All-Atom Molecular Dynamics Simulations Indicated the Involvement of a Conserved Polar Signaling Channel in the Activation Mechanism of the Type I Cannabinoid Receptor.

The type I cannabinoid G protein-coupled receptor (CB1, GPCR) is an intensely investigated pharmacological target, owing to its involvement in numerous physiological functions as well as pathological processes such as cancers, neurodegenerative diseases, metabolic disorders and neuropathic pain. In order to develop modern medications that exert their effects through binding to the CB1 receptor, it is essential to understand the structural mechanism of activation of this protein. The pool of atomic resolution experimental structures of GPCRs has been expanding rapidly in the past decade, providing invaluable information about the function of these receptors. According to the current state of the art, the activity of GPCRs involves structurally distinct, dynamically interconverting functional states and the activation is controlled by a cascade of interconnecting conformational switches in the transmembrane domain. A current challenge is to uncover how different functional states are activated and what specific ligand properties are responsible for the selectivity towards those different functional states. Our recent studies of the µ-opioid and ß2-adrenergic receptors (MOP and ß2AR, respectively) revealed that the orthosteric binding pockets and the intracellular surfaces of these receptors are connected through a channel of highly conserved polar amino acids whose dynamic motions are in high correlation in the agonist- and G protein-bound active states. This and independent literature data led us to hypothesize that, in addition to consecutive conformational transitions, a shift of macroscopic polarization takes place in the transmembrane domain, which is furnished by the rearrangement of polar species through their concerted movements. Here, we examined the CB1 receptor signaling complexes utilizing microsecond scale, all-atom molecular dynamics (MD) simulations in order to see if our previous assumptions could be applied to the CB1 receptor too. Apart from the identification of the previously proposed general features of the activation mechanism, several specific properties of the CB1 have been indicated that could possibly be associated with the signaling profile of this receptor.

Universal Properties and Specificities of the ß2-Adrenergic Receptor-Gs Protein Complex Activation Mechanism Revealed by All-Atom Molecular Dynamics Simulations.

G protein-coupled receptors (GPCRs) are transmembrane proteins of high pharmacological relevance. It has been proposed that their activity is linked to structurally distinct, dynamically interconverting functional states and the process of activation relies on an interconnecting network of conformational switches in the transmembrane domain. However, it is yet to be uncovered how ligands with different extents of functional effect exert their actions. According to our recent hypothesis, based on indirect observations and the literature data, the transmission of the external stimulus to the intracellular surface is accompanied by the shift of macroscopic polarization in the transmembrane domain, furnished by concerted movements of highly conserved polar motifs and the rearrangement of polar species. In this follow-up study, we have examined the ß2-adrenergic receptor (ß2AR) to see if our hypothesis drawn from an extensive study of the µ-opioid receptor (MOP) is fundamental and directly transferable to other class A GPCRs. We have found that there are some general similarities between the two receptors, in agreement with previous studies, and there are some receptor-specific differences that could be associated with different signaling pathways.

Correlated Motions of Conserved Polar Motifs Lay out a Plausible Mechanism of G Protein-Coupled Receptor Activation.

Recent advancements in the field of experimental structural biology have provided high-resolution structures of active and inactive state G protein-coupled receptors (GPCRs), a highly important pharmaceutical target family, but the process of transition between these states is poorly understood. According to the current theory, GPCRs exist in structurally distinct, dynamically interconverting functional states of which populations are shifted upon binding of ligands and intracellular signaling proteins. However, explanation of the activation mechanism, on an entirely structural basis, gets complicated when multiple activation pathways and active receptor states are considered. Our unbiased, atomistic molecular dynamics simulations of the µ opioid receptor (MOP) revealed that transmission of external stimulus to the intracellular surface of the receptor is accompanied by subtle, concerted movements of highly conserved polar amino acid side chains along the 7th transmembrane helix. This may entail the rearrangement of polar species and the shift of macroscopic polarization in the transmembrane domain, triggered by agonist binding. Based on our observations and numerous independent indications, we suggest amending the widely accepted theory that the initiation event of GPCR activation is the shift of macroscopic polarization between the ortho- and allosteric binding pockets and the intracellular G protein-binding interface.

