Molecular Modeling Studies to Probe the Binding Hypothesis of Novel Lead Compounds against Multidrug Resistance Protein ABCB1.

The expression of drug efflux pump ABCB1/P-glycoprotein (P-gp), a transmembrane protein belonging to the ATP-binding cassette superfamily, is a leading cause of multidrug resistance (MDR). We previously curated a dataset of structurally diverse and selective inhibitors of ABCB1 to develop a pharmacophore model that was used to identify four novel compounds, which we showed to be potent and efficacious inhibitors of ABCB1. Here, we dock the inhibitors into a model structure of the human transporter and use molecular dynamics (MD) simulations to report the conformational dynamics of human ABCB1 induced by the binding of the inhibitors. The binding hypotheses are compared to the wider curated dataset and those previously reported in the literature. Protein-ligand interactions and MD simulations are in good agreement and, combined with LipE profiling, statistical and pharmacokinetic analyses, are indicative of potent and selective inhibition of ABCB1

Impact of today\u27s media on university student\u27s body image in Pakistan: a conservative, developing country\u27s perspective

Background: Living in a world greatly controlled by mass media makes it impossible to escape its pervading influence. As media in Pakistan has been free in the true sense of the word for only a few years, its impact on individuals is yet to be assessed. Our study aims to be the first to look at the effect media has on the body image of university students in a conservative, developing country like Pakistan. Also, we introduced the novel concept of body image dissatisfaction as being both negative and positive. Methods: A cross-sectional study was conducted among 7 private universities over a period of two weeks in the city of Karachi, Pakistan\u27s largest and most populous city. Convenience sampling was used to select both male and female undergraduate students aged between 18 and 25 and a sample size of 783 was calculated. Results: Of the 784 final respondents, 376 (48%) were males and 408 (52%) females. The mean age of males was 20.77 (+/-1.85) years and females was 20.38 (+/-1.63) years. Out of these, 358 (45.6%) respondents had a positive BID (body image dissatisfaction) score while 426 (54.4%) had a negative BID score. Of the respondents who had positive BID scores, 93 (24.7%) were male and 265 (65.0%) were female. Of the respondents with a negative BID score, 283 (75.3%) were male and 143 (35.0%) were female. The results for BID vs. media exposure were similar in both high and low peer pressure groups. Low media exposure meant positive BID scores and vice versa in both groups (p \u3c 0.0001) showing a statistically significant association between high media exposure and negative body image dissatisfaction. Finally, we looked at the association between gender and image dissatisfaction. Again a statistically significant association was found between positive body image dissatisfaction and female gender and negative body image dissatisfaction and male gender (p \u3c 0.0001). Conclusions: Our study confirmed the tendency of the media to have an overall negative effect on individuals\u27 body image. A striking feature of our study, however, was the finding that negative body image dissatisfaction was found to be more prevalent in males as compared to females. Likewise, positive BID scores were more prevalent amongst females

Blockchain-based DDoS attack mitigation protocol for device-to-device interaction in smart homes

Smart home devices are vulnerable to a variety of attacks. The matter gets more complicated when a number of devices collaborate to launch a colluding attack (e.g. Distributed-Denial-of-Service (DDoS)) in a network (e.g., Smart home). To handle these attacks, most studies have hitherto proposed authentication protocols that cannot necessarily be implemented in devices, especially during Device-to-Device (D2D) interactions. Tapping into the potential of Ethereum blockchain and smart contracts, this work proposes a lightweight authentication mechanism that enables safe D2D interactions in a smart home. The Ethereum blockchain enables the implementation of a decentralized prototype as well as a peer-to-peer distributed ledger system. The work also uses a single server queuing system model and the authentication mechanism to curtail DDoS attacks by controlling the number of service requests in the system. The simulation was conducted twenty times, each with varying number of devices chosen at random (ranging from 1 to 30). Each requester device sends an arbitrary request with a unique resource requirement at a time. This is done to measure the system’s consistency across a variety of device capabilities. The experimental results show that the proposed protocol not only prevents colluding attacks, but also outperforms the benchmark protocols in terms of computational cost, message processing, and response time

3D QSAR and pharmacophore studies on inhibitors of insuline like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) as potential anti-cancer agents

Insulin like growth factor receptor (IGF-1R) and Insulin receptor (IR) are widely accepted to play a prominent role in cancer drug discovery due to their well-established involvement in various stages of tumorigenesis. Previously, neutralization of IGF-1R via monoclonal antibodies was in focus, which failed because of compensatory activation of IR-A upon inhibition of IGF-1R. Recent studies have demonstrated high homology between IGF-IR and IR particularly in tyrosine kinase domain and targeting both receptors have produced efficient therapeutic approaches such as inhibition of cancer cell cycle proliferation. Herein, we have made an attempt to analyze the unique data set from different chemical classes, containing potent ATP competitors against tyrosine kinase domain. We performed the 2D, 3D quantitative structure–activity relationship (QSAR) studies on inhibitors of these receptors to predict useful pharmacophoric features. We have optimized virtual screening of structurally diverse data set of dual inhibitors of IGF-1R and IR. Based on QSAR studies, we predict potential novel clinical candidates with a demonstrated absorption, distribution, metabolism, elimination, and toxicology (ADMETox) track. We also demonstrated comprehensive analysis of co–crystal complexes along with their inhibitors and built 3D- GRid INdependent Descriptors (GRIND) model to obtain insightful features such as H-bond donors and acceptors, overall topology and Vander Waal volume (vdw_vol) which are found to be responsible for dual inhibition of receptors. These findings lead to further description that Tirofiban, Practolol, Edoxaban, Novobiocin have potential to perform dual inhibition of both targets

