A potent antibiotic-loaded bone-cement implant against staphylococcal bone infections.

New antibiotics should ideally exhibit activity against drug-resistant bacteria, delay the development of bacterial resistance to them and be suitable for local delivery at desired sites of infection. Here, we report the rational design, via molecular-docking simulations, of a library of 17 candidate antibiotics against bone infection by wild-type and mutated bacterial targets. We screened this library for activity against multidrug-resistant clinical isolates and identified an antibiotic that exhibits potent activity against resistant strains and the formation of biofilms, decreases the chances of bacterial resistance and is compatible with local delivery via a bone-cement matrix. The antibiotic-loaded bone cement exhibited greater efficacy than currently used antibiotic-loaded bone cements against staphylococcal bone infections in rats. Potent and locally delivered antibiotic-eluting polymers may help address antimicrobial resistance.

Tuning the Properties of Zero-Field Room Temperature Ferromagnetic Skyrmions by Interlayer Exchange Coupling.

Magnetic materials offer an opportunity to overcome the scalability and energy consumption limits affecting the semiconductor industry. New computational device architectures, such as low-power solid state magnetic logic and memory-in-logic devices, have been proposed which rely on the unique properties of magnetic materials. Magnetic skyrmions, topologically protected quasi-particles, are at the core of many of the newly proposed spintronic devices. Many different materials systems have been shown hosting ferromagnetic skyrmions at room temperature. However, a magnetic field is a key ingredient to stabilize skyrmions, and this is not desirable for applications, due to the poor scalability of active components generating magnetic fields. Here we report the observation of ferromagnetic skyrmions at room temperature and zero magnetic field, stabilized through interlayer exchange coupling (IEC) between a reference magnet and a free magnet. Most importantly, by tuning the strength of the IEC, we are able to tune the skyrmion size and areal density. Our findings are relevant to the development of skyrmion-based spintronic devices suitable for general-use applications which go beyond modern nanoelectronics.

Orbitally dominated Rashba-Edelstein effect in noncentrosymmetric antiferromagnets.

Efficient manipulation of magnetic order with electric current pulses is desirable for achieving fast spintronic devices. The Rashba-Edelstein effect, wherein spin polarization is electrically induced in noncentrosymmetric systems, provides a mean to achieve staggered spin-orbit torques. Initially predicted for spin, its orbital counterpart has been disregarded up to now. Here we report a generalized Rashba-Edelstein effect, which generates not only spin polarization but also orbital polarization, which we find to be far from being negligible. We show that the orbital Rashba-Edelstein effect does not require spin-orbit coupling to exist. We present first-principles calculations of the frequency-dependent spin and orbital Rashba-Edelstein tensors for the noncentrosymmetric antiferromagnets CuMnAs and Mn[Formula: see text]Au. We show that the electrically induced local magnetization can exhibit Rashba-like or Dresselhaus-like symmetries, depending on the magnetic configuration. We compute sizable induced magnetizations at optical frequencies, which suggest that electric-field driven switching could be achieved at much higher frequencies.

Distinct multiple fermionic states in a single topological metal.

Among the quantum materials that have recently gained interest are the topological insulators, wherein symmetry-protected surface states cross in reciprocal space, and the Dirac nodal-line semimetals, where bulk bands touch along a line in k-space. However, the existence of multiple fermion phases in a single material has not been verified yet. Using angle-resolved photoemission spectroscopy (ARPES) and first-principles electronic structure calculations, we systematically study the metallic material Hf2Te2P and discover properties, which are unique in a single topological quantum material. We experimentally observe weak topological insulator surface states and our calculations suggest additional strong topological insulator surface states. Our first-principles calculations reveal a one-dimensional Dirac crossing-the surface Dirac-node arc-along a high-symmetry direction which is confirmed by our ARPES measurements. This novel state originates from the surface bands of a weak topological insulator and is therefore distinct from the well-known Fermi arcs in semimetals.

In silico modelling of azole derivatives with tyrosinase inhibition ability: Application of the models for activity prediction of new compounds.

