94 research outputs found

    Synthesis, anticancer activity, molecular docking and molecular dynamics studies of some pyrazole–chalcone hybrids

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    Four new hybrid compounds (H1–H4) bearing pyrazole (S1 and S2) and chalcone (P1 and P2) fragments were synthesized and characterized. Compounds were assayed for their ability to inhibit the proliferation of human lung (A549) and colon (Caco-2) cancer cell lines. Besides, toxicity against normal cells was determined using the human umbilical vein endothelial cells (HUVEC). In silico molecular docking, molecular dynamics (MD) simulation and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were carried out to predict the binding modes, protein stability, drug-likeness and toxicity of the reported compounds. The in vitro anticancer activity of the tested compounds revealed dose-dependent cell-specific cytotoxicity. In silico studies revealed that the compounds have a good binding affinity, possess appropriate drug-likeness properties and have low toxicity profiles. Communicated by Ramaswamy H. Sarma</p

    Reduction of handover delay in WiMAX for high mobility

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    In emerging technologies, WiMAX is identified as a cheaper replacement to mobile and wireless technologies such as 3G, 4G or any other future generation technologies and can provide highspeed data transfer over long distances and at suitable Quality of Service (QoS) at high mobility. WiMAX requires support and capacity for high mobility to avoid the loss of quality of service. The goal of faster mobility can be achieved, but WiMAX needs the support of an effective handover mechanism to ensure continuous and without any interruption in data transfer. This thesis focusses to solve the handover problem in mobile WiMAX (IEEE 802.16e and IEEE802.16m) and to find and identify the factors which directly affect the handover process. There is a range of factors which can affect the mobility process in Mobile WiMAX. The acceptable handover delay is 50 ms as per IEEE WiMAX standards (Radio-Electronics.com, 2012). This study has identified that there is a total of 16 factors which have direct and indirect effect but after detailed simulation and analysis, it has been found out that only 7 factors could be used to improve handover delay in WiMAX and that’s why the initial RIVERBED simulations tried to identify the extent of these factors which directly affect the handover delay in WiMAX. The following parameters that are directly linked to the handover success are identified are as follows: a) Link goes down faster b) Scan iteration c) Interleaving Interval d) Timeout Parameter e) Frame Duration f) Client Timeout g) Scan Duration The simulation experiments on individual factors has identified that these factors result in a minimum handover delay at specific values which are called best performing values. When these best performing values of the 7 factors were applied to single WiMAX experiment, the improvement was identified, which showed that there have been better handover delay results due to the better-received signal strength, better average delay per Second and the throughput was drastically improved. There was further need to improve the handover decisions and therefor handover algorithm was used for this purpose. The handover algorithm used was a dual trigger algorithm which improved the handover delay, but resulted in packet loss and consequently resulted in retransmissions. To solve to problem of handover delay without downgrading the WiMAX signal, a new algorithm was suggested and tested which has shown results in lowering the handover delay and increasing the signal level. The handover improvement was done in stages and therefore there was a gradual improvement in handover delay in each individual stage. The overall problem has been divided into stages considering that the solution is dependent on many factors. The development of the WiMAX model is the main issue in this research. Different types of scenarios were adopted on RIVERBED simulations to produce significant data for analysis and validation

    Molecular Modeling and Synthesis of Indoline-2,3-dione-Based Benzene Sulfonamide Derivatives and Their Inhibitory Activity against α‑Glucosidase and α‑Amylase Enzymes

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    Diabetes is also known as a critical and noisy disease. Hyperglycemia, that is, increased blood glucose level is a common effect of uncontrolled diabetes, and over a period of time can cause serious effects on health such as blood vessel damage and nervous system damage. However, many attempts have been made to find suitable and beneficial solutions to overcome diabetes. Considering this fact, we synthesized a novel series of indoline-2,3-dione-based benzene sulfonamide derivatives and evaluated them against α-glucosidase and α-amylase enzymes. Out of the synthesized sixteen compounds (1–16), only three compounds showed better results; the IC50 value was in the range of 12.70 ± 0.20 to 0.90 ± 0.10 μM for α-glucosidase against acarbose 11.50 ± 0.30 μM and 14.90 ± 0.20 to 1.10 ± 0.10 μM for α-amylase against acarbose 12.20 ± 0.30 μM. Among the series, only three compounds showed better inhibitory potential such as analogues 11 (0.90 ± 0.10 μM for α-glucosidase and 1.10 ± 0.10 μM for α-amylase), 1 (1.10 ± 0.10 μM for α-glucosidase and 1.30 ± 0.10 μM for α-amylase), and 6 (1.20 ± 0.10 μM for α-glucosidase and 1.60 ± 0.10 μM for α-amylase). Molecular modeling was performed to determine the binding affinity of active interacting residues against these enzymes, and it was found that benzenesulfonohydrazide derivatives can be indexed as suitable inhibitors for diabetes mellitus

    Table_1_Xanthine oxidase inhibitory study of eight structurally diverse phenolic compounds.DOCX

