiments of two bitumen droplets in an emulsion environment have been carried out by a newly developed test procedure. In this study, different types of emulsifiers were selected to understand the coalescence process with respect to changes in the water phase surface tension due to addition of different surfactants and other additives such as salts. The research showed that the relaxation kinetics of bitumen droplets varied with the type of emulsifier, its concentration as well as with and without presence of salt in the water phase. Moreover, kinetics of the coalescence process was also investigated with the temperature variation.

Keywords: bitumen emulsions, breaking and coalescence, cold mix asphalt, emulsifiers, relaxation, salts

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Authors: Stephen Eyije Abechi, Casimir Emmanuel Gimba, Zaharaddeen Nasiru Garba, Sani Shamsudeen, David Ebuka Authur

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Corrosion inhibition of mild steel in acid medium using Acalypha chamaedrifolia leaves extract as potential green inhibitor was investigated. Gravimetric (weight loss) technique was used for the corrosion studies. Mild steel coupons of 2cm × 1cm × 0.27 cm dimensions were exposed for varying durations of between 24 to 120 hours, in 1M HCl medium containing a varying concentrations of the leaves extract (0.25g/L, - 1.25g/L). The results show that corrosion rates dropped from a value of 0.49 mgcm-2hr-1 for the uninhibited medium to a value of 0.15 mgcm-2hr-1 for the inhibited medium of 1M HCl in 0.25 g/l of the extract. Values of corrosion inhibition efficiencies of 70.38-85.11% were observed as the concentration of the inhibitor were increased from 0.25g/L, - 1.25g/L. Corrosion Inhibition was found to increase with increase in immersion time and temperature. The magnitude of the Ea indicates that the interaction between the metal surface and the inhibitor was chemisorptions. The Adsorption process fit into the Langmuir isotherm model with a correlation coefficient of 0.97. Evidence from molecular dynamics model shows that Methyl stearate (Line 5) and (3Z, 13Z)-2-methyloctadeca-3,13-dien-1-ol (line 11) were found to have the highest binding energy of -197.69 ± 3.12 and-194.56 ± 10.04 in kcal/mol respectively. The binding energy of these compounds indicates that they would be a very good corrosion inhibitor for mild steel and other Fe related materials.

Keywords: binding energy, corrosion, inhibitor, langmuir isotherm, mild steel

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Authors: Nikhil Agrawal, Adam A. Skelton

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Alzheimer’s disease (AD) is one of the most common forms of dementia, which is caused by misfolding and aggregation of amyloid beta (Aβ) peptides into amyloid-β fibrils (Aβ fibrils). To disrupt the remodeling of Aβ fibrils, a number of candidate molecules have been proposed. To study the molecular mechanisms of Aβ fibrils remodeling we performed a series of all-atom molecular dynamics simulations, a total time of 3µs, in explicit solvent. Several previously undiscovered candidate molecule-Aβ fibrils binding modes are unraveled; one of which shows the direct conformational change of the Aβ fibril by understanding the physicochemical factors responsible for binding and subsequent remodeling of Aβ fibrils by the candidate molecule, open avenues into structure-based drug design for AD can be opened.

Keywords: alzheimer’s disease, amyloid, MD simulations, misfolded protein

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Authors: Stephen Eyije Abechi, Casimir Emmanuel Gimba, Zaharaddeen Nasiru Garba, Sani Shamsudeen, David Ebuka Authur

Abstract:

The mechanisms of corrosion inhibition of mild steel in acid medium using Acalypha chamaedrifolia leaves extract as potential green inhibitor were investigated. Gravimetric (weight loss) technique was used for the corrosion studies. Mild steel coupons of 2cm × 1cm × 0.27 cm dimensions were exposed for varying durations of between 24 to 120 hours, in 1M HCl medium containing a varying concentrations of the leaves extract (0.25g/L, - 1.25g/L). The results show that corrosion rates dropped from a value of 0.49 mgcm-2hr-1 for the uninhibited medium to a value of 0.15 mgcm-2hr-1 for the inhibited medium of 1M HCl in 0.25 g/l of the extract. Values of corrosion inhibition efficiencies of 70.38-85.11% were observed as the concentration of the inhibitor were increased from 0.25g/L, - 1.25g/L. Corrosion Inhibition was found to increase with increase in immersion time and temperature. The magnitude of the Ea indicates that the interaction between the metal surface and the inhibitor was chemisorptions. The Adsorption process fit into the Langmuir isotherm model with a correlation coefficient of 0.97. Evidence from molecular dynamics model shows that Methyl stearate (Line 5) and (3Z, 13Z)-2-methyloctadeca-3,13-dien-1-ol (line 11) were found to have the highest binding energy of -197.69 ± 3.12 and-194.56 ± 10.04 in kcal/mol respectively. The binding energy of these compounds indicates that they would be a very good corrosion inhibitor for mild steel and other Fe related materials.

