Simulation Reveals the Chameleonic Behavior of Macrocycles.

Conformational analysis is central to the design of bioactive molecules. It is particularly challenging for macrocycles due to noncovalent transannular interactions, steric interactions, and ring strain that are often coupled. Herein, we simulated the conformations of five macrocycles designed to express a progression of increasing complexity in environment-dependent intramolecular interactions and verified the results against NMR measurements in chloroform and dimethyl sulfoxide. Molecular dynamics using an explicit solvent model, but not the Monte Carlo method with implicit solvation, handled both solvents correctly. Refinement of conformations at the ab initio level was fundamental to reproducing the experimental observations─standard state-of-the-art molecular mechanics force fields were insufficient. Our simulations correctly predicted the intramolecular interactions between side chains and the macrocycle and revealed an unprecedented solvent-induced conformational switch of the macrocyclic ring. Our results provide a platform for the rational, prospective design of molecular chameleons that adapt to the properties of the environment.

Design of need-based phosphors and scintillators by compositional modulation in the ZnGa2-xAlxO4:Cr3+ spinel: pure compound versus solid solutions.

Materials that can depict persistent deep red light under both ultraviolet (UV) and X-ray illumination can be a boon to sustainable economy, particularly for optical imaging, solid state lighting, and anticounterfeiting applications. Herein, we have made a series of compounds starting from ZnGa2O4:Cr3+ to ZnAl2O4:Cr3+ (individual spinel) by substituting the varied concentration of Al3+ in place of Ga3+ in ZnGa2-xAlxO4:Cr3+ (solid solution). By virtue of the structural and defect engineering doping strategy, the photo and radioluminescence are expected to be improved. Both Cr and Al doping was found to be energetically favorable in ZnGa2O4, where the same does not hold true for Ga doping in ZnAl2O4, as indicated by the DFT-calculated defect formation energies. There seems to be ordering around the dopant ion in the solid solutions compared to either ZnGa2O4 or ZnAl2O4 and is also reflected to as lower persistent luminescence (PerL) lifetimes. PerL under UV, in general. was found to be lower with the enhancement in the Al3+ content endowed by the formation of Cr-Cr ion pair, lower probability of antisite formation, and widening band gap. On the other hand, X-ray excited emission enhances in the solid solution due to the decrease in cation inversion and associated defects. Confocal Microscopy showed that larger particles depicted much brighter deep red emission but failed to percolate to the human cells to a detectable limit; hence, future work is needed for the functionalization of the ZnGa2-xAlxO4:Cr3+ spinel. This work could be of great implication in designing need-based materials, where UV and X-ray excitation is required, for deep red emission with persistent characteristics from chromium-doped spinels.

Tandem Ring Opening/Intramolecular [2 + 2] Cycloaddition Reaction for the Synthesis of Cyclobutane Fused Thiazolino-2-Pyridones.

Reaction of thiazoline fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generates N-alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via a [2 + 2] cycloaddition between an in situ generated allene and the α,ß-unsaturated methyl ester. This method enabled the synthesis of a variety of cyclobutane fused thiazolino-2-pyridones, of which a few analogues inhibit amyloid ß1-40 fibril formation. Furthermore, other analogues were able to bind mature α-synuclein and amyloid ß1-40 fibrils. Several thiazoline fused 2-pyridones with biological activity tolerate this transformation, which in addition provides an exocyclic alkene as a potential handle for tuning bioactivity.

K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones.

We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones via K2S2O8-mediated oxidative coupling of 6-amino-7-(aminomethyl)-thiazolino-2-pyridones with aldehydes. The developed protocol is mild, has wide substrate scope, and does not require transition metal catalyst or base. Some of the synthesized compounds have an ability to inhibit the formation of Amyloid-ß fibrils associated with Alzheimer's disease, while others bind to mature amyloid-ß and α-synuclein fibrils.

Drug Syntheses Beyond the Rule of 5.

