Dual acting therapeutic proteins for intraocular use

Antibody-based medicines that target vascular endothelial growth factor (VEGF) are administered by intravitreal injection to treat chronic neovascular retinal diseases. Much ongoing effort is focused on enhancing therapeutic outcome of these medicines. One strategy is the use of dual acting drugs (e.g. bispecific antibodies) to simultaneously bind to more than one intraocular biological target. A dual acting molecule targeting components within the vitreal cavity could also potentially extend vitreous residence time. In this review, the applications of bispecific antibodies within the eye are described with consideration to potential targets, applications and suitable bispecific formats

A splitting approach for the fully nonlinear and weakly dispersive Green-Naghdi model

The fully nonlinear and weakly dispersive Green-Naghdi model for shallow water waves of large amplitude is studied. The original model is first recast under a new formulation more suitable for numerical resolution. An hybrid finite volume and finite difference splitting approach is then proposed. The hyperbolic part of the equations is handled with a high-order finite volume scheme allowing for breaking waves and dry areas. The dispersive part is treated with a classical finite difference approach. Extensive numerical validations are then performed in one horizontal dimension, relying both on analytical solutions and experimental data. The results show that our approach gives a good account of all the processes of wave transformation in coastal areas: shoaling, wave breaking and run-up

THE GEOMATICS CONTRIBUTION FOR THE VALORISATION PROJECT IN THE ROCCA OF SAN SILVESTRO LANDSCAPE SITE

This paper proposes an emblematic project where several multi-sensor strategies for spatial data acquisition and management, range based and image based, were combined to create a series of integrated territorial and architectural scale products characterized by a rich multi-content nature. The work presented here was finalized in a test site that is composed by an ensemble of diversified cultural deposits; the objects that were surveyed and modelled range from the landscape with its widespread mining sites, the main tower with its defensive role, the urban configuration of the settlement, the building systems and techniques, a medieval mine. For this reason, the Rocca of San Silvestro represented a perfect test case, due to its complex and multi-stratified character. This archaeological site is a medieval fortified village near the municipality of Campiglia Marittima (LI), Italy. The Rocca is part of an Archaeological Mines Park and is included in the Parchi della Val di Cornia (a system of archaeological parks, natural parks and museums in the south-west of Tuscany). The fundamental role of a deep knowledge about a cultural artefact before the planning of a restoration and valorisation project is globally recognized; the qualitative and quantitative knowledge provided by geomatics techniques is part of this process. The paper will present the different techniques that were used, the products that were obtained and will focus on some mapping and WEB GIS applications and analyses that were performed and considerations that were made

THE GEOMATICS CONTRIBUTION FOR THE VALORISATION PROJECT IN THE ROCCA OF SAN SILVESTRO LANDSCAPE SITE

This paper proposes an emblematic project where several multi-sensor strategies for spatial data acquisition and management, range based and image based, were combined to create a series of integrated territorial and architectural scale products characterized by a rich multi-content nature. The work presented here was finalized in a test site that is composed by an ensemble of diversified cultural deposits; the objects that were surveyed and modelled range from the landscape with its widespread mining sites, the main tower with its defensive role, the urban configuration of the settlement, the building systems and techniques, a medieval mine. For this reason, the Rocca of San Silvestro represented a perfect test case, due to its complex and multi-stratified character. This archaeological site is a medieval fortified village near the municipality of Campiglia Marittima (LI), Italy. The Rocca is part of an Archaeological Mines Park and is included in the Parchi della Val di Cornia (a system of archaeological parks, natural parks and museums in the south-west of Tuscany). The fundamental role of a deep knowledge about a cultural artefact before the planning of a restoration and valorisation project is globally recognized; the qualitative and quantitative knowledge provided by geomatics techniques is part of this process. The paper will present the different techniques that were used, the products that were obtained and will focus on some mapping and WEB GIS applications and analyses that were performed and considerations that were made