Low-noise, high-detectivity, polarization-sensitive, room-temperature infrared photodetectors based on Ge quantum dot-decorated Si-on-insulator nanowire field-effect transistors.

A CMOS-compatible infrared (IR; 1200-1700 nm) detector based on Ge quantum dots (QDs) decorated on a single Si-nanowire channel on a silicon-on-insulator (SOI) platform with a superior detectivity at room temperature is presented. The spectral response of a single nanowire device measured in a back-gated field-effect transistor geometry displays a very high value of peak detectivity ∼9.33 × 1011Jones at ∼1500 nm with a relatively low dark current (∼20 pA), which is attributed to the fully depleted Si nanowire channel on SOI substrates. The noise power spectrum of the devices exhibits a1/fγ,with the exponent,γshowing two different values of 0.9 and 1.8 owing to mobility fluctuations and generation-recombination of carriers, respectively. Ge QD-decorated nanowire devices exhibit a novel polarization anisotropy with a remarkably high photoconductive gain of ∼104. The superior performance of a Ge QDs/Si nanowire phototransistor in IR wavelengths is potentially attractive to integrate electro-optical devices into Si for on-chip optical communications.

Graphene-Based Nanomaterials for Flexible and Stretchable Batteries.

Recently, as flexible and wearable electronic devices have become widely popular, research on light weight and large-capacity batteries suitable for powering such devices has been actively conducted. In particular, graphene has attracted considerable attention from researchers in the battery field owing to its good mechanical properties and its applicability in various processes to fabricate electrodes for batteries. Graphene is classified into two types: flake-type, fabricated from graphite, and film-type, synthesized using chemical vapor deposition. The unique processes involved in these two types enable the fabrication of flexible and stretchable batteries with various shapes and functions. In this article, the recent progress in the development of flexible and stretchable batteries based on graphene, as well as its important technical issues are reviewed.

Design, Synthesis and Functional Analysis of Cyclic Opioid Peptides with Dmt-Tic Pharmacophore.

The opioid receptors are members of the G-protein-coupled receptor (GPCR) family and are known to modulate a variety of biological functions, including pain perception. Despite considerable advances, the mechanisms by which opioid agonists and antagonists interact with their receptors and exert their effect are still not completely understood. In this report, six new hybrids of the Dmt-Tic pharmacophore and cyclic peptides, which were shown before to have a high affinity for the µ-opioid receptor (MOR) were synthesized and characterized pharmacologically in calcium mobilization functional assays. All obtained ligands turned out to be selective antagonists of the δ-opioid receptor (DOR) and did not activate or block the MOR. The three-dimensional structural determinants responsible for the DOR antagonist properties of these analogs were further investigated by docking studies. The results indicate that these compounds attach to the DOR in a slightly different orientation with respect to the Dmt-Tic pharmacophore than Dmt-TicΨ[CH2-NH]Phe-Phe-NH2 (DIPP-NH2[Ψ]), a prototypical DOR antagonist peptide. Key pharmacophoric contacts between the DOR and the ligands were maintained through an analogous spatial arrangement of pharmacophores, which could provide an explanation for the predicted high-affinity binding and the experimentally observed functional properties of the novel synthetic ligands.

Unraveling the stability of plasma proteins upon interaction of synthesized uridine products: biophysical and molecular dynamics approach.