Mixotrophic cultivation of Scenedesmus dimorphus in sugarcane bagasse hydrolysate

Overuse of the fossil fuels to fulfill existing energy requirements has generated various environmental problems like global warming. Emergence of environmental issues due to burning of the fossil fuel resources has provoked researchers to explore alternative sources of fuel. In this scenario, microalgal biofuels could present a promising alternative fuel if produced cost-effectively without competing for freshwater resources and arable land. Aim of the present study was to grow microalgae by employing lignocellulosic waste for production of lipids. Scenedesmus dimorphus NT8c was chosen based on its ability to tolerate heat, rapid growth, and ease of harvesting by overnight settling. Biochemical composition and growth parameters of microalgae were analyzed when cultivated mixotrophically on sugarcane bagasse hydrolysate, a low-value agricultural by-product, that is, currently underutilized. Despite a slight increase in turbidity in the medium, S. dimorphus NT8c cultures raised mixotrophically in 5 g/L sugarcane bagasse hydrolysate displayed significantly higher growth rates compared to photoautotrophic cultivation with an overall biomass productivity of 119.5 mg L d, protein contents of 34.82% and fatty acid contents of 15.41%. Thus, microalgae cultivated mixotrophically are capable of photosynthesizing while metabolizing and assimilating organic carbon, significant increases of biomass and lipid productivity can be achieved. However, high supplementation with organic carbon can result in unfavorable levels of turbidity and bacterial growth, reducing microalgal biomass productivity

Lipid A-Ara4N as an alternate pathway for (colistin) resistance in Klebsiella pneumonia isolates in Pakistan

Objectives: This study aimed to explore mechanism of colistin resistance amongst Klebsiella pneumoniae isolates through plasmid mediated mcr-1 gene in Pakistan. Carbapenem and Colistin resistant K. pneumoniae isolates (n = 34) stored at - 80 °C as part of the Aga Khan University Clinical Laboratory strain bank were randomly selected and subjected to mcr-1 gene PCR. To investigate mechanisms of resistance, other than plasmid mediated mcr-1 gene, whole genome sequencing was performed on 8 clinical isolates, including 6 with colistin resistance (MIC \u3e 4 μg/ml) and 2 with intermediate resistance to colistin (MIC \u3e 2 μg/ml).Results: RT-PCR conducted revealed absence of mcr-1 gene in all isolates tested. Whole genome sequencing results revealed modifications in Lipid A-Ara4N pathway. Modifications in Lipid A-Ara4N pathway were detected in ArnA_ DH/FT, UgdH, ArnC and ArnT genes. Mutation in ArnA_ DH/FT gene were detected in S3, S5, S6 and S7 isolates. UgdH gene modifications were found in all isolates except S3, mutations in ArnC were present in all except S1, S2 and S8 and ArnT were detected in all except S4 and S7. In the absence of known mutations linked with colistin resistance, lipid pathway modifications may possibly explain the phenotype resistance to colistin, but this needs further exploration

Folk Knowledge and Perceptions about the Use of Wild Fruits and Vegetables–Cross-Cultural Knowledge in the Pipli Pahar Reserved Forest of Okara, Pakistan

\ua9 2024 by the authors.Wild fruits and vegetables (WFVs) have been vital to local communities for centuries and make an important contribution to daily life and income. However, traditional knowledge of the use of wild fruits is at risk of being lost due to inadequate documentation. This study aimed to secure this knowledge through intermittent field visits and a semi-structured questionnaire. Using various ethnobotanical data analysis tools and SPSS (IBM 25), this study identified 65 WFV species (52 genera and 29 families). These species, mostly consumed as vegetables (49%) or fruits (43%), were predominantly herbaceous (48%) in wild and semi-wild habitats (67%). 20 WFVs were known to local communities (highest RFC), Phoenix sylvestris stood out as the most utilized species (highest UV). Surprisingly, only 23% of the WFVs were sold at markets. The survey identified 21 unique WFVs that are rarely documented for human consumption in Pakistan (e.g., Ehretia obtusifolia, Euploca strigosa, Brassica juncea, Cleome brachycarpa, Gymnosporia royleana, Cucumis maderaspatanus, Croton bonplandianus, Euphorbia prostrata, Vachellia nilotica, Pongamia pinnata, Grewia asiatica, Malvastrum coromandelianum, Morus serrata, Argemone mexicana, Bambusa vulgaris, Echinochloa colonum, Solanum virginianum, Physalis angulata, Withania somnifera, Zygophyllum creticum, and Peganum harmala), as well as 14 novel uses and five novel edible parts. Despite their ecological importance, the use of WFVs has declined because local people are unaware of their cultural and economic value. Preservation of traditional knowledge through education on conservation and utilization could boost economies and livelihoods in this and similar areas worldwide

Wetting of Ga on SiOx and Its Impact on GaAs Nanowire Growth

Ga-assisted growth of GaAs nanowires on silicon provides a path for integrating high-purity III-Vs on silicon. The nature of the oxide on the silicon surface has been shown to impact the overall possibility of nanowire growth and their orientation with the substrate. In this work, we show that not only the exact thickness, but also the nature of the native oxide determines the feasibility of nanowire growth. During the course of formation of the native oxide, the surface energy varies and results in a different contact angle of Ga droplets. We find that, only for a contact angle around 90 degrees (i.e., oxide thickness similar to 0.9 nm), nanowires grow perpendicularly to the silicon substrate. This native oxide engineering is the first step toward controlling the self-assembly process, determining mainly the nanowire density and orientation