Keywords: binding energy, corrosion, inhibitor, Langmuir isotherm, mild steel.

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Authors: Varun A Baheti, Sanjay Kashyap, Kamanio Chattopadhyay, Praveen Kumar, Aloke Paul

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Ni–Sn system finds applications in the microelectronics industry, especially with respect to flip–chip or direct chip, attach technology. Here the region of interest is under bump metallization (UBM), and solder bump (Sn) interface due to the formation of brittle intermetallic phases there. Understanding the growth of these phases at UBM/Sn interface is important, as in many cases it controls the electro–mechanical properties of the product. Cu and Ni are the commonly used UBM materials. Cu is used for good bonding because of fast reaction with solder and Ni often acts as a diffusion barrier layer due to its inherently slower reaction kinetics with Sn–based solders. Investigation on the growth kinetics of phases in Ni–Sn system is reported in this study. Just for simplicity, Sn being major solder constituent is chosen. Ni–Sn electroplated diffusion couples are prepared by electroplating pure Sn on Ni substrate. Bulk diffusion couples prepared by the conventional method are also studied along with Ni–Sn electroplated diffusion couples. Diffusion couples are annealed for 25–1000 h at 50–215°C to study the phase evolutions and growth kinetics of various phases. The interdiffusion zone was analysed using field emission gun equipped scanning electron microscope (FE–SEM) for imaging. Indexing of selected area diffraction (SAD) patterns obtained from transmission electron microscope (TEM) and composition measurements done in electron probe micro−analyser (FE–EPMA) confirms the presence of various product phases grown across the interdiffusion zone. Time-dependent experiments indicate diffusion controlled growth of the product phase. The estimated activation energy in the temperature range 125–215°C for parabolic growth constants (and hence integrated interdiffusion coefficients) of the Ni₃Sn₄ phase shed light on the growth mechanism of the phase; whether its grain boundary controlled or lattice controlled diffusion. The location of the Kirkendall marker plane indicates that the Ni₃Sn₄ phase grows mainly by diffusion of Sn in the binary Ni–Sn system.

Keywords: diffusion, equilibrium phase, metastable phase, the Ni-Sn system

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Authors: Mohd Javaid, Shahbaz Khan, Abid Haleem

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Purpose: Large numbers of 3D printing technologies are now available for sophisticated applications in different fields. Additive manufacturing has established its dominance in design, development, and customisation of the product. In the era of developing technologies, there is a need to identify the appropriate technology for different application. In order to fulfil this need, two widely used printing technologies such as Fused Deposition Modeling (FDM), and Binding-Jet 3D Printing are compared for effective utilisation in the current scenario for different applications. Methodology: Systematic literature review conducted for both technologies with applications and associated factors enabling for the same. Appropriate MCDM tool is used to compare critical factors for both the technologies. Findings: Both technologies have their potential and capabilities to provide better direction to the industry. Additionally, this paper is helpful to develop a decision support system for the proper selection of technologies according to their continuum of applications and associated research and development capability. The vital issue is raw materials, and research-based material development is key to the sustainability of the developed technologies. FDM is a low-cost technology which provides high strength product as compared to binding jet technology. Researcher and companies can take benefits of this study to achieve the required applications in lesser resources. Limitations: Study has undertaken the comparison with the opinion of experts, which may not always be free from bias, and some own limitations of each technology. Originality: Comparison between these technologies will help to identify best-suited technology as per the customer requirements. It also provides development in this different field as per their extensive capability where these technologies can be successfully adopted. Conclusion: FDM and binding jet technology play an active role in industrial development. These help to assist the customisation and production of personalised parts cost-effectively. So, there is a need to understand how these technologies can provide these developments rapidly. These technologies help in easy changes or in making revised versions of the product, which is not easily possible in the conventional manufacturing system. High machine cost, the requirement of skilled human resources, low surface finish, and mechanical strength of product and material changing option is the main limitation of this technology. However, these limitations vary from technology to technology. In the future, these technologies are to be commercially viable for efficient usage in direct manufacturing of varied parts.