Most of the drugs binding to human serum albumin (HSA) are transported to various parts of the body. Here, we have studied the molecular interaction between HSA and synthesized uridine derivatives, 1-[(3R, 4S, 5 R)-2-methyl-3, 4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dion.)(C-MU); [(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl] methyl methyl phosphochloridate (CM-MU) and [(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-2-methyl-3,4-dihydroxyoxolan-2-yl] methyl dihydrogen phosphate (P-MU). Cytotoxic studies of these synthesized compounds with mouse macrophages (RAW 246.7) and HeLa cells (human cervical cancer cells) and binding mechanism of these uridine derivatives with HSA were performed. Subsequently, fluorescence quenching was observed upon titration of uridine derivatives with HSA via static mode of quenching, and the binding constants (K2-C-MU = 4 ± 0.03 × 104M-1, K5-CM-MU = 1.95 ± 0.03 × 104 M-1 and K5-P-MU =1.56 ± 0.03 × 104 M-1) were found to be in sync with the computational results. Further, molecular displacement and molecular docking data revealed that all the derivatives are binding in the subdomain IIA and IIB regions of HSA. The protein secondary structure of complexes was determined by circular dichroism, indicating partial unfolding of the protein upon addition of the uridine derivatives. Furthermore, atomic force microscopy data reveal the change in topology upon binding of 2-C-MU, 5-CM-MU and 5-P-MU with HSA, indicating change in the microenvironment around tryptophan region. Additionally, cytotoxicity studies on HeLa and Raw Cell lines suggested that these molecules have significant anti-proliferative and anti-inflammatory properties. Hence, the study may be of help for development of new drugs based on uridine derivatives which may be helpful for combating various potential diseases.Communicated by Ramaswamy H. Sarma.

Superior optical (λ ∼ 1550 nm) emission and detection characteristics of Ge microdisks grown on virtual Si0.5Ge0.5/Si substrates using molecular beam epitaxy.

We report the optical characteristics of relatively large sized (∼7.0-8.0 µm) but low aspect ratio Ge microdisks grown on a virtual Si0.5Ge0.5 substrate using molecular beam epitaxy following the Stranski-Krastanov growth mechanism. Grown microdisks with very low aspect ratio Ge islands exhibit direct band gap (∼0.8 eV) photoluminescence emission sustainable up to room temperature, enabled by the confinement of carriers into the microdisks. p-i-n diodes with an intrinsic layer containing Ge microdisks have been fabricated to study their emission and photoresponse characteristics at an optical communication wavelength of ∼1550 nm. A strong electroluminescence at 1550 nm has been achieved at low temperatures in the device for a very low threshold current density of 2.56 µA cm-2 due to the strong confinement of injected holes. The emission characteristics of the fabricated device with respect to the injected current density and temperature have been studied. Novel emission and optical modulation characteristics at 1550 nm of the fabricated p-i-n device containing Ge microdisks grown on a virtual SiGe substrate indicate its potential for Si CMOS compatible on-chip optical communications.

Photoresponse characteristics of MoS2 QDs/Si nanocone heterojunctions utilizing geometry controlled light trapping mechanism in black Si.

A unique light trapping mechanism associated with nano-conical textured black Si templates has been utilized to achieve improved photoresponse in MoS2QDs/Si heterojunctions over a wide wavelength range from visible to near infrared. Black Si templates have been fabricated by a simple and cost effective metal assisted chemical etching technique followed by spin-coating of colloidal MoS2 quantum dots (QDs) to form the heterojunction. A peak responsivity of as high as ∼1.39 A W-1 at ∼665 nm for a bias of 5 V has been achieved. The responsivity value is higher as compared to recently published results having similar device structure. The combination of MoS2 QDs and black Si has resulted in a broader spectral response with enhanced optical absorption in the nano-conical heterojunction devices. Finite element based optical simulation results revealed the superiority of MoS2 QDs/Si nano-conical heterojunctions due to improved light trapping. The results appear attractive for next generation Si CMOS compatible broad band photodetectors using two dimensional semiconductors.

Extraction of levetiracetam for therapeutic drug monitoring by transdermal reverse iontophoresis.

