Zebrafish studies identify serotonin receptors mediating antiepileptic activity in Dravet syndrome.

Dravet syndrome is a life-threatening early-onset epilepsy not well controlled by antiepileptic drugs. Drugs that modulate serotonin (5-HT) signalling, including clemizole, locaserin, trazodone and fenfluramine, have recently emerged as potential treatment options for Dravet syndrome. To investigate the serotonin receptors that could moderate this antiepileptic activity, we designed and synthesized 28 novel analogues of clemizole, obtained receptor binding affinity profiles, and performed in vivo screening in a scn1lab mutant zebrafish (Danio rerio) model which recapitulates critical clinical features of Dravet syndrome. We discovered three clemizole analogues with 5-HT receptor binding that exert powerful antiepileptic activity. Based on structure-activity relationships and medicinal chemistry-based analysis, we then screened an additional set of known 5-HT receptor specific drug candidates. Integrating our in vitro and in vivo data implicates 5-HT2B receptors as a critical mediator in the mechanism of seizure suppression observed in Dravet syndrome patients treated with 5-HT modulating drugs

Congenital Epulis in a Newborn: A Case Report, Immunoprofiling and Review of Literature

Background: Congenital epulis is a rare lesion of the newborn, presenting as mass in the oral cavity which can interfere with respiration and feeding. It should be distinguished from other lesions which can occur in newborns, both clinically and histopathologically.Case details: Here, we report a case of congenital epulis in a newborn female on the right alveolar ridge, along with an extensive review of literature and discuss the immunoprofiling.Conclusion: Early diagnosis of CE in a newborn is of paramount importance in the successful management of these rare cases.Keywords: congenital epulis, congenital granular cell lesion, Neumann’s tumo

Eye of horus – Erratum revealed a prescription survey

Background: The aim of this study was to survey the quality and the content of prescription of practitioners and also assess the legibility of alphabet, and short form of the drug.Methods: A survey of all prescription received by the patients that were written by general practitioners, consulting physicians and dentists in and around Virajpet and Madikeri (south Coorg) was included.The prescriptions were photocopied and returned back to the patients. The prescription was scored and analyzed by a qualified medical investigator.Results: A total of 171 prescription samples were collected. In most prescriptions, one or more aspects of patient’s personal details were missing. Concerned doctor’s details also lacked in most cases. 40.3% of the prescriptions were obtained wherein short form of the drug was used for prescribing drug. Legibility of alphabet was also evaluated and the most confusing letter noted in our study was letter “C”; followed by A, T, S, O, G, and D in this study the letter Rx was written in 7% of the prescription and in 19% prescription it was replaced by word “Adv” and 74% of prescription without symbol of Rx.Conclusions: The present data shows most prescriptions in the study was inadequate and important details were lacking, legibility of prescription was poor in rating

Relation between land cover parameters and BRDF model coefficients: a case study using MODIS BRDF product over parts of Western India

In this paper, the BRDF data product from Moderate Resolution Imaging ,Spectrometer (MODIS) on EOS is used along with IRS - ID WiFS and IRS ID LISS-III sensors to explore relations between land cover classes, LAI and the BRDF model coefficients. The IRS -ID WiFS data was aggregated to the spatial resolution of MODIS (- l krn) and the three BRDF model parameters corresponding to isotropic, volume and geometric components of surface reflectance for sand, water and crop classes are extracted and analyzed in this study. Using field measurements of LAI carried out at the Central State Farm, Suratgarh, Rajasthan along with LISS-lII image of the same area, an LAI image of the farm was generated and the LA! values were correlated with the three MODIS BRDF model parameters. Small but significant negative correlations (- 0.5) were found between LAI and angle independent isotropic term at both red and near infrared wavelengths and higher significant correlations were observed among the BRDF model coefficients

Niemann–Pick Type C2 Proteins in Aedes aegypti: Molecular Modelling and Prediction of Their Structure–Function Relationships