Keywords: 3D printing, comparison, fused deposition modeling, FDM, binding jet technology

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Authors: Mohammad Hossein Modarressi, Mozhgan Mondeali, Khabat Barkhordari, Ali Etemadi

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The COVID-19 pandemic, caused by SARS-CoV-2, has led to significant concerns worldwide due to its catastrophic effects on public health. The SARS-CoV-2 infection is initiated with the binding of the receptor-binding domain (RBD) in its spike protein to the ACE2 receptor in the host cell membrane. Due to the error-prone entity of the viral RNA-dependent polymerase complex, the virus genome, including the coding region for the RBD, acquires new mutations, leading to the appearance of multiple variants. These variants can potentially impact transmission, virulence, antigenicity and evasive immune properties. S477N mutation located in the RBD has been observed in the SARS-CoV-2 omicron (B.1.1. 529) variant. In this study, we investigated the consequences of S477N mutation at the molecular level using computational approaches such as molecular dynamics simulation, protein-protein interaction analysis, immunoinformatics and free energy computation. We showed that displacement of Ser with Asn increases the stability of the spike protein and its affinity to ACE2 and thus increases the transmission potential of the virus. This mutation changes the folding and secondary structure of the spike protein. Also, it reduces antibody neutralization, raising concern about re-infection, vaccine breakthrough and therapeutic values.

Keywords: S477N, COVID-19, molecular dynamic, SARS-COV2 mutations

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Authors: Sumeyra Sevim, Gulsum Gizem Topal, Mercan Merve Tengilimoglu-Metin, Mevlude Kizil

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Aflatoxin M1 (AFM1) is a major toxic and carcinogenic molecule in milk and milk products. Therefore, it poses a risk for public health. Probiotics can be biological agent to remove AFM1. The aim of this study is to evaluate the effect of probiotic bacteria on AFM1 detoxification in phosphate buffer saline. The PBS samples artificially contaminated with AFM1 at concentration 100 pg/ml were prepared with probiotics bacteria that including monoculture (L. plantarum, B. bifidum ATCC, B. animalis ATCC 27672) and binary culture (L. bulgaricus + S. thermophiles, B. bifidum ATCC + B. animalis ATCC 27672, L. plantarum+B. bifidum ATCC, L. plantarum+ B. animalis ATCC 27672). The samples were incubated at 37°C for 4 hours and stored for 1, 5 and 10 days. The toxin was measured by the ELISA. The highest levels of AFM1 binding ability (63.6%) in PBS were detected yoghurt starter bacteria, while L. plantarum had the lowest levels of AFM1 binding ability (35.5%) in PBS. In addition, it was found that there was significant effect of storage on AFM1 binding ability in all groups except the one including B. animalis (p < 0.05). Consequently, results demonstrate that AFM1 detoxification by probiotic bacteria has a potential application to reduce toxin concentrations in yoghurt. Moreover, probiotic strains can react with itself as synergic or antagonist.

Keywords: aflatoxin M1, ELISA, probiotics, storage

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Authors: N. Naga Subrahmanyeswara Rao, Parag Arvind Deshpande

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Understanding nucleotide synthesis reaction of any organism is beneficial to know the growth of it as in Mycobacterium tuberculosis to design anti TB drug. One of the reactions of de novo pathway which takes place in all organisms was considered. The reaction takes places between phosphoribosyl pyrophosphate and orotate catalyzed by orotate phosphoribosyl transferase and divalent metal ion gives orotdine monophosphate, a nucleotide. All the reaction steps of three experimentally proposed mechanisms for this reaction were considered to develop kinetic rate expression. The model was validated using the data for four organisms. This model could successfully describe the kinetics for the reported data. The developed model can serve as a reliable model to describe the kinetics in new organisms without the need of mechanistic determination. So an organism-independent model was developed.

Keywords: mechanism, nucleotide, organism, tuberculosis

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Authors: Anon Paserakung, Chaloemphon Muangyen, Suban Foiklang, Yanin Opatpatanakit

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Improving nutritive values and digestibility of maize stover is an alternative way to increase their utilization in ruminant and reduce air pollution from open burning of maize stover in the northern Thailand. The present study, 2x3 factorial arrangements in completely randomized design was conducted to investigate the effect of maize stover components (whole and upper stover; cut above 5th node). Urea treatment at levels 0, 3, and 6% DM on dry matter digestibility and fermentation kinetics of maize stover using in vitro gas production. After 21 days of urea treatment, results illustrated that there was no interaction between maize stover components and urea treatment on 48h in vitro dry matter digestibility (IVDMD). IVDMD was unaffected by maize stover components (P > 0.05), average IVDMD was 55%. However, using whole maize stover gave higher cumulative gas and gas kinetic parameters than those of upper stover (P<0.05). Treating maize stover by ensiling with urea resulted in a significant linear increase in IVDMD (P<0.05). IVDMD increased from 42.6% to 53.9% when increased urea concentration from 0 to 3% and maximum IVDMD (65.1%) was observed when maize stover was ensiled with 6% urea. Maize stover treated with urea at levels of 0, 3, and 6% linearly increased cumulative gas production at 96h (31.1 vs 50.5 and 59.1 ml, respectively) and all gas kinetic parameters excepted the gas production from the immediately soluble fraction (P<0.50). The results indicate that maize stover treated with 6% urea enhance in vitro dry matter digestibility and fermentation kinetics. This study provides a practical approach to increasing utilization of maize stover in feeding ruminant animals.