Drugs in the chemical space beyond the rule of 5 (bRo5) can modulate targets with difficult binding sites while retaining cell permeability and oral absorption. Reviewing the syntheses of bRo5 drugs approved since 1990 highlights synthetic chemistry's contribution to drug discovery in this space. Initially, bRo5 drugs were mainly natural products and semi-synthetic derivatives. Later, peptidomimetics and de novo designed compounds, that include up to seven chiral centres and macrocyclic rings became dominant. These drugs are prepared by total synthesis, sometimes by routes of more than 25 steps with stereocentres originating from the chiral pool, or being installed by chiral induction or enzymatic resolution. Interestingly, ring-closing metathesis proved to be the method of choice for macrocyclisation in hepatitis C virus protease inhibitors. We conclude that structural simplification, planning of synthetic routes regarding incorporation of stereocentres and macrocyclisation, as well as incorporation of structural knowledge and consideration of chameleonic properties in design, should facilitate drug discovery in bRo5 space.

Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine Fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-ß Fibrils.

A BF3·OEt2 catalyzed intramolecular Povarov reaction was used to synthesize 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with several O-alkylated salicylaldehydes and amino functionalized thiazolino-2-pyridones, to generate polyheterocycles with diverse substitution. The synthesized compounds were screened for their ability to bind α-synuclein and amyloid ß fibrils in vitro. Analogues substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group.

Airway Management in an Infant with a Large Supraglottic Mass after Failed Fiberoptic Intubation.

BACKGROUND: Fiberoptic bronchoscope-guided tracheal intubation is the gold standard for managing patients with supraglottic growths. In infants with a large and overhanging epiglottis, the success of fiberoptic-guided intubation relies heavily on the available space between the inferior surface of the epiglottis and the posterior pharyngeal wall or, more specifically, the superior surface of the supraglottic growth. CASE REPORT: We describe the inability to negotiate the tip of the fiberscope between the epiglottis and the supraglottic growth and the successful use of direct laryngoscopy to improve the available space along with the usefulness of "bubbling of air" to locate the glottic opening in an infant. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: We emphasize the role of the emergency physician in managing such patients. Most of the time, the setting is not ideal in such emergency situations and the most qualified clinician to treat them is the emergency physician. The knowledge and skills of the emergency physician, along with awareness of the possible techniques for airway management, can be lifesaving.

Avenues of decarbonisation in the dynamics of processed food supply chains: Towards responsible production consumption.

Nowadays, the demand for processed food items is surging. To fulfil the enhanced demand, a significant impact is laid on the environment, which enhances the carbon footprint being generated. Hence, to overcome this, the avenues of decarbonisation need to be explored. The presented work is aimed at promoting the decarbonisation of the existing practices within the processed food supply chains. It finds strong compliance with the sustainable development goal (SDG-12), focusing on responsible production-consumption mechanisms. For the same, key enactors of decarbonisation are identified and mapped with the practices at various stages of food supply chains, i.e. upstream, downstream, and other allied practices. Based upon these enactors, a relational, hierarchical framework is developed to provide a comprehensive perspective on complex intricacies. This framework is analysed with an innovative approach which comprises the fundamentals of Interval-Valued Intuitionistic Hesitant Fuzzy Set with the Entropy measures. It results in the outranking of the enactors relative to its importance in the decarbonisation of processed food supply chains. Furthermore, the empirical findings are validated by the sensitivity analysis to felicitate robust decision-making. The outcomes of the presented work provide a roadmap and stepped approach to achieve the decarbonisation goals and make production-consumption mechanisms sustainable. It finds implications in the development of the framework, policy formulation, and decisional attributes for the decarbonisation of food supply chains. It focuses on the adoption of strategies that align with global efforts to mitigate climate change and promote a sustainable future.

A silicon photomultiplier based compact gamma spectrometer for environmental gamma radiation monitoring networks.