Aedes aegypti is a major vector that transmits arboviruses through the saliva injected into the host. Salivary proteins help in uninterrupted blood intake and enhance the transmission of pathogens. We studied Niemann–Pick Type C2 (NPC2) proteins, a superfamily of saliva proteins that play an important role in arbovirus infections. In vertebrates, a single conserved gene encodes for the NPC2 protein that functions in cholesterol trafficking. Arthropods, in contrast, have several genes that encode divergent NPC2 proteins. We compared the sequences of 20 A. aegypti NPC2 proteins to the cholesterol-binding residues of human and bovine, and fatty-acid-binding residues of ant NPC2 protein. We identified four mosquito NPC2 proteins as potential sterol-binding proteins. Two of these proteins (AAEL006854 and/or AAEL020314) may play a key role in ecdysteroid biosynthesis and moulting. We also identified one mosquito NPC2 protein as a potential fatty-acid-binding protein. Through molecular modelling, we predicted the structures of the potential sterol- and fatty-acid-binding proteins and compared them to the reference proteins

Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3σ/ERα Protein-Protein Interaction from Nonselective Fragments

The stabilization of protein-protein interactions (PPIs) has emerged as a promising strategy in chemical biology and drug discovery. The identification of suitable starting points for stabilizing native PPIs and their subsequent elaboration into selective and potent molecular glues lacks structure-guided optimization strategies. We have previously identified a disulfide fragment that stabilized the hub protein 14-3-3σ bound to several of its clients, including ERα and C-RAF. Here, we show the structure-based optimization of the nonselective fragment toward selective and highly potent small-molecule stabilizers of the 14-3-3σ/ERα complex. The more elaborated molecular glues, for example, show no stabilization of 14-3-3σ/C-RAF up to 150 μM compound. Orthogonal biophysical assays, including mass spectrometry and fluorescence anisotropy, were used to establish structure-activity relationships. The binding modes of 37 compounds were elucidated with X-ray crystallography, which further assisted the concomitant structure-guided optimization. By targeting specific amino acids in the 14-3-3σ/ERα interface and locking the conformation with a spirocycle, the optimized covalent stabilizer 181 achieved potency, cooperativity, and selectivity similar to the natural product Fusicoccin-A. This case study showcases the value of addressing the structure, kinetics, and cooperativity for molecular glue development. </p

Predicting Hemiwicking Dynamics on Textured Substrates

The ability to predict liquid transport rates on textured surfaces is key to the design and optimization of devices and processes such as oil recovery, coatings, reaction-separation, high-throughput screening, and thermal management. In this work we develop a fully analytical model to predict the propagation coefficients for liquids hemiwicking through micropillar arrays. This is carried out by balancing the capillary driving force and a viscous resistive force and solving the Navier–Stokes equation for representative channels. The model is validated against a large data set of experimental hemiwicking coefficients harvested from the literature and measured in-house using high-speed imaging. The theoretical predictions show excellent agreement with the measured values and improved accuracy compared to previously proposed models. Furthermore, using lattice Boltzmann (LB) simulations, we demonstrate that the present model is applicable over a broad range of geometries. The scaling of velocity with texture geometry, implicit in our model, is compared against experimental data, where good agreement is observed for most practical systems. The analytical expression presented here offers a tool for developing design guidelines for surface chemistry and microstructure selection for liquid propagation on textured surfaces

A fractional K-BKZ constitutive formulation for describing the nonlinear rheology of multiscale complex fluids

