Fixed-wing MAV attitude stability in atmospheric turbulence, part 1: Suitability of conventional sensors

Fixed-wing Micro-Aerial Vehicles (MAVs) need effective sensors that can rapidly detect turbulence induced motion perturbations. Current MAV attitude control systems rely on inertial sensors. These systems can be described as reactive; detecting the disturbance only after the aircraft has responded to the disturbing phenomena. In this part of the paper, the current state of the art in reactive attitude sensing for fixed-wing MAVs are reviewed. A scheme for classifying the range of existing and emerging sensing techniques is presented. The features and performance of the sensing approaches are discussed in the context of their application to MAV attitude control systems in turbulent environments. It is found that the use of single sensors is insufficient for MAV control in the presence of turbulence and that potential gains can be realised from multi-sensor systems. A successive paper to be published in this journal will investigate novel attitude sensors which have the potential to improve attitude control of MAVs in Turbulenc

Fixed-wing MAV attitude stability in atmospheric turbulence-part 2: Investigating biologically-inspired sensors

Challenges associated with flight control of agile fixed-wing Micro Air Vehicles (MAVs) operating in complex environments is significantly different to any larger scale vehicle. The micro-scale of MAVs can make them particularly sensitive to atmospheric disturbances thus limiting their operation. As described in Part 1, current conventional reactive attitude sensing systems lack the necessary response times for attitude control in high turbulence environments. This paper reviews in greater detail novel and emerging biologically inspired sensors, which can sense the disturbances before a perturbation is induced. A number of biological mechanoreceptors used by flying animals are explored for their utility in MAVs. Man-made attempts of replicating mechanoreceptors have thus been reviewed. Bio-inspired flow and pressure-based sensors were found to be the most promising for complementing or replacing current inertial-based reactive attitude sensors. Achieving practical implementations that meet the size, weight and power constraints of MAVs remains a significant challenge. Biological systems were found to rely on multiple sensors, potentially implying a number of research opportunities in the exploration of heterogeneous bio-inspired sensing solution

Blue biotechnology: Computational screening of sarcophyton cembranoid diterpenes for SARS-CoV-2 main protease inhibition

The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (Mpro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target Mpro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 Mpro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as Mpro inhibitors with ΔGbinding \u3c -33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against Mpro than darunavir with ΔGbinding values of -43.8 and -34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to re-modulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2

Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies

MNK-2 and PIM-2 kinases play an indispensable role in cell proliferation signaling pathways linked to tyrosine kinase inhibitors resistance. In this study, pharmacophore modeling studies have been conducted on the co-crystalized ligands of MNK-2 and PIM-2 enzyme crystal structures to determine the essential features required for the identification of potential dual inhibitors. The obtained pharmacophore features were then screened against a library of 270,540 natural products from the ZINC database. The matched natural molecules were docked into the binding sites of MNK-2 and PIM-2 enzymes. The compounds with high docking scores with the two enzymes were further subjected to MM-GBSA calculations and ADME prediction. This led to the identification of compound 1 (ZINC000085569211), compound 2 (ZINC000085569178), and compound 3 (ZINC000085569190), with better docking scores compared to the reference co-crystallized ligands of MNK-2 and PIM-2. Moreover, compounds 1‒3 displayed better MM-GBSA binding free energies compared to the reference ligands. Finally, molecular dynamics (MD) study was used to assess the interaction stability of the compounds with MNK-2. To this end, compounds 1 and 3 bound strongly to the target during the whole period of MD simulation. The findings of the current study may further help the researchers in the discovery of novel molecules against MNK-2 and PIM-2

Integrating computational methods guided the discovery of phytochemicals as potential Pin1 inhibitors for cancer: pharmacophore modeling, molecular docking, MM-GBSA calculations and molecular dynamics studies

Pin1 is a pivotal player in interactions with a diverse array of phosphorylated proteins closely linked to critical processes such as carcinogenesis and tumor suppression. Its axial role in cancer initiation and progression, coupled with its overexpression and activation in various cancers render it a potential candidate for the development of targeted therapeutics. While several known Pin1 inhibitors possess favorable enzymatic profiles, their cellular efficacy often falls short. Consequently, the pursuit of novel Pin1 inhibitors has gained considerable attention in the field of medicinal chemistry. In this study, we employed the Phase tool from Schrödinger to construct a structure-based pharmacophore model. Subsequently, 449,008 natural products (NPs) from the SN3 database underwent screening to identify compounds sharing pharmacophoric features with the native ligand. This resulted in 650 compounds, which then underwent molecular docking and binding free energy calculations. Among them, SN0021307, SN0449787 and SN0079231 showed better docking scores with values of −9.891, −7.579 and −7.097 kcal/mol, respectively than the reference compound (−6.064 kcal/mol). Also, SN0021307, SN0449787 and SN0079231 exhibited lower free binding energies (−57.12, −49.81 and −46.05 kcal/mol, respectively) than the reference ligand (−37.75 kcal/mol). Based on these studies, SN0021307, SN0449787, and SN0079231 showed better binding affinity that the reference compound. Further the validation of these findings, molecular dynamics simulations confirmed the stability of the ligand-receptor complex for 100 ns with RMSD ranging from 0.6 to 1.8 Å. Based on these promising results, these three phytochemicals emerge as promising lead compounds warranting comprehensive biological screening in future investigations. These compounds hold great potential for further exploration regarding their efficacy and safety as Pin1 inhibitors, which could usher in new avenues for combating cancer