In this paper, the details of the development and performance characterisation of a compact, low-power gamma spectrometer for environmental gamma radiation monitoring networks are presented. To reduce the power consumption and the size of the spectrometer, a gamma detector comprising a silicon photomultiplier coupled to a Gd3Ga3Al2O12:Ce,B (GGAG:Ce,B) scintillator has been used for gamma spectrometry. Initially, a Monte Carlo simulation study was carried out to verify the suitability of the 5 mm × 5 mm × 5 mm GGAG:Ce,B crystal for spectrometry of gamma sources in the energy range 60-1332 keV. For minimising the power consumption, the signal processing electronics has been custom designed. This electronics was realised using standard off-the-shelf components to reduce the cost. The developed spectrometer is of size 16 cm × 10 cm × 6 cm, weighs 600 g and consumes 600 mW power. The spectrometer is developed such that it could be directly interfaced with GSM/Xbee for wireless communication with the radiation monitoring networks. The lower-level discriminator threshold of the system is 40 keV and the total electronic noise is <20 keV. The experimentally measured sensitivity of the spectrometer for 137Cs (662 keV) is 2.4 cps/µGy/h at 3.5 V overvoltage. The spectrometer offers excellent linearity over the measured energy range of 60-1332 keV and an energy resolution of ~10% for 662 keV gamma-ray at room temperature.

Harvesting Light from BaHfO3/Eu3+ through Ultraviolet, X-ray, and Heat Stimulation: An Optically Multifunctional Perovskite.

Materials with optical multifunctionality such as photoluminescence (PL), radioluminescence, and thermoluminescence (TL) are a boon for a sustainable society. BaHfO3 (barium hafnium oxide [BHO]) under UV irradiation demonstrated visible PL endowed by oxygen vacancies (OVs). Eu3+ doping in BHO (BHOE) introduces f-state impurity levels just below the conduction band for both Eu@Ba and Eu@Hf sites, causing efficient host-to-dopant energy transfer, generating intense 5D0 → 7F1 magnetic dipole transitions (MDT) with internal quantum yield of ∼70%. X-ray photoelectron spectroscopy and electron paramagnetic resonance showed the formation of OVs in both BHO and BHOE samples with more vacancies in the doped sample. The positron lifetime measurements suggested that Eu3+ ions are distributed at both Ba2+ and Hf4+ sites. The association of OVs with Hf4+ and Eu3+ ions due to high charge/radius ratio is considered to be responsible for lowering the symmetry around Eu3+ ions to C 4v in BHOE. Density functional theory studies of defect formation energy justified the same. Time-resolved emission spectroscopy showed distinct spectra for Eu@Ba and Eu@Hf sites corresponding to symmetric and asymmetric environments, respectively. This could be highly relevant in designing color tunable phosphor by forcing dopant ions at one specific site because Eu@Ba displayed orange emission whereas Eu@Hf displayed red emission. We could further harness BHOE for X-ray scintillator application by designing a thin film, which showed efficient conversion of high-energy X-ray into visible light. Under beta irradiation; both BHO and BHOE showed distinct TL glow curves as shallow traps were formed in the former and deep traps in the latter, which could have long-term implications in harnessing this material for persistent luminescence. We believe that BHO/BHOE demonstrated an extraordinary credential as a perovskite for multifunctional applications in the area of defect-induced light emission, UV phosphor, X-ray scintillator, and TL crystals.

An environmental gamma spectrometry system with CsI(Tl) scintillator and FPGA based MCA for open field deployment.

Inorganic scintillator-based gamma spectrometry is typically carried out under laboratory conditions by using systems that require AC mains supply and dedicated computers for their operation. In this study, an in-house grown CsI(Tl) single crystal scintillator is optically coupled to a bialkali photomultiplier tube (PMT). The output of the PMT is fed to a pulse processing chain consisting of a preamplifier followed by an in-house designed and developed field programmable gate array (FPGA) based multichannel analyzer (MCA). Spectral data from this MCA is sent via serial communication to a microcontroller. A global system for mobile communications (GSM) modem transmits this data in the form of short message service (SMS) packets to a central receiving station, where the spectrum is reconstructed. The requirement of on-site data logging computer to store large spectral data has thereby been eliminated, which, in turn, has eliminated the requirement of AC power supply, reduced the overall power consumption and size of the system, and made it possible to develop a standalone solar-powered unit. For further reduction of overall power consumption, the spectrometer is turned-on only when a Geiger Mueller (GM) counter based gross gamma detection circuit, also included in the system, detects an ambient gamma dose rate beyond a pre-set threshold level. A mathematical methodology has also been implemented for restoration of recorded spectra, shifted due to temperature variations in the environment. All these features have been integrated and a standalone, solar-powered and battery operated field-deployable environmental gamma spectrometry system (EGSS) has been developed and tested for open field deployment. Presence of 41Ar in ambient air was successfully detected by the system.