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    This project was designed to explore the xanthine oxidase (XO) inhibitory mechanism of eight structurally diverse phenolic compounds [quercetin: C1, quercetin-3-rhamnoside: C2, 4, 5-O-dicaffeoylquinic acid: C3, 3, 5-O-dicaffeoylquinic acid: C4, 3, 4-O-di-caffeoylquinic acid: C5, 4-O-caffeoylquinic acid (C6), 3-O-caffeoylquinic acid: C7, and caffeic acid: C8]. For this purpose, in-vitro and different computational methods were applied to determine the xanthine oxidase (XO) inhibitory potential of eight structurally diverse phenolic compounds. The results revealed that phenolic compounds (C1–C8) possess strong to weak XO inhibitory activity. These results were further confirmed by atomic force microscopy (AFM) and 1H NMR analysis. Furthermore, computational study results revealed that phenolic compounds (C1–C8) bind with the surrounding amino acids of XO at the molybdenum (MO) site. These in-vitro and in-silico results divulge that phenolic compounds have a strong potential to lower uric acid levels via interacting with the XO enzyme and can be used to combat hyperuricemia.</p

    DataSheet1_The Long-Term Efficacy of “Social Buffering” in Artificial Social Agents: Contextual Affective Perception Matters.ZIP

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    In dynamic (social) environments, an affective state of “stress” can be adaptive and promote agent wellbeing, but maladaptive if not appropriately regulated. The presence of (and interactions with) affect-based social support has been hypothesised to provide mechanisms to regulate stress (the “social buffering” hypothesis), though the precise, underlying mechanisms are still unclear. However, the hormone oxytocin has been implicated in mediating these effects in at least two ways: by improving social appraisals and reducing the short-term release of stress hormones (i.e., cortisol), and adapting an agent’s long-term stress tolerance. These effects likely facilitate an agent’s long-term adaptive ability by grounding their physiological and behavioural adaptation in the (affective) social environment, though these effects also appear to be context-dependent. In this paper, we investigate whether two of the hypothesised hormonal mechanisms that underpin the “social buffering” phenomenon affect the long-term wellbeing of (artificial) social agents who share affective social bonds, across numerous social and physical environmental contexts. Building on previous findings, we hypothesise that “social buffering” effects can improve the long-term wellbeing of agents who share affective social bonds in dynamic environments, through regular prosocial interactions with social bond partners. We model some of the effects associated with oxytocin and cortisol that underpin these hypothesised mechanisms in our biologically-inspired, socially-adaptive agent model, and conduct our investigation in a small society of artificial agents whose goal is to survive in challenging environments. Our results find that, while stress can be adaptive and regulated through affective social support, long-term behavioural and physiological adaptation is determined by the contextual perception of affective social bonds, which is influenced by early-stage interactions between affective social bond partners as well as the degree of the physical and social challenges. We also show how these low-level effects associated with oxytocin and cortisol can be used as “biomarkers” of social support and environmental stress. For socially-situated artificial agents, we suggest that these “social buffering” mechanisms can adapt the (adaptive) stress mechanisms, but that the long-term efficacy of this adaptation is related to the temporal dynamics of social interactions and the contextual perception of the affective social and physical environments.</p

    Image1_The Long-Term Efficacy of “Social Buffering” in Artificial Social Agents: Contextual Affective Perception Matters.PNG

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    In dynamic (social) environments, an affective state of “stress” can be adaptive and promote agent wellbeing, but maladaptive if not appropriately regulated. The presence of (and interactions with) affect-based social support has been hypothesised to provide mechanisms to regulate stress (the “social buffering” hypothesis), though the precise, underlying mechanisms are still unclear. However, the hormone oxytocin has been implicated in mediating these effects in at least two ways: by improving social appraisals and reducing the short-term release of stress hormones (i.e., cortisol), and adapting an agent’s long-term stress tolerance. These effects likely facilitate an agent’s long-term adaptive ability by grounding their physiological and behavioural adaptation in the (affective) social environment, though these effects also appear to be context-dependent. In this paper, we investigate whether two of the hypothesised hormonal mechanisms that underpin the “social buffering” phenomenon affect the long-term wellbeing of (artificial) social agents who share affective social bonds, across numerous social and physical environmental contexts. Building on previous findings, we hypothesise that “social buffering” effects can improve the long-term wellbeing of agents who share affective social bonds in dynamic environments, through regular prosocial interactions with social bond partners. We model some of the effects associated with oxytocin and cortisol that underpin these hypothesised mechanisms in our biologically-inspired, socially-adaptive agent model, and conduct our investigation in a small society of artificial agents whose goal is to survive in challenging environments. Our results find that, while stress can be adaptive and regulated through affective social support, long-term behavioural and physiological adaptation is determined by the contextual perception of affective social bonds, which is influenced by early-stage interactions between affective social bond partners as well as the degree of the physical and social challenges. We also show how these low-level effects associated with oxytocin and cortisol can be used as “biomarkers” of social support and environmental stress. For socially-situated artificial agents, we suggest that these “social buffering” mechanisms can adapt the (adaptive) stress mechanisms, but that the long-term efficacy of this adaptation is related to the temporal dynamics of social interactions and the contextual perception of the affective social and physical environments.</p