Tyrosinase is a metal containing multifunctional enzymes found in animals, fruits and vegetables and constitutes the primary cause for diseases resulting from overproduction of melanin as well as for browning of fruits. Inhibitors of the enzyme have thus gained increased importance in food and cosmetic industry. In the present work, a group of azole derivatives with tyrosinase inhibitory activity were explored to analyse the prime structural attributes of the potent inhibitors. In silico models have been developed in order to have a close insight regarding features of the molecular fragments that may affect the activity of the molecules conducively. The biological pharmacophore of the inhibitors that accounts for their interaction with the tyrosinase enzyme has been ascertained based on the development of a 3D pharmacophore model. The models thus developed were subsequently utilised for screening a set of compounds that were previously synthesised in-house and were reported to possess antioxidant activity. The final selection of active molecules in the screening process was done based on the docking interactions of the molecules with the tyrosinase enzyme and assessment of their degree of binding to the protein. Thus the developed models have been successfully utilised for identifying active compounds from a series of untested molecules.

A Comparative Study on Selective PPAR Modulators through Quantitative Structure-activity Relationship, Pharmacophore and Docking Analyses.

BACKGROUND: Metabolic syndrome is a matrix of different metabolic disorders which are the leading cause of death in human beings. Peroxysome proliferated activated receptor (PPAR) is a nuclear receptor involved in metabolism of fats and glucose. OBJECTIVE: In order to explore structural requirements for selective PPAR modulators to control lipid and carbohydrate metabolism, the multi-cheminformatics studies have been performed. METHODS: In silico modeling studies have been performed on a diverse set of PPAR modulators through quantitative structure-activity relationship (QSAR), pharmacophore mapping and docking studies. RESULTS: It is observed that the presence of an amide fragment (-CONHRPh) has a detrimental effect while an aliphatic ether linkage has a beneficial effect on PPARα modulation. On the other hand, the presence of an amide fragment has a positive effect on PPARδ modulation, but the aliphatic ether linkage and substituted aromatic ring in the molecular scaffold are very much essential for imparting potent and selective PPARγ modulation. Negative ionizable features (i.e. polar fragments) must be present in PPARδ and α modulators, but a hydrophobic feature is the prime requirement for PPARγ modulation. CONCLUSION: Here, the essential structural features have been explored for selective modulation of each subtype of PPAR in order to design new modulators with improved activity/selectivity.

Taraxerol, a pentacyclic triterpenoid, from Abroma augusta leaf attenuates diabetic nephropathy in type 2 diabetic rats.

Persistent hyperglycaemia coupled with inflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). Present study examined the therapeutic potential of taraxerol isolated from the methanol extract of Abroma augusta leaf against DN using rodent model of type 2 diabetes (T2D). T2D was experimentally induced by high fat diet and a single low-single dose of streptozotocin (35mg/kg, i.p.). Accumulation of serum creatinine, urea, and uric acid, activation of lactate dehydrogenase and creatinin kinase, and release of urinary albumin represented the glomerular damage and the progression of nephropathy in T2D rats. Taraxerol (20mg/kg, p.o.) treatment significantly reinstated the aforementioned changes in biochemical parameters near to normalcy. Molecular mechanism studies demonstrated an impaired signaling cascade, IRS1/PI3K/Akt/AMPK/GLUT4/GSK3ß, of glucose metabolism in the skeletal muscle and increase in serum levels of pro-inflammatory cytokines, CRP and MCP1 in T2D rats. Activation of polyol pathway, enhanced production of AGEs, up-regulation of NF-κB/PKCs/PARP signaling, and renal fibrosis was also observed in T2D rats. Taraxerol (20mg/kg, p.o.) treatment stimulated glucose metabolism in skeletal muscle, regulated blood glycaemic status and lipid profile in the sera, reduced the secretion of pro-inflammatory cytokines, and restored the renal physiology in T2D rats. Histological assessments were also in agreement with the above findings. Molecular docking study again supported the probable interactions of taraxerol with PKCß, PKCδ, NF-κB, PARP, PI3K, IRS, Akt and AMPK. In silico ADME study predicted the drug-likeness character of taraxerol. Results suggest a possibility of taraxerol to be a new therapeutic agent for DN in future.