Unlocking the potential of approved drugs for the allosteric inhibition of tropomyosin-receptor kinase A using molecular docking and molecular dynamics studies

Tropomyosin-receptor kinase A (TrkA) is the primary isoform among the tropomyosin-receptor kinases that have been associated with human cancer development, contributing to approximately 7.4% of all cancer cases. TrkA represents an attractive target for cancer treatment; however, currently available TrkA inhibitors face limitations in terms of resistance development and potential toxicity. Hence, the objective of this study was to identify new allosteric-approved inhibitors of TrkA that can overcome these challenges and be employed in cancer therapy. To achieve this goal, a screening of 9,923 drugs from the ChEMBL database was conducted to assess their repurposing potential using molecular docking. The top 49 drug candidates, exhibiting the highest docking scores (−11.569 to −7.962 kcal/mol), underwent MM-GBSA calculations to evaluate their binding energies. Delanzomib and tibalosin, the top two drugs with docking scores of −10.643 and −10.184 kcal/mol, respectively, along with MM-GBSA dG bind values of −67.96 and −50.54 kcal/mol, were subjected to 200 ns molecular dynamic simulations, confirming their stable interactions with TrkA. Based on these findings, we recommend further experimental evaluation of delanzomib and tibalosin to determine their potential as allosteric inhibitors of TrkA. These drugs have the potential to provide more effective and less toxic therapeutic alternatives. The approach employed in this study, which involves repurposing drugs through molecular docking and molecular dynamics, serves as a valuable tool for identifying novel drug candidates with distinct therapeutic uses. This methodology can contribute to reducing the attrition rate and expediting the process of drug discovery

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Development and flight testing of a turbulence mitigation system for micro air vehicles

There are significant challenges associated with the flight control of fixed-wing micro air vehicles (MAVs) operating in complex environments. The scale of MAVs makes them particularly sensitive to atmospheric disturbances thus limiting their ability to sustain controlled flight. Bio-inspired, phase-advanced sensors have been identified as promising sensory solutions for complementing current inertial-only attitude sensors. This paper describes the development and flight testing of a bio-inspired, phase-advanced sensor and associated control system that mitigates the impact of turbulence on MAVs. Multihole pressure probes, inspired by the sensory function of bird feathers, are used to measure the flow pitch angle and velocity magnitude ahead of the MAV's wing. The sensors provide information on the disturbing phenomena before it causes an inertial response in the aircraft. The sensor output is input to a simple feed-forward control architecture, which enables the MAV to generate a mitigating response to the turbulence. The results from wind-tunnel and outdoor testing in high levels of turbulence are presented. The disturbance rejection performance of the phase-advanced sensory system is compared against that of a conventional inertial-based control system. The developed sensory system shows significant improvement in terms of disturbance rejection performance compared to that of standard inertial-only control system. It is concluded that a phase-advanced sensory systems can complement conventional inertial-based sensors to improve the attitude-tracking performance of MAVs

The influence of turbulence on MAV roll perturbations

There are significant challenges in the control of fixed-wing Micro Air Vehicles (MAVs) in high turbulence environments. Birds can sustain stable flight in such environments by obtaining flow information through mechanoreceptors embedded in their wings. Inspired by nature's flyers, an investigation into replicating the function of mechanoreceptors with commercially available pressure sensors is presented. Implementation requires an indepth understanding of the level of correlation that exists between pressure variations over the wing and the roll perturbation of the MAV. This paper investigates the variation in correlation and coherence along a representative wing-chord and wing-span of a MAV. Highest correlation and coherence is found to exist in the vicinity of the leading edge, with significant perturbations which are evident up to ~35Hz for a 0.49m wingspan MAV

Synthesis of Benzimidazole Derived Chalcones and their Heterocyclic Derivatives

A number of benzimidazole derivatives were prepared via the condensation reaction of o-phenylene diamine with various aromatic carboxylic acids in the presence of hydrochloric acid. The acetylated benzimidazoles then allowed to react with benzaldehyde derivatives to give chalcones. In order to achieve the final heterocyclic compounds those chalcones were treated with hydroxylamine hydrochloride, hydrazine hydrate and thiourea through Claisen-Schmidt condensation. The structure of all synthesized compounds were established by physical and spectral methods