Mining Natural Products for Macrocycles to Drug Difficult Targets.

Lead generation for difficult-to-drug targets that have large, featureless, and highly lipophilic or highly polar and/or flexible binding sites is highly challenging. Here, we describe how cores of macrocyclic natural products can serve as a high-quality in silico screening library that provides leads for difficult-to-drug targets. Two iterative rounds of docking of a carefully selected set of natural-product-derived cores led to the discovery of an uncharged macrocyclic inhibitor of the Keap1-Nrf2 protein-protein interaction, a particularly challenging target due to its highly polar binding site. The inhibitor displays cellular efficacy and is well-positioned for further optimization based on the structure of its complex with Keap1 and synthetic access. We believe that our work will spur interest in using macrocyclic cores for in silico-based lead generation and also inspire the design of future macrocycle screening collections.

Significant applications of virtual reality for COVID-19 pandemic.

BACKGROUND AND AIMS: During COVID-19 pandemic, researchers are using innovative technologies for fast-tracking the development to end this menace. Virtual Reality (VR) also offers an imperative role for fighting this pandemic, through audiovisual-based virtual communication. METHODS: A brief study on Virtual Reality and its applications for the COVID-19 pandemic is carried out by employing keywords as Virtual reality or VR and COVID-19 from the databases of SCOPUS, Google Scholar, PubMed, Web of science Academia and ResearchGate. RESULTS: VR is beneficial for remote sites for exploring telemedicine, planning, treatment, and controlling of the infections by providing proper awareness to the people regarding this disease. CONCLUSIONS: VR technology develops a platform to reduce the face to face interaction of doctors with the infected COVID-19 patients. Through live video streaming, it helps to improve surveillance systems on the ongoing situation.

Effect of doping concentration on spectroscopic and structural properties of Nd:NaY(WO(4))(2) crystal.

The optical and structural properties of NaNd(x)Y(1-x)(WO(4))(2) (NYW) single crystals grown from melt containing 1-10 at. % of Nd have been investigated. Optical absorption, photoluminescence, x-ray diffraction, and x-ray florescence studies have been carried out on grown crystals. The crystal is found to exhibit a broad absorption peak of ~16 nm width at 806 nm for 6 at. % of Nd doping. A decrease in fluorescence lifetime from 150 to 80 mus with an increase in Nd(3+) concentration is observed for 1.06 mum emission. Spectroscopic quality parameters (Omega(4)/Omega(6)) and quantum efficiency calculated from the above measurements and application of Judd-Ofelt theory are found to be 1.1 and 68%, respectively. Structural analysis through Rietveld refinement of x-ray diffraction data showed that the oxygen sublattice of NYW is not affected by changes in Nd dopant concentration, though the lattice dimensions are found to increase proportionately. The study for the first time shows that the high doping levels do not introduce any strain into the lattice. As a consequence the optical quality of the crystal does not deteriorate at high doping levels. The selection of doping concentration is therefore solely governed by the decay time requirement for a particular application.

Supramolecular gels from sugar-linked triazole amphiphiles for drug entrapment and release for topical application.

A simple molecular framework obtained by cross-linking a hydrophobic chain with S,S- and R,R-tetritol by the copper-catalysed azide-alkyne cycloaddition reaction is found to serve as an excellent bioisostere for self-assembly. The hexadecyl-linked triazolyl tetritol composite spontaneously self-assembles in n-hepane and methanol to form hierarchical organogels. Microscopic analyses and X-ray diffraction studies demonstrate eventual formation of nanotubes through lamellar assembly of the amphiphiles. A rheological investigation shows solvent-dictated mechanical properties that obey power law behavior similar to other low molecular weight gelators (LMOGs). The gel network was then utilized for the entrapment of drugs e.g. ibuprofen and 5-fluorouracil, with tunable mechanical behaviour under applied stress. The differential release profiles of the drugs over a period of a few hours as a result of the relative spatio-temporal location in the supramolecular network can be utilized for topical formulations.

Toward the Design of Molecular Chameleons: Flexible Shielding of an Amide Bond Enhances Macrocycle Cell Permeability.