Protocatechuic Acid, a Phenolic from Sansevieria roxburghiana Leaves, Suppresses Diabetic Cardiomyopathy via Stimulating Glucose Metabolism, Ameliorating Oxidative Stress, and Inhibiting Inflammation.

Persistent hyperglycemia, impairment of redox status and establishment of inflammatory pathophysiology integrally play important role in the pathogenesis of diabetic cardiomyopathy (DC). Present study examined the therapeutic potential of protocatechuic acid isolated from the Sansevieria roxburghiana rhizomes against DC employing rodent model of type 2 diabetes (T2D). T2D was induced by high fat diet + a low-single dose of streptozotocin (35 mg/kg, i.p.). T2D rats exhibited significantly (p < 0.01) high fasting blood glucose level. Alteration in serum lipid profile (p < 0.01) and increased levels of lactate dehydrogenase (p < 0.01) and creatine kinase (p < 0.01) in the sera of T2D rats revealed the occurrence of hyperlipidemia and diabetic pathophysiology. A significantly (p < 0.01) high levels of serum C-reactive protein and pro-inflammatory mediators revealed the establishment of inflammatory occurrence in T2D rats. Besides, significantly high levels of troponins in the sera revealed the establishment of cardiac dysfunctions in T2D rats. However, protocatechuic acid (50 and 100 mg/kg, p.o.) treatment could significantly reverse the changes in serum biochemical parameters related to cardiac dysfunctions. Molecular mechanism studies demonstrated impairment of signaling cascade, IRS1/PI3K/Akt/AMPK/p 38/GLUT4, in glucose metabolism in the skeletal muscle of T2D rats. Significant (p < 0.01) activation of polyol pathway, enhanced production of AGEs, oxidative stress and up-regulation of inflammatory signaling cascades (PKC/NF-κB/PARP) were observed in the myocardial tissue of T2D rats. However, protocatechuic acid (50 and 100 mg/kg, p.o.) treatment could significantly (p < 0.05-0.01) stimulate glucose metabolism in skeletal muscle, regulated glycemic and lipid status, reduced the secretion of pro-inflammatory cytokines, and restored the myocardial physiology in T2D rats near to normalcy. Histological assessments were also in agreement with the above findings. In silico molecular docking study again supported the interactions of protocatechuic acid with different signaling molecules, PI3K, IRS, Akt, AMPK PKC, NF-κB and PARP, involved in glucose utilization and inflammatory pathophysiology. In silico ADME study predicted that protocatechuic acid would support the drug-likeness character. Combining all, results would suggest a possibility of protocatechuic acid to be a new therapeutic agent for DC in future.

Pharmacoinformatics study of Piperolactam A from Piper betle root as new lead for non steroidal anti fertility drug development.

Fertility control is a burning problem all over the world to regulate population overflow and maintain ecological balance. This study is an in-silico approach to explore a non-steroidal lead as contraceptive agent in order to avoid several contraindications generated by steroidal analogues. Piperolactam A, an aristolactam isolated from Piper betle Linn. showed binding affinity towards estrogen and progesterone receptor as -8.9 and -9.0Kcal/mol (inhibition constant Ki=0.294µM and 0.249µM) respectively which is even larger than that of reported antagonists such as Rohitukine and OrgC (binding affinity -8.7 and -8.4Kcal/mol; Ki 0.443µM and 0.685µM respectively). The binding site exploration displayed more hydrogen bonding of Piperolactam A (His 524, Leu 346, Thr 347) than Rohitukine and OrgC (Leu 718) with associated receptors which was further confirmed by molecular dynamics simulations. The drug-likeliness of the compound has been proved from its tally with Lipinsky's Rule of Five and lowered toxicity such as cardiac toxicity, liver toxicity, mutagenicity and ecological toxicity. Endocrine disruptome and later docking guided molecular simulations revealed that Piperolactam A has weaker binding affinity and/or lower probability of binding with nuclear receptors especially hERG and cytochrome P450. The high Caco-2 permeability suggested more bioavailability hence more therapeutic efficacy of the drug.

Quantitative Analysis of Essential Molecular Features of Coumarin Derivatives with Antioxidant Activity Using Chemometric Tools.