Recently, transdermal reverse iontophoresis across the skin has been investigated as a novel technology for the purpose of diagnosis as well as therapeutic drug monitoring. Accordingly, the objective of this study was to investigate ex vivo and in vivo transdermal extraction of levetiracetam, an antiepileptic drug, across the pig ear skin by reverse iontophoresis. Reverse iontophoresis experiments were performed using three chambered diffusion cells. Extractions profiles were generated in phosphate buffers at different current intensities, pH and ionic strength as well donor drug concentrations. This was followed by ex vivo extraction in gels and in vivo extractions using New Zealand rabbits. Results indicate that levetiracetam was extracted at both anode and cathode. Flux values were unaffected by increase in current intensities (0.5 mA and 0.6 mA) but affected by pH and ionic strength. Neither in cathodal nor in anodal extraction, flux values did show a proportional relationship with the donor drug concentration. At low and medium concentration levels, flux values did not show any major change but the extraction flux at high donor concentration was much higher. In contrast, in vivo experiment with rabbits resulted in wide variation of fluxes with very high fluxes recorded at the cathodal end. Reasons attributed to this difference may include lower current intensity, and species variation. The most significant finding of this study is that measurable amounts of the levetiracetam were extracted at both the ends indicating its feasibility for non-invasive drug monitoring.

P-type ß-MoO2 nanostructures on n-Si by hydrogenation process: synthesis and application towards self-biased UV-visible photodetection.

We report on the synthesis and UV-vis photodetection application of p-type MoO2 nanostructures (NSs) on Si substrate. ß-MoO2 NSs have been synthesized from previously grown α-MoO3 structures/n-type Si via a hydrogenation process at 450 °C. After hydrogenation, the α-MoO3 structures were completely converted into ß-MoO2 NSs without the presence of sub-oxidized phases of molybdenum oxide. The as-grown NSs exhibited very good p-type electrical conductivity of ≈2.02 × 103 S-cm-1 with hole mobility of ≈7.8 ± 1.3 cm2-V-1-Sec-1. To explore optoelectronic properties of p-type ß-MoO2 NSs, we have fabricated a p-MoO2/n-Si heterojunction photodetector device with Au as the top and Al as the bottom contacts. The device exhibits peak photoresponsivity of ≈0.155 A W-1 with maximum detectivity ≈1.28 × 1011 cm-Hz1/2-W-1 and 44% external quantum efficiency around ≈436 nm, following the highest photoresponse (I ph/I d ≈ 6.4 × 102) and good response speed (rise time ∼29 ms and decay time ∼38 ms) at -1.5 V. Importantly, this device also shows good self-powered high-speed (rise time ∼47 ms and decay time ∼70 ms) photodetection performance with peak responsivity and detectivity of ≈45 mA W-1 and ≈4.05 × 1010 cm-Hz1/2-W-1, respectively. This broadband UV-visible light detection feature can be attributed to the coordinated effects of MoO2 band-edge absorption, interfacial defects and self absorption in Si. The photodetection behavior of the device has been understood by proposed energy-band diagrams with the help of an experimentally derived work function, band gap and valence band maximum position of MoO2 NSs.

Trinuclear Lanthanide Coordination Clusters: Single-Molecule-Magnet Behavior and Catalytic Activity in the Friedel-Crafts Alkylation Reaction.

A new multidentate ligand (H3 L) was synthesized by the condensation reaction of 4-tert-butyl-2,6-diformylphenol and 2-amino-4-nitrophenol. The reaction of the ligand with hydrated lanthanide nitrate produced two isostructural trinuclear coordination clusters: [DyLn3 L3 (DMF)3 (H2 O)2 ] ⋅ 3.8DMFLn=Dy (1) and Nd (2) (DMF=N, N-dimethylformamide). Single-crystal X-ray diffraction analysis revealed that there are three lanthanide ions arranged in an almost perfect linear fashion in both complexes. Magnetic studies show single-molecule-magnet (SMM) behavior in the Dy derivative with τ0 =1.7×10-6 s and a thermal energy barrier of 7.0 cm-1 . Both complexes were used as catalysts towards the Friedel-Crafts alkylation reaction of indole with different aldehydes with yields varying from 59-98 %. Complex 1 showed better catalytic efficiency than complex 2. This is the first report of using trinuclear lanthanide coordination clusters as catalysts for the Friedel-Crafts alkylation reaction.