Keywords: maize stover, urea treatment, ruminant feed, gas production

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Authors: Mustafa Ali Abugila, Basma Nuri Kajruba, Hanan Elhadi, Rehab Ramadan Wali

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Iron deficiency anemia is characterized by a decrease of Hb (hemoglobin), serum iron, ferritin, and RBC (red blood cells) (shape and size). Also, it is characterized by an increase in total iron binding capacity (TIBC). Red blood cells become microctytic and hypochromic due to a decrease in iron content. This study was conducted in the north west of Libya and included 210 women in childbearing age (18-45 years) who were visiting women clinic. After filling the questionnaire, blood samples were taken and analyzed for hematological and biochemical profiles. Biochemical tests included measurement of serum iron, ferritin, and total iron binding capacity (TIBC). Among the total sample (210 women), there were 87 (41.42%) pregnant and 123 (58.57%) non-pregnant women (includes married and single). Pregnant women (87) were classified according to the gestational age into first, second, and third trimesters. The means of biochemical and hematological parameters in the studied samples were: Hb = 10.37± 2.02 g/dl, RBC = 3.78± 1.037 m/m3, serum iron 61.86± 40.28 µg/dl, and TIBC = 386.01 ± 94.91 µg/dl. In this study, we considered that any women have hemoglobin below 11.5 g/dl is anemic. 89.1%, 69.5%, and 47.8% of pregnant women who belong to third trimester had low (below normal value) Hb, serum iron, and ferritin, i.e. iron deficiency anemia was more common in third trimester among the first and the second trimesters. Third trimester pregnant women also had high TIBC more than first and second trimesters.

Keywords: red blood cells, hemoglobin, total iron binding capacity, ferritin

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Authors: Anika Chebrolu

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Mono-targeted drugs can be of limited efficacy against complex diseases. Recently, multi-target drug design has been approached as a promising tool to fight against these challenging diseases. However, the scope of current computational approaches for multi-target drug design is limited. DeepLig presents a de-novo drug discovery platform that uses reinforcement learning to generate and optimize novel, potent, and multitargeted drug candidates against protein targets. DeepLig’s model consists of two networks in interplay: a generative network and a predictive network. The generative network, a Stack- Augmented Recurrent Neural Network, utilizes a stack memory unit to remember and recognize molecular patterns when generating novel ligands from scratch. The generative network passes each newly created ligand to the predictive network, which then uses multiple Graph Attention Networks simultaneously to forecast the average binding affinity of the generated ligand towards multiple target proteins. With each iteration, given feedback from the predictive network, the generative network learns to optimize itself to create molecules with a higher average binding affinity towards multiple proteins. DeepLig was evaluated based on its ability to generate multi-target ligands against two distinct proteins, multi-target ligands against three distinct proteins, and multi-target ligands against two distinct binding pockets on the same protein. With each test case, DeepLig was able to create a library of valid, synthetically accessible, and novel molecules with optimal and equipotent binding energies. We propose that DeepLig provides an effective approach to design multi-targeted drug therapies that can potentially show higher success rates during in-vitro trials.

Keywords: drug design, multitargeticity, de-novo, reinforcement learning

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Authors: Hari Bezwada, Michelle Cheon, Ryan Divan, Hannah Escritor, Michelle Kagramian, Isha Korgaonkar, Maya MacAdams, Udgita Pamidigantam, Richard Pilny, Eleanor Race, Angadh Singh, Nathan Zhang, LeeAnn Nguyen, Fina Liotta

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Malaria is a deadly disease caused by the Plasmodium parasite, which continues to develop resistance to current antimalarial drugs. In this research project, the effectiveness of numerous thiazole derivatives was explored in inhibiting the PfPKG, a crucial part of the Plasmodium life cycle. This study involved the synthesis of six thiazole-derived amides to inhibit the PfPKG pathway. Nuclear Magnetic Resonance (NMR) spectroscopy and Infrared (IR) spectroscopy were used to characterize these compounds. Furthermore, AutoDocking software was used to predict binding affinities of these thiazole-derived amides in silico. In silico, compound 6 exhibited the highest predicted binding affinity to PfPKG, while compound 5 had the lowest affinity. Compounds 1-4 displayed varying degrees of predicted binding affinity. In-vitro, it was found that compound 4 had the best percent inhibition, while compound 5 had the worst percent inhibition. Overall, all six compounds had weak inhibition (approximately 30-39% at 10 μM), but these results provide a foundation for future drug discovery experiments.