BACKGROUND: The endogeneous antioxidant mechanism often fails to combat the huge free radical overload necessitating external antioxidant supplementation. Thus identification and definite structural manipulation of the naturally available antioxidant derivatives using in silico methodology help to design new moieties with improved therapeutic potential. OBJECTIVE: The present work has been performed with the aim to identify the essential molecular fragments that contribute to the antioxidant property of the coumarin derivatives. METHOD: In this work three separate chemometric methods were utilised to highlight the structural requisites of the coumarin derivatives. RESULTS: The QSAR model thus developed helps to highlight the prime molecular fragments, while the 3D pharmacophore model denotes the features constituting the biological pharmacophore for the coumarin derivatives. Again, the HQSAR contour signifies the relative contribution of the different molecular fragments. CONCLUSION: In silico techniques thus adapted in the present work highlight a significant paradigm in the process of screening and designing therapeutically active antioxidant moieties.

Switching of chiral magnetic skyrmions by picosecond magnetic field pulses via transient topological states.

Magnetic chiral skyrmions are vortex like spin structures that appear as stable or meta-stable states in magnetic materials due to the interplay between the symmetric and antisymmetric exchange interactions, applied magnetic field and/or uniaxial anisotropy. Their small size and internal stability make them prospective objects for data storage but for this, the controlled switching between skyrmion states of opposite polarity and topological charge is essential. Here we present a study of magnetic skyrmion switching by an applied magnetic field pulse based on a discrete model of classical spins and atomistic spin dynamics. We found a finite range of coupling parameters corresponding to the coexistence of two degenerate isolated skyrmions characterized by mutually inverted spin structures with opposite polarity and topological charge. We demonstrate how for a wide range of material parameters a short inclined magnetic field pulse can initiate the reliable switching between these states at GHz rates. Detailed analysis of the switching mechanism revealed the complex path of the system accompanied with the excitation of a chiral-achiral meron pair and the formation of an achiral skyrmion.

Interlayer Exchange Coupling: A General Scheme Turning Chiral Magnets into Magnetic Multilayers Carrying Atomic-Scale Skyrmions.

We report on a general principle using interlayer exchange coupling to extend the regime of chiral magnetic films in which stable or metastable magnetic Skyrmions can appear at a zero magnetic field. We verify this concept on the basis of a first-principles model for a Mn monolayer on a W(001) substrate, a prototype chiral magnet for which the atomic-scale magnetic texture is determined by the frustration of exchange interactions, impossible to unwind by laboratory magnetic fields. By means of ab initio calculations for the Mn/W_{m}/Co_{n}/Pt/W(001) multilayer system we show that for certain thicknesses m of the W spacer and n of the Co reference layer, the effective field of the reference layer fully substitutes the required magnetic field for Skyrmion formation.

KO2: realization of orbital ordering in a p-orbital system.

KO2 is a molecular solid consisting of oxygen dimers. K present in the lattice donates an electron which goes on to occupy the O p levels. As the basic electronic structure is similar to that of an oxygen molecule, except for broadening due to solid state effects, KO2 represents the realization of the doping of oxygen molecules arranged in a lattice. These considerations alone result in magnetism with high ordering temperatures as our calculations reveal. However, we find that the high temperature structure is unstable to an orbital ordering (OO) transition. The microscopic considerations driving the OO transition, however, are electrostatic interactions instead of the often encountered superexchange driven ordering within the Kugel-Khomskii model often used to describe the OO. This OO transition is also found to preclude any possibility of high magnetic ordering temperatures, which otherwise seemed possible.

Can nano silicon be made optically active?

There has been a lot of effort to make Silicon optically active. In this work we examine two methods of generating nanocrystals of Silicon from bulk fragments. This approach of ours allows us to play with the shape of the nanocrystals and therefore the degeneracy of the conduction band minimum. We go on to examine whether similar sized particles with different shapes have the same physical properties, and finally whether Silicon may be rendered optically active by this route. While we do find that similar sized particles with different shapes may have different band gaps, this route of modifying the degeneracy of the conduction band minimum makes nano Si slightly optically active.