A series of macrocycles inspired by natural products were synthesized to investigate how side-chains may shield amide bonds and influence cell permeability. NMR spectroscopy and X-ray crystallography revealed that the phenyl group of phenylalanine, but not the side-chains of homologous or aliphatic amino acids, shields the adjacent amide bond through an intramolecular NH-π interaction. This resulted in increased cell permeability, suggesting that NH-π interactions may be used in the design of molecular chameleons.

High Fidelity Virtual Reality Orthognathic Surgery Simulator.

Surgical simulators are powerful tools that assist in providing advanced training for complex craniofacial surgical procedures and objective skills assessment such as the ones needed to perform Bilateral Sagittal Split Osteotomy (BSSO). One of the crucial steps in simulating BSSO is accurately cutting the mandible in a specific area of the jaw, where surgeons rely on high fidelity visual and haptic cues. In this paper, we present methods to simulate drilling and cutting of the bone using the burr and the motorized oscillating saw respectively. Our method allows low computational cost bone drilling or cutting while providing high fidelity haptic feedback that is suitable for real-time virtual surgery simulation.

Dynamics Determine Signaling in a Multicomponent System Associated with Rheumatoid Arthritis.

Strategies that target multiple components are usually required for treatment of diseases originating from complex biological systems. The multicomponent system consisting of the DR4 major histocompatibility complex type II molecule, the glycopeptide CII259-273 from type II collagen, and a T-cell receptor is associated with development of rheumatoid arthritis (RA). We introduced non-native amino acids and amide bond isosteres into CII259-273 and investigated the effect on binding to DR4 and the subsequent T-cell response. Molecular dynamics simulations revealed that complexes between DR4 and derivatives of CII259-273 were highly dynamic. Signaling in the overall multicomponent system was found to depend on formation of an appropriate number of dynamic intramolecular hydrogen bonds between DR4 and CII259-273, together with the positioning of the galactose moiety of CII259-273 in the DR4 binding groove. Interestingly, the system tolerated modifications at several positions in CII259-273, indicating opportunities to use analogues to increase our understanding of how rheumatoid arthritis develops and for evaluation as vaccines to treat RA.

Improving three-dimensional mechanical imaging of breast lesions with principal component analysis.

PURPOSE: Elastography has emerged as a new tool for detecting and diagnosing many types of diseases including breast cancer. To date, most clinical applications of elastography have utilized two-dimensional strain images. The goal of this paper is to present a new quasi-static elastography technique that yields shear modulus images in three dimensions. METHODS: An automated breast volume scanner was used to acquire ultrasound images of the breast as it was gently compressed. Cross-correlation between successive images was used to determine the displacement within the tissue. The resulting displacement field was filtered of all but compressive motion through principal component analysis. This displacement field was used to infer spatial distribution of shear modulus by solving a 3D elastic inverse problem. RESULTS: Three dimensional shear modulus images of benign breast lesions for two subjects were generated using the techniques described above. It was found that the lesions were visualized more clearly in images generated using the displacement data de-noised through the use of principal components. CONCLUSIONS: We have presented experimental and algorithmic techniques that lead to three-dimensional imaging of shear modulus using quasi-static elastography. This work demonstrates feasibility of this approach, and lays the foundation for images of other, more informative, mechanical parameters.

Organic-Inorganic Composite Films Based on Gd3Ga3Al2O12:Ce Scintillator Nanoparticles for X-ray Imaging Applications.

Organic-inorganic nanocomposite self-standing films of Gd3Ga3Al2O12 (GGAG) uniformly dispersed in poly(methyl methacrylate) (PMMA) and polystyrene polymer are prepared for radiography application. GGAG:Ce nanoscintillator has been chosen because of its high light output and fast decay time. The nanopowder of GGAG is synthesized by coprecipitation method and dispersed in the polymer matrix by a simple blending technique. The nanocomposite films of thickness in the range of 150-450 µm with a very high inorganic content is achieved by this technique. These films are characterized by their uniformity, optical absorption, photoluminescence, and radioluminescence. These films are further tested for their application in radiography by recording X-ray images using a commercially available charge-coupled device camera. A resolution of 10 lp/mm is obtained using GGAG:PMMA composite film with 50% loading, confirming their application in imaging devices.