Keywords: Medicinal Chemistry, Malaria, drug discovery, PfPKG, Thiazole, Plasmodium

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Authors: Chinmayee Choudhury

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Human Melanocortin 4 Receptor (HMC4R) is one of the most potential drug targets for the treatment of obesity which controls the appetite. A deletion of the residues 88-92 in HMC4R is sometimes the cause of severe obesity in the humans. In this study, two homology models are constructed for the normal as well as mutated HMC4Rs and some phytochemicals present in Green Tea, Honey and Cinnamon have been docked to them to study their differential binding to the normal and mutated HMC4R as compared to the natural agonist α- MSH. Two homology models have been constructed for the normal as well as mutated HMC4Rs using the Modeller9v7. Some of the phytochemicals present in Green Tea, Honey, and Cinnamon, which have appetite suppressant activities are constructed, minimized and docked to these normal and mutated HMC4R models using ArgusLab 4.0.1. The mode of binding of the phytochemicals with the Normal and Mutated HMC4Rs have been compared. Further, the mode of binding of these phytochemicals with that of the natural agonist α- Melanocyte Stimulating Hormone(α-MSH) to both normal and mutated HMC4Rs have also been studied. It is observed that the phytochemicals Kaempherol, Epigallocatechin-3-gallate (EGCG) present in Green Tea and Honey, Isorhamnetin, Chlorogenic acid, Chrysin, Galangin, Pinocambrin present in Honey, Cinnamaldehyde, Cinnamyl acetate and Cinnamyl alcohol present in Cinnamon have capacity to form more stable complexes with the Mutated HMC4R as compared to α- MSH. So they may be potential agonists of HMC4R to suppress the appetite.

Keywords: HMC4R, α-MSH, docking, photochemical, appetite suppressant, homology modelling

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Authors: H. Abu-Ali, A. Nabok, T. Smith

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Aptamers are single-strand of DNA or RNA nucleotides sequence which is designed in vitro using selection process known as SELEX (systematic evolution of ligands by exponential enrichment) were developed for the selective detection of many toxic materials. In this work, we have developed an electrochemical biosensor for highly selective and sensitive detection of Hg2+ and Pb2+ using a specific aptamer probe (SAP) labelled with ferrocene (or methylene blue) in (5′) end and the thiol group at its (3′) termini, respectively. The SAP has a specific coil structure that matching with G-G for Pb2+ and T-T for Hg2+ interaction binding nucleotides ions, respectively. Aptamers were immobilized onto surface of screen-printed gold electrodes via SH groups; then the cyclic voltammograms were recorded in binding buffer with the addition of the above metal salts in different concentrations. The resulted values of anode current increase upon binding heavy metal ions to aptamers and analyte due to the presence of electrochemically active probe, i.e. ferrocene or methylene blue group. The correlation between the anodic current values and the concentrations of Hg2+ and Pb2+ ions has been established in this work. To the best of our knowledge, this is the first example of using a specific DNA aptamers for electrochemical detection of heavy metals. Each increase in concentration of 0.1 μM results in an increase in the anode current value by simple DC electrochemical test i.e (Cyclic Voltammetry), thus providing an easy way of determining Hg2+ and Pb2+concentration.

Keywords: aptamer, based, biosensor, DNA, electrochemical, highly, specific

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Authors: Sabiha Chouchane, Toufik Chouchane, Azzedine Hani

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The wastewater was treated with a natural asorbent “Diatomite” to eliminate chromium three. Diatomite is an element that comes from Sig (west of Algeria). The physicochemical characterization revealed that the diatomite is mainly made up of silica, lime and a lower degree of alumina. The process considered in static regime, at 20°C, an ion stirring speed of 150 rpm, a pH = 4 and a grain diameter of between 100 and 150µm, shows that one gram of diatomite purified can fix according to the Langmuir model up to 39.64 mg/g of chromium with pseudo 1st order kinetics. The pseudo-equilibrium time highlighted is 25 minutes. The affinity between the adsorbent and the adsorbate follows the value of the RL ratio indicates us that the solid used has a good adsorption capacity. The external transport of the metal ions from the solution to the adsorbent seems to be a step controlling the speed of the overall process. On the other hand, internal transport in the pores is not the only limiting mechanism of sorption kinetics. Thermodynamic parameters show that chromium sorption is spontaneous and exothermic with negative entropy.

Keywords: adsorption, diatomite, crIII, wastewater

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Authors: Mohd Farooq Naqshbandi

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The four fractions of aqueous extract of Sesame Seeds (Sesamum indicum L.) were studied for invitro DNA fragmentation, cell migration, and cellular apoptosis on SW480 and HTC116 human colorectal cancer cell lines. The seeds of Sesamum indicum were extracted with six solvents, including Methanol, Ethanol, Aqueous, Chloroform, Acetonitrile, and Hexane. The aqueous extract (IC₅₀ value 154 µg/ml) was found to be the most active in terms of cytotoxicity with SW480 human colorectal cancer cell lines. Further fractionation of this aqueous extract on flash chromatography gave four fractions. These four fractions were studied for anticancer and DNA binding studies. Cell viability was assessed by colorimetric assay (MTT). IC₅₀ values for all these four fractions ranged from 137 to 548 µg/mL for the HTC116 cancer cell line and 141 to 402 µg/mL for the SW480 cancer cell line. The four fractions showed good anticancer and DNA binding properties. The DNA binding constants ranged from 10.4 ×10⁴ 5 to 28.7 ×10⁴, showing good interactions with DNA. The DNA binding interactions were due to intercalative and π-π electron forces. The results indicate that aqueous extract fractions of sesame showed inhibition of cell migration of SW480 and HTC116 human colorectal cancer cell lines and induced DNA fragmentation and apoptosis. This was demonstrated by calculating the low wound closure percentage in cells treated with these fractions as compared to the control (80%). Morphological features of nuclei of cells treated with fractions revealed chromatin compression, nuclear shrinkage, and apoptotic body formation, which indicate cell death by apoptosis. The flow cytometer of fraction-treated cells of SW480 and HTC116 human colorectal cancer cell lines revealed death due to apoptosis. The results of the study indicate that aqueous extract of sesame seeds may be used to treat colorectal cancer.

Keywords: Sesamum indicum, cell migration inhibition, apoptosis induction, anticancer activity, colorectal cancer

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Authors: Geetakshi Arora, Danish Malhotra

Abstract:

Diabetic wounds are serious health issues and often fail to heal, leading to limb amputation that makes the life of the patient miserable. Delayed wound healing has been characterized by an increase in matrix metalloproteinase-9 (MMP-9). Thus research throughout the world has been going on to develop selective MMP-9 inhibitors for aiding diabetic wound healing. Bioactive constituents from natural sources always served as potential leads in drug development with high rates of success. Considering the need for novel selective MMP-9 inhibitors and the importance of natural bioactive compounds in drug development, we have screened a library of bioactive constituents from plant sources that were effective in diabetic wound healing on human MMP-9 (hMMP-9) using molecular docking studies. Screened constituents are ranked according to their dock score, ∆G value (binding affinity), and Ligand efficiency evaluated from FleXX docking and Hyde scoring modules available with drug designing platform LeadIT. Rhamnocitrin showed the highest correlation between dock score, ∆G value (binding affinity), and Ligand efficiency was further explored for binding interactions with hMMP-9. The overall study suggest that Rhamnocitrin is sufficiently decorated with both hydrophilic and hydrophobic substitutions that perfectly block hMMP-9 and act as a potential lead in the design and development of selective hMMP-9 inhibitors.

Keywords: MMP-9, diabetic wound, molecular docking, phytoconstituents

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Authors: Nihar Ranjan, Derrick Watkins, Dev P. Arya

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Current methods in the study of antibiotic activity of ribosome targeted antibiotics are dependent on cell based bacterial inhibition assays or various forms of ribosomal binding assays. These assays are typically independent of each other and little direct correlation between the ribosomal binding and bacterial inhibition is established with the complementary assay. We have developed novel high-throughput capable assays for ribosome targeted drug discovery. One such assay examines the compounds ability to bind to a model ribosomal RNA A-site. We have also coupled this assay to other functional orthogonal assays. Such analysis can provide valuable understanding of the relationships between two complementary drug screening methods and could be used as standard analysis to correlate the affinity of a compound for its target and the effect the compound has on a cell.