The relaxation processes of a wide variety of soft materials frequently contain one or more broad regions of power-law like or stretched exponential relaxation in time and frequency. Fractional constitutive equations have been shown to be excellent models for capturing the linear viscoelastic behavior of such materials, and their relaxation modulus can be quantitatively described very generally in terms of a Mittag–Leffler function. However, these fractional constitutive models cannot describe the nonlinear behavior of such power-law materials. We use the example of Xanthan gum to show how predictions of nonlinear viscometric properties, such as shear-thinning in the viscosity and in the first normal stress coefficient, can be quantitatively described in terms a nonlinear fractional constitutive model. We adopt an integral K-BKZ framework and suitably modify it for power-law materials exhibiting Mittag–Leffler type relaxation dynamics at small strains. Only one additional parameter is needed to predict nonlinear rheology, which is introduced through an experimentally measured damping function. Empirical rules such as the Cox–Merz rule and Gleissle mirror relations are frequently used to estimate the nonlinear response of complex fluids from linear rheological data. We use the fractional model framework to assess the performance of such heuristic rules and quantify the systematic offsets, or shift factors, that can be observed between experimental data and the predicted nonlinear response. We also demonstrate how an appropriate choice of fractional constitutive model and damping function results in a nonlinear viscoelastic constitutive model that predicts a flow curve identical to the elastic Herschel-Bulkley model. This new constitutive equation satisfies the Rutgers-Delaware rule, which is appropriate for yielding materials. This K-BKZ framework can be used to generate canonical three-element mechanical models that provide nonlinear viscoelastic generalizations of other empirical inelastic models such as the Cross model. In addition to describing nonlinear viscometric responses, we are also able to provide accurate expressions for the linear viscoelastic behavior of complex materials that exhibit strongly shear-thinning Cross-type or Carreau-type flow curves. The findings in this work provide a coherent and quantitative way of translating between the linear and nonlinear rheology of multiscale materials, using a constitutive modeling approach that involves only a few material parameters

From Tethered to Freestanding Stabilizers of 14-3-3 Protein-Protein Interactions through Fragment Linking

Small-molecule stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. However, the systematic discovery of PPI stabilizers remains a largely unmet challenge. Herein we report a fragment-linking approach targeting the interface of 14-3-3 and a peptide derived from the estrogen receptor alpha (ERα) protein. Two classes of fragments—a covalent and a noncovalent fragment—were co-crystallized and subsequently linked, resulting in a noncovalent hybrid molecule in which the original fragment interactions were largely conserved. Supported by 20 crystal structures, this initial hybrid molecule was further optimized, resulting in selective, 25-fold stabilization of the 14-3-3/ERα interaction. The high-resolution structures of both the single fragments, their co-crystal structures and those of the linked fragments document a feasible strategy to develop orthosteric PPI stabilizers by linking to an initial tethered fragment.</p

Extensional flow of hyaluronic acid solutions in an optimized micofluidic cross-slot device

We utilize a recently developed microfluidic device, the Optimized Shape Cross-slot Extensional Rheometer (OSCER), to study the elongational flow behavior and rheological properties of hyaluronic acid (HA) solutions representative of the synovial fluid (SF) found in the knee joint. The OSCER geometry is a stagnation point device that imposes a planar extensional flow with a homogenous extension rate over a significant length of the inlet and outlet channel axes. Due to the compressive nature of the flow generated along the inlet channels, and the planar elongational flow along the outlet channels, the flow field in the OSCER device can also be considered as representative of the flow field that arises between compressing articular cartilage layers of the knee joints during running or jumping movements. Full-field birefringence microscopy measurements demonstrate a high degree of localized macromolecular orientation along streamlines passing close to the stagnation point of the OSCER device, while micro-particle image velocimetry is used to quantify the flow kinematics. The stress-optical rule is used to assess the local extensional viscosity in the elongating fluid elements as a function of the measured deformation rate. The large limiting values of the dimensionless Trouton ratio, Tr ∼ O(50), demonstrate that these fluids are highly extensional-thickening, providing a clear mechanism for the load-dampening properties of SF. The results also indicate the potential for utilizing the OSCER in screening of physiological SF samples, which will lead to improved understanding of, and therapies for, disease progression in arthritis sufferers