A lipid-based delivery platform for thermo-responsive delivery of teriparatide

Teriparatide (and analogue peptides) are the only FDA approved anabolic treatments for osteoporosis. Current therapies are administered as a daily subcutaneous injection, which limits patient adherence and clinical efficacy. To achieve the desired anabolic effect, a controlled delivery system must ensure a pulsatile release profile over a prolonged period. Thermo-responsive formulations (e.g. liposomes) can undergo a temperature-related phase-transition which can allow active control of drug release. Herein, thermo-responsive liposomes were developed to permit precise control over the teriparatide release rate through modulation of temperature. Entrapment of hydrophilic molecules, including peptides within liposomes remains challenging due to the large volume of hydration. In this work, hydrophobic ion pairing was employed for the first time to enhance peptide entrapment within liposomes. The method resulted in a hydrophobic complex that achieved high teriparatide entrapment (>75 %) in sub-200 nm, monodispersed liposomes. Hydrophobic ion pairing outperformed other entrapment approaches. Several liposomal formulations with transition temperatures between 38 – 50 °C were obtained by modulation of the phospholipid composition. In vitro release assays demonstrated temperature-dependent release kinetics with faster rates of release observed at/above the transition temperature. The maintenance of biological activity of released teriparatide was demonstrated in a cell-based assay utilising the PTH1 receptor. Overall, this provides the first proof-of-concept of the suitability of thermo-responsive systems for pulsatile delivery of teriparatide and similar peptides

THE GEOMATICS CONTRIBUTION FOR THE VALORISATION PROJECT IN THE ROCCA OF SAN SILVESTRO LANDSCAPE SITE

This paper proposes an emblematic project where several multi-sensor strategies for spatial data acquisition and management, range based and image based, were combined to create a series of integrated territorial and architectural scale products characterized by a rich multi-content nature. The work presented here was finalized in a test site that is composed by an ensemble of diversified cultural deposits; the objects that were surveyed and modelled range from the landscape with its widespread mining sites, the main tower with its defensive role, the urban configuration of the settlement, the building systems and techniques, a medieval mine. For this reason, the Rocca of San Silvestro represented a perfect test case, due to its complex and multi-stratified character. This archaeological site is a medieval fortified village near the municipality of Campiglia Marittima (LI), Italy. The Rocca is part of an Archaeological Mines Park and is included in the Parchi della Val di Cornia (a system of archaeological parks, natural parks and museums in the south-west of Tuscany). The fundamental role of a deep knowledge about a cultural artefact before the planning of a restoration and valorisation project is globally recognized; the qualitative and quantitative knowledge provided by geomatics techniques is part of this process. The paper will present the different techniques that were used, the products that were obtained and will focus on some mapping and WEB GIS applications and analyses that were performed and considerations that were made

Local Ugandan Production of Stable 0.2% Chlorhexidine Eye Drops

Purpose: The purpose of this study was to develop a protocol to prepare buffered chlorhexidine (CHX) eye drops (0.2% w/v) in the United Kingdom that can be reproduced at a production facility in Uganda. Buffered CHX eye drops can prevent CHX degradation and improve ocular tolerability during the treatment of fungal keratitis. Methods: Buffered CHX eye drops in amber glass containers were prepared using sodium acetate buffer at pH 5.90 to 6.75. Two commercial CHX solutions and CHX in water were used as controls. Eye drops were stored at 40°C (70% humidity, 21 months) in the United Kingdom and at ambient temperature in Uganda (30 months). High-performance liquid chromatography was used to determine CHX stability over time, and pH was monitored. Sterility was achieved using an autoclave (121°C, 15 minutes) and water bath (100°C, 30 minutes). Results: The pH of acetate-buffered CHX eye drops did not change over 21 months a40°C or at ambient temperature (30 months), whereas the pH of the unbuffered aqueouCHX displayed significant fluctuations, with an increase in acidity. The CHX concentration remained the same in both buffered and unbuffered eye-drop solutions. Eye dropsterilization was successful using an autoclave and a water bath. Conclusions: Stable, sterile, buffered CHX eye drops (pH 6.75) were successfully prepared first in the United Kingdom and then reproducibly in Uganda. This eye drops can be prepared in a hospital or pharmacy setting with limited resources, thus providing a cost-effective treatment for fungal keratitis. Translational Relevance: A protocol has been developed to prepare buffered CHX eydrops in low-and middle-income countries to treat fungal keratitis