Elucidating the active interaction mechanism of phytochemicals withanolide and withanoside derivatives with human serum albumin.

Withania somnifera (Ashwagandha) is an efficient medicinal plant known in Ayurveda and Chinese medicine since ancient times, whose extracts are consumed orally as food supplement or as a health tonic owing to its several restorative properties for various CNS disorders, inflammation, tumour, stress, rheumatism etc. In this study, we have analyzed the binding interaction of four derivatives of Withania somnifera (Withanolide A, Withanolide B, Withanoside IV and Withanoside V) with HSA because of their important pharmacological properties. To unravel the binding between derivatives of Withania somnifera and HSA, fluorescence spectroscopy was used. Binding studies were further studied by molecular docking and dynamics and results confirmed greater stability upon binding of derivatives with HSA. Circular dichroism data illustrated change in the secondary structure of protein upon interaction with these derivatives, particularly the helical structure was increased and ß-sheets and random coils were decreased. Furthermore, morphological and topological changes were observed using AFM and TEM upon binding of ligands with HSA indicating that HSA-withnoside/withanolide complexes were formed. All the results cumulatively demonstrate strong binding of withanosides and withanolides derivatives with serum albumin, which should further be explored to study the pharmacokinetics and pharmacodynamics of these derivatives.

Aerosol, a health hazard during ultrasonic scaling: A clinico-microbiological study.

CONTEXT: Ultrasonic scaling is a routinely used treatment to remove plaque and calculus from tooth surfaces. These scalers use water as a coolant which is splattered during the vibration of the tip. The splatter when mixed with saliva and plaque of the patients causes the aerosol highly infectious and acts as a major risk factor for transmission of the disease. In spite of necessary protection, sometimes, the operator might get infected because of the infectious nature of the splatter. AIM: To evaluate the aerosol contamination produced during ultrasonic scaling by the help of microbiological analysis. MATERIALS AND METHODS: This clinico-microbiological study consisted of twenty patients. Two agar plates were used for each patient; the first was kept at the center of the operatory room 20 min before the treatment while the second agar plate was kept 40 cm away from the patient's chest during the treatment. Both the agar plates were sent for microbiological analysis. STATISTICAL ANALYSIS: The statistical analysis was done with the help of STATA 11.0 (StataCorp. 2013. Stata Statistical Software, Release 13. College Station, TX: StataCorp LP, 4905 Lakeway Drive College Station, Texas, USA). Statistical software was used for data analysis and the P < 0.001 was considered to be statistically significant. RESULTS: The results for bacterial count were highly significant when compared before and during the treatment. The Gram staining showed the presence of Staphylococcus and Streptococcus species in high numbers. CONCLUSIONS: The aerosols and splatters produced during dental procedures have the potential to spread infection to dental personnel. Therefore, proper precautions should be taken to minimize the risk of infection to the operator.

Hydrodynamic interactions of deformable polymeric nanocarriers and the effect of crosslinking.