Keywords: bacterial resistance, aminoglycosides, screening, drugs

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Authors: Olushola Ayanda, Simphiwe Nelana, Eliazer Naidoo

Abstract:

In the present study, the kinetics, equilibrium and thermodynamics of the adsorption of As(III) ions from aqueous solution onto fly ash (FA) was investigated in batch adsorption system. Prior to the adsorption studies, the FA was characterized by means of x-ray fluorescence (XRF), x-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and Brunauer-Emmett-Teller (BET) surface area determination. The effect of contact time, initial As(III) concentration, FA dosage, stirring speed, solution pH and temperature was examined on the adsorption rate. Experimental results showed a very good compliance with the pseudo-second-order equation, while the equilibrium study showed that the sorption of As(III) ions onto FA fitted the Langmuir and Freundlich isotherms. The adsorption process is endothermic and spontaneous, moreover, the maximum percentage removal of As(III) achieved with approx. 2.5 g FA mixed with 25 mL of 100 mg/L As(III) solution was 65.4 % at pH 10, 60 min contact time, temperature of 353 K and a stirring speed of 120 rpm.

Keywords: arsenic, fly ash, kinetics, isotherm, thermodynamics

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Authors: Deepa Kundu, Prabhakar Sharma, Sayan Bhattacharya, Jianying Shang

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The discharge of dye-containing effluents in the water bodies has raised concern due to the potential hazards related to their toxicity in the environment. There are various treatment technologies available for the removal of dyes from wastewaters. The use of biosorbent to remove dyes from wastewater is one of the effective and inexpensive techniques. In the study, the adsorption of phenothiazine dye methylene blue onto biosorbent prepared from Lantana camara L. has been studied in aqueous solutions. The batch adsorption experiments were conducted and the effects of various parameters such as pH (3-12), contact time, adsorbent dose (100-400 mg/L), initial dye concentration (5-20 mg/L), and temperature (303, 313 and 323 K) were investigated. The prepared leaf (BCL600) and shoot (BCS600) biochar of Lantana were characterized using FTIR, SEM, elemental analysis, and zeta potential (pH~7). A comparison between the adsorption potential of both the biosorbent was also evaluated. The results indicated that the amount of methylene blue dye (mg/g) adsorbed onto the surface of biochar was highly dependent on the pH of the dye solutions as it increased with an increase in pH from 3 to 12. It was observed that the dye treated with BCS600 and BCL600 attained an equilibrium within 60 and 100 minutes, respectively. The rate of the adsorption process was determined by performing the Lagergren pseudo-first-order and pseudo-second-order kinetics. It was found that dye treated with both BCS600 and BCL600 followed pseudo-second-order kinetics implying the multi-step nature of the adsorption process involving external adsorption and diffusion of dye molecules into the interior of the adsorbents. The data obtained from batch experiments were fitted well with Langmuir and Freundlich isotherms (R² > 0.98) to indicate the multilayer adsorption of dye over the biochar surfaces. The thermodynamic studies revealed that the adsorption process is favourable, spontaneous, and endothermic in nature. Based on the results, the inexpensive and easily available Lantana camara biomass can be used to remove methylene blue dye from wastewater. It can also help in managing the growth of the notorious weed in the environment.

Keywords: adsorption kinetics, biochar, Lantana camara, methylene blue dye, possible mechanism, thermodynamics

Procedia PDF Downloads 115

Authors: Zahid Manzoor, Shaukat Hussain Munawar, Zahid Iqbal, Imran Ahmad Khan, Abdul Aziz, Hafiz Muhammad Qasim

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The present study was aimed to investigate the pharmacokinetics behavior and optimal dosage regimen of danofloxacin in 8 adult healthy buffaloes of local breed (Nili Ravi) following single intravenous administration at the dose of 2.5 mg/kg body weight. Plasma drug concentrations at various time intervals were measured by HPLC method. In vitro plasma protein binding was determined employing the ultrafiltration technique. The distribution and elimination of danofloxacin was rapid, as indicated by the values (Mean±SD) of distribution half-life (t1/2α = 0.25±0.09 hours) and elimination half life (t1/2β = 3.26±0.43 hours), respectively. Volume of distribution at steady state (Vss) was 1.14±0.12 L/kg, displaying its extensive distribution into various body fluids and tissues. The high value of AUC (9.80±2.14 µg/ml.hr) reflected the vast area of the body covered by drug concentration. The mean residence time was noted to be 4.78±0.52 hours. On the basis of pharmacokinetic parameters, a suitable intravenous regimen for danofloxacin in adult buffaloes would be 6.5 mg/kg to be repeated after 12 hours intervals. The present study is the foremost pharmacokinetic study of danofloxacin in the local species which would provide the valueable contribution in the local manufacturing of danofloxacin in Pakistan in future.