Interferon dimers: IFN-PEG-IFN

Increasingly complex proteins can be made by a recombinant chemical approach where proteins that can be made easily can be combined by site-specific chemical conjugation to form multifunctional or more active protein therapeutics. Protein dimers may display increased avidity for cell surface receptors. The increased size of protein dimers may also increase circulation times. Cytokines bind to cell surface receptors that dimerise, so much of the solvent accessible surface of a cytokine is involved in binding to its target. Interferon (IFN) homo-dimers (IFN-PEG-IFN) were prepared by two methods: site-specific bis-alkylation conjugation of PEG to the two thiols of a native disulphide or to two imidazoles on a histidine tag of two His8-tagged IFN (His8IFN). Several control conjugates were also prepared to assess the relative activity of these IFN homo-dimers. The His8IFN-PEG20-His8IFN obtained by histidine-specific conjugation displayed marginally greater in vitro antiviral activity compared to the IFN-PEG20-IFN homo-dimer obtained by disulphide re-bridging conjugation. This result is consistent with previous observations in which enhanced retention of activity was made possible by conjugation to an N-terminal His-tag on the IFN. Comparison of the antiviral and antiproliferative activities of the two IFN homo-dimers prepared by disulphide re-bridging conjugation indicated that IFN-PEG10-IFN was more biologically active than IFN-PEG20-IFN. This result suggests that the size of PEG may influence the antiviral activity of IFN-PEG-IFN homo-dimers

Turbulence and aeration in hydraulic jumps: free-surface fluctuation and integral turbulent scale measurements

In an open channel, a change from a supercritical to subcritical flow is a strong dissipative process called a hydraulic jump. Herein some new measurements of free-surface fluctuations of the impingement perimeter and integral turbulent time and length scales in the roller are presented with a focus on turbulence in hydraulic jumps with a marked roller. The observations highlighted the fluctuating nature of the impingement perimeter in terms of both longitudinal and transverse locations. The results showed further the close link between the production and detachment of large eddies in jump shear layer, and the longitudinal fluctuations of the jump toe. They highlighted the importance of the impingement perimeter as the origin of the developing shear layer and a source of vorticity. The air–water flow measurements emphasised the intense flow aeration. The turbulent velocity distributions presented a shape similar to a wall jet solution with a marked shear layer downstream of the impingement point. The integral turbulent length scale distributions exhibited a monotonic increase with increasing vertical elevation within 0.2 < Lz/d1 < 0.8 in the shear layer, where Lz is the integral turbulent length scale and d1 the inflow depth, while the integral turbulent time scales were about two orders of magnitude smaller than the period of impingement position longitudinal oscillations

Practical computational toolkits for dendrimers and dendrons structure design

Dendrimers and dendrons offer an excellent platform for developing novel drug delivery systems and medicines. The rational design and further development of these repetitively branched systems are restricted by difficulties in scalable synthesis and structural determination, which can be overcome by judicious use of molecular modelling and molecular simulations. A major difficulty to utilise in silico studies to design dendrimers lies in the laborious generation of their structures. Current modelling tools utilise automated assembly of simpler dendrimers or the inefficient manual assembly of monomer precursors to generate more complicated dendrimer structures. Herein we describe two novel graphical user interface (GUI) toolkits written in Python that provide an improved degree of automation for rapid assembly of dendrimers and generation of their 2D and 3D structures. Our first toolkit uses the RDkit library, SMILES nomenclature of monomers and SMARTS reaction nomenclature to generate SMILES and mol files of dendrimers without 3D coordinates. These files are used for simple graphical representations and storing their structures in databases. The second toolkit assembles complex topology dendrimers from monomers to construct 3D dendrimer structures to be used as starting points for simulation using existing and widely available software and force fields. Both tools were validated for ease-of-use to prototype dendrimer structure and the second toolkit was especially relevant for dendrimers of high complexity and size.Peer reviewe