We report theoretical as well as numerical investigations of deformable nanocarriers (NCs) under physiologically relevant flow conditions. Specifically, to model the deformable lysozyme-core/dextran-shell crosslinked polymer based NC with internal nanostructure and subject it to external hydrodynamic shear, we have introduced a coarse-grained model for the NC and have adopted a Brownian dynamics framework, which incorporates hydrodynamic interactions, in order to describe the static and dynamic properties of the NC. In order to represent the fluidity of the polymer network in the dextran brush-like corona, we coarse-grain the structure of the NC based on the hypothesis that Brownian motion, polymer melt reptations, and crosslinking density dominate their structure and dynamics. In our model, we specify a crosslinking density and employ the simulated annealing protocol to mimic the experimental synthesis steps in order to obtain the appropriate internal structure of the core-shell polymer. We then compute the equilibrium as well as steady shear rheological properties as functions of the Péclet number and the crosslinking density, in the presence of hydrodynamic interactions. We find that with increasing crosslinking, the stiffness of the nanocarrier increases, the radius of gyration decreases, and as a consequence the self-diffusivity increases. The nanocarrier under shear deforms and orients along the direction of the applied shear and we find that the orientation and deformation under shear are dependent on the shear rate and the crosslinking density. We compare various dynamic properties of the NC as a function of the shear force, such as orientation, deformation, intrinsic stresses etc., with previously reported computational and experimental results of other model systems. The computational approach described here serves as a powerful tool for the rational design of NCs by taking both the physiological as well as the hydrodynamic environments into consideration. Development of such models is essential in order to gain useful insights that may be translated into the optimal design of NCs for diagnostic as well as targeted drug delivery applications.

Gingival Biotype Assessment in a Healthy Periodontium: Transgingival Probing Method.

BACKGROUND: Gingival biotype is the thickness of the gingiva in the faciopalatal dimension. It has a significant impact on the outcome of the restorative, regenerative and implant therapy. It has been suggested that a direct co-relation exists with the susceptibility of gingival recession followed by any surgical procedure. So, the study was aimed to assess gingival biotype in different age groups of males and females using transgingival probing method. MATERIALS AND METHODS: Gingival thickness (GT) was evaluated in 336 patients including males and females of different age groups. The latter was based on the transparency of the periodontal probe through the gingival margin while probing the buccal sulcus. Final data collected was then used for statistical analysis. RESULTS: A significant difference was found between males and females with males showing thick biotype. Out of the total samples 76.9% of males showed thick biotype compared to 13.3 % of females which was statistically significant. CONCLUSION: This was probably one of the few attempts to correlate gingival biotype with different age groups in males and females. A clear thick gingiva was found in more than two-third of the male subjects whereas majority of female subjects showed thin biotype. Also, it was seen that in females, the gingival biotype varies with age unlike in male.

Asymptotic analysis of stresses near a crack tip in a two-dimensional colloidal packing saturated with liquid.

The consolidation of colloidal particles in drying colloidal dispersions is influenced by various factors such as particle size and shape, and interparticle potential. The capillary pressure induced by the menisci, formed between the top layer of particles in the packed bed, compresses the bed of particles while the constraints imposed by the boundaries result in tensile stresses in the packing. Presence of flaws or defects in the bed determines its ultimate strength under such circumstances. In this study, we determine the asymptotic stress distribution around a flaw in a two-dimensional colloidal packing saturated with liquid and compare the results with those obtained from the full numerical solution of the problem. Using the Griffith's criterion for equilibrium cracks, we relate the critical capillary pressure at equilibrium to the crack size and the mechanical properties of the packed bed. The analysis also gives the maximum allowable flaw size for obtaining a crack-free packing.

Consolidation of charged colloids during drying.

We consider the drying of latex dispersions containing submicrometer-sized particles dispersed in water. It is well known that the consolidation of colloidal particles is influenced by a number of factors such as particle size and shape and interparticle potential. In this work, we focus on the effect of surface charge on the consolidation front. Recent experimental and theoretical investigations on the sedimentation of charged colloidal spheres have shown that the large mass difference between noninteracting colloids and ions sets up a macroscopic electric field, thereby enhancing the diffusivity of the particles and resulting in an inflated sedimentation profile. Our experimental measurements of the concentration profile during drying-induced consolidation also reveal similar charge effects. We present a model for the consolidation of charged particles that accounts for the presence of an induced external electric field. As expected, the predicted particle diffusivity is enhanced by the onset of the electric field at low particle concentration. Fluorescence and bright-field microscopy were used to detect the particle concentration variation in a dispersion dried in a capillary, and the measured profile agrees with the prediction confirming the influence of particle charge on consolidation.