Keywords: danofloxacin, pharmacokinetics, plasma protein binding, buffaloes, dosage regimen

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Authors: Fatemeh Saadat Ghareh Bagh, Srimanta Ray, Jerald Lalman

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Lignin, the largest inventory of organic carbon with a high caloric energy value is a major component in woody and non-woody biomass. In pulping mills, a large amount of the lignin is burned for energy. At the same time, the phenolic structure of lignin enables it to be converted to value-added compounds.This study has focused on extracting lignin from black liquor using deep eutectic solvents (DESs). Therefore, three choline chloride (ChCl)-DESs paired with lactic acid (LA) (1:11), oxalic acid.2H₂O (OX) (1:4), and malic acid (MA) (1:3) were synthesized at 90oC and atmospheric pressure. The kinetics of lignin recovery from black liquor using DES was investigated at three moderate temperatures (338, 353, and 368 K) at time intervals from 30 to 210 min. The extracted lignin (acid soluble lignin plus Klason lignin) was characterized by Fourier transform infrared spectroscopy (FTIR). The FTIR studies included comparing the extracted lignin with a model Kraft lignin. The extracted lignin was characterized spectrophotometrically to determine the acid soluble lignin (ASL) [TAPPI UM 250] fraction and Klason lignin was determined gravimetrically using TAPPI T 222 om02. The lignin extraction reaction using DESs was modeled by first-order reaction kinetics and the activation energy of the process was determined. The ChCl:LA-DES recovered lignin was 79.7±2.1% at 368K and a DES:BL ratio of 4:1 (v/v). The quantity of lignin extracted for the control solvent, [emim][OAc], was 77.5+2.2%. The activation energy measured for the LA-DES system was 22.7 KJ mol⁻¹, while the activation energy for the OX-DES and MA-DES systems were 7.16 KJ·mol⁻¹ and 8.66 KJ·mol⁻¹ when the total lignin recovery was 75.4 ±0.9% and 62.4 ±1.4, % respectively.

Keywords: black liquor, deep eutectic solvents, kinetics, lignin

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Authors: Anna Trusek-Holownia, Andrzej Noworyta

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Using an enzyme of known specificity the hydrolysis of protein was carried out in a controlled manner. The aim was to obtain oligopeptides being the so-called active peptides or their direct precursors. An original way of expression of the protein hydrolysis kinetics was introduced. Peptide bonds contained in the protein were recognized as a diverse-quality substrate for hydrolysis by the applied protease. This assumption was positively verified taking as an example the hydrolysis of albumin by thermolysin. Peptide linkages for this system should be divided into at least four groups. One of them is a group of bonds non-hydrolyzable by this enzyme. These that are broken are hydrolyzed at a rate that differs even by tens of thousands of times. Designated kinetic constants were k'F = 10991.4 L/g.h, k'M = 14.83L/g.h, k'S about 10-1 L/g.h for fast, medium and slow bonds, respectively. Moreover, a procedure for unfolding of the protein, conducive to the improved susceptibility to enzymatic hydrolysis (approximately three-fold increase in the rate) was proposed.

Keywords: peptide bond hydrolysis, kinetics, enzyme specificity, biologically active peptides

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Authors: Divya Vats, Sanjay Mahajani

Abstract:

The clarification of sugarcane juice plays a pivotal role in the production of non-centrifugal sugar (NCS), profoundly influencing the quality of the final NCS product. In this study, we have investigated the kinetics and mathematical modeling of the batch clarification process. The turbidity of the clarified cane juice (NTU) emerges as the determinant of the end product’s color. Moreover, this parameter underscores the significance of considering other variables as performance indicators for accessing the efficacy of the clarification process. Temperature-controlled experiments were meticulously conducted in a laboratory-scale batch mode. The primary objective was to discern the essential and optimized parameters crucial for augmenting the clarity of cane juice. Additionally, we explored the impact of pH and flocculant loading on the kinetics. Particle Image Velocimetry (PIV) is employed to comprehend the particle-particle and fluid-particle interaction. This technique facilitated a comprehensive understanding, paving the way for the subsequent multiphase computational fluid dynamics (CFD) simulations using the Eulerian-Lagrangian approach in the Ansys fluent. Impressively, these simulations accurately replicated comparable velocity profiles. The final mechanism of this study helps to make a mathematical model and presents a valuable framework for transitioning from the traditional batch process to a continuous process. The ultimate aim is to attain heightened productivity and unwavering consistency in product quality.

Keywords: non-centrifugal sugar, particle image velocimetry, computational fluid dynamics, mathematical modeling, turbidity

Procedia PDF Downloads 49