    DataSheet1_New quinoline-based triazole hybrid analogs as effective inhibitors of α-amylase and α-glucosidase: Preparation, in vitro evaluation, and molecular docking along with in silico studies.docx

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    The 7-quinolinyl-bearing triazole analogs were synthesized (1d–19d) and further assessed in vitro for their inhibitory profile against α-amylase andα-glucosidase. The entire analogs showed a diverse range of activities having IC50 values between 0.80 ± 0.05 µM to 40.20 ± 0.70 µM (α-amylase) and 1.20 ± 0.10 µM to 43.30 ± 0.80 µM (α-glucosidase) under the positive control of acarbose (IC50 = 10.30 ± 0.20 µM) (IC50 = 9.80 ± 0.20 µM) as the standard drug. Among the synthesized scaffolds, seven scaffolds 12d, 10d, 8d, 9d, 11d, 5d, and 14d showed excellent α-amylase and α-glucosidase inhibitory potentials with IC50 values of 4.30 ± 0.10, 2.10 ± 0.10, 1.80 ± 0.10, 1.50 ± 0.10, 0.80 ± 0.05, 5.30 ± 0.20, and 6.40 ± 0.30 µM (against α-amylase) and 3.30 ± 0.10, 2.40 ± 0.10, 1.20 ± 0.10, 1.90 ± 0.10, 8.80 ± 0.20, 7.30 ± 0.40, and 5.50 ± 0.10 µM (against α-glucosidase), respectively, while the remaining 12 scaffolds 19d, 8d, 17d, 16d, 15d, 7d, 4d, 3d, 1d, 2d, 13d and 6 d showed less α-amylase and α-glucosidase inhibitory potentials than standard acarbose but still found to be active. Structure–activity connection studies also showed that scaffolds with electron-withdrawing groups like -Cl, -NO2, and -F linked to the phenyl ring had higher inhibitory potentials for -amylase and -glucosidase than scaffolds with -OCH3, -Br, and -CH3 moieties. In order to better understand their binding sites, the powerful scaffolds 11d and 9d were also subjected to molecular docking studies. The results showed that these powerful analogs provide a number of important interactions with the active sites of both of these targeted enzymes, including conventional hydrogen bonding, pi–pi stacking, pi–sulfur, pi–anion, pi–pi, pi–sigma, T-shaped, and halogen (fluorine). Furthermore, various techniques (spectroscopic), including 1H, 13C-NMR, and HREI-MS mass, were used to explore the correct structure of newly afforded hybrid scaffolds based on quinoline-bearing triazole ring.</p

    Toxicoproteomic assessment of liver responses to acute pyrrolizidine alkaloid intoxication in rats

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    <p>A toxicoproteomic study was performed on liver of rats treated with retrorsine (RTS), a representative hepatotoxic pyrrolizidine alkaloid at a toxic dose (140 mg/kg) known to cause severe acute hepatotoxicity. By comparing current data with our previous findings in mild liver lesions of rats treated with a lower dose of RTS, seven proteins and three toxicity pathways of vascular endothelial cell death, which was further verified by observed sinusoidal endothelial cell losses, were found uniquely associated with retrorsine-induced hepatotoxicity. This toxicoproteomic study of acute pyrrolizidine alkaloid intoxication lays a foundation for future investigation to delineate molecular mechanisms of pyrrolizidine alkaloid-induced hepatotoxicity.</p

    Circulating tumour-derived DNA in metastatic soft tissue sarcoma.

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    Following treatment 40% of soft tissue sarcoma (STS) patients suffer disease recurrence. In certain cancers circulating cell free DNA (cfDNA) and circulating tumour-derived DNA (ctDNA) characteristics correlate closely with disease burden, making them exciting potential sources of biomarkers. Despite this, the circulating nucleic acid characteristics of only 2 STS patients have been reported to date. To address this we used an Ion AmpliSeq™ panel custom specifically designed for STS patients to conduct a genetic characterisation of plasma cfDNA, buffy coat (germline) DNA and where available Formalin-Fixed Paraffin-Embedded (FFPE) primary STS tissue DNA in a cohort of 11 metastatic STS patients. We found that total cfDNA levels were significantly elevated in the STS patients analysed, and weakly correlated with disease burden. Using our Ion AmpliSeq™ panel we also successfully detected ctDNA in 4/11 (36%) patients analysed with a wide variety of STS subtypes and disease burdens. This evidence included the presence of cancer associated TP53 / PIK3CA mutations in 2 patients' plasma and matched primary STS tumour tissue, and in the plasma alone for 2 patients. We also identified 2 potential examples of allelic loss of heterozygosity in an additional patient's STS DNA and cfDNA. This is the largest study performed characterising STS patient cfDNA/ctDNA and confirms that the field remains an attractive potential source of novel STS biomarkers. Further work is required to investigate the circulating nucleic acid characteristics of individual STS subtypes, and the potential prognostic or therapeutic roles that cfDNA/ctDNA may hold for patients with these complex tumours
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