Search

Implementing screening assays that identify functional and structural cardiotoxicity earlier in the drug development pipeline has the potential to improve safety and decrease the cost and time required to bring new drugs to market. In this study, a metabolic biomarker-based assay was developed that predicts the cardiotoxicity potential of a drug based on changes in the metabolism and viability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Assay development and testing was conducted in 2 phases: (1) biomarker identification and (2) targeted assay development. In the first phase, metabolomic data from hiPSC-CM spent media following exposure to 66 drugs were used to identify biomarkers that identified both functional and structural cardiotoxicants. Four metabolites that represent different metabolic pathways (arachidonic acid, lactic acid, 2′-deoxycytidine, and thymidine) were identified as indicators of cardiotoxicity. In phase 2, a targeted, exposure-based biomarker assay was developed that measured these metabolites and hiPSC-CM viability across an 8-point concentration curve. Metabolite-specific predictive thresholds for identifying the cardiotoxicity potential of a drug were established and optimized for balanced accuracy or sensitivity. When predictive thresholds were optimized for balanced accuracy, the assay predicted the cardiotoxicity potential of 81 drugs with 86% balanced accuracy, 83% sensitivity, and 90% specificity. Alternatively, optimizing the thresholds for sensitivity yields a balanced accuracy of 85%, 90% sensitivity, and 79% specificity. This new hiPSC-CM-based assay provides a paradigm that can identify structural and functional cardiotoxic drugs that could be used in conjunction with other endpoints to provide a more comprehensive evaluation of a drug's cardiotoxicity potential. [ABSTRACT FROM AUTHOR]

Abstract Background Autism spectrum disorder (ASD) is behaviorally and biologically heterogeneous and likely represents a series of conditions arising from different underlying genetic, metabolic, and environmental factors. There are currently no reliable diagnostic biomarkers for ASD. Based on evidence that dysregulation of branched-chain amino acids (BCAAs) may contribute to the behavioral characteristics of ASD, we tested whether dysregulation of amino acids (AAs) was a pervasive phenomenon in individuals with ASD. This is the first article to report results from the Children's Autism Metabolome Project (CAMP), a large-scale effort to define autism biomarkers based on metabolomic analyses of blood samples from young children. Methods Dysregulation of AA metabolism was identified by comparing plasma metabolites from 516 children with ASD with those from 164 age-matched typically developing children recruited into the CAMP. ASD subjects were stratified into subpopulations based on shared metabolic phenotypes associated with BCAA dysregulation. Results We identified groups of AAs with positive correlations that were, as a group, negatively correlated with BCAA levels in ASD. Imbalances between these two groups of AAs identified three ASD-associated amino acid dysregulation metabotypes. The combination of glutamine, glycine, and ornithine amino acid dysregulation metabotypes identified a dysregulation in AA/BCAA metabolism that is present in 16.7% of the CAMP subjects with ASD and is detectable with a specificity of 96.3% and a positive predictive value of 93.5% within the ASD subject cohort. Conclusions Identification and utilization of metabotypes of ASD can lead to actionable metabolic tests that support early diagnosis and stratification for targeted therapeutic interventions. [ABSTRACT FROM AUTHOR]

Abstract Mucoadhesive molecules such as chitosan, can allow targeting of a particular tissue to prolong residence time and subsequently improve bioavailability. The purpose of this study was to investigate chitosan-tripolyphosphate (CS:TPP) nanoparticles and to evaluate the interaction between nanoparticles of different CS:TPP ratios with mucin using viscosity, particle size analysis and ζ-potential. For all CS:TPP ratios examined, a minimum value of viscosity was reached for a 3:1 CS:TPP ratio, however chitosan nanoparticles at this ratio were not stable (<+30 mV), whereas a CS:TPP ratio of 4:1 displayed the strongest interaction. This suggests a minimum CS:TPP ratio of 4:1 is required to produce stable nanoparticles able to form strong interactions, which is consistent with a greater mucin binding efficiencies at CS:TPP ratios of 4:1 and higher, which were quantified using a colorimetric assay. Further analysis of similar systems could lead potentially to tuneable chitosan nanoparticles for specific applications. Highlights • The interactions between CS:TPP nanoparticles and mucin were evaluated. • The degree of interaction depends on the CS:TPP ratio, ζ-potential and viscosity. • A CS:TPP ratio of 4:1 displayed the strongest interaction with mucin. • Greater mucin binding efficiencies achieved at CS:TPP ratios of 4:1 and higher. • A minimum CS:TPP ratio of 4:1 is required for stable interactions with mucin. [ABSTRACT FROM AUTHOR]

A water-soluble mucilage extracted from the leaves of Hoheria populnea was chemically and physically studied. Monosaccharide composition and linkages were determined by high performance anion exchange chromatography (HPAEC), gas chromatography–mass spectrometry (GC–MS) and nuclear magnetic resonance (NMR) spectroscopy. Lacebark mucilage was composed of rhamnose, galactose, galacturonic acid and glucuronic acid (2:1:2:1). Proton and 13 C NMR spectroscopy, and linkage analysis, revealed a predominantly rhamnogalacturonan I-type (RG I-type) structure comprising of a backbone of → 4]-α-D-Gal p A-[1 → 2]-α-L-Rha p -[1 →. Data indicated the mucilage likely comprises of a polymer containing several structurally discrete domains or possibly more than one discrete polymer. One domain contains a RG I-type backbone with branching at O -3 of Gal p A residues to terminal β-D-Glc p A residues, another similarly contains a RG I-type backbone but is branched at O -4 of the Rha p residues to terminal Gal p A residues or oligosaccharides containing α-linked 4-Gal p and terminal Gal p A residues. A possible third domain contains contiguous 2-Rha p residues, some branched at O -3. Hydrated mucilage exhibited pseudoplastic flow behaviour and viscoelastic properties of an entangled biopolymer network. These rheological behaviours were only slightly affected by pH and may prove advantageous in potential end-product applications including oral pharmaceuticals or as a food ingredient. [ABSTRACT FROM AUTHOR]

The relative developmental toxicity potency of a series of retinoid analogues was evaluated using a human induced pluripotent stem (iPS) cell assay that measures changes in the biomarkers ornithine and cystine. Analogue potency was predicted, based on the assay endpoint of the ornithine/cystine (o/c) ratio, to be all- trans -retinoic acid > TTNPB > 13- cis -retinoic acid ≈ 9- cis -retinoic acid > acitretin > etretinate > retinol. These rankings correlate with in vivo data and demonstrate successful application of the assay to rank a series of related toxic and non-toxic compounds. The retinoic acid receptor α (RARα)-selective antagonist Ro 41–5253 inhibited the cystine perturbation caused by all- trans -retinoic acid, TTNPB, 13- cis -retinoic acid, 9- cis -retinoic acid, and acitretin. Ornithine was altered independent of RARα in all retinoids except acitretin. These results suggest a role for an RARα-mediated mechanism in retinoid-induced developmental toxicity through altered cystine metabolism. [ABSTRACT FROM AUTHOR]

Chitosan (CS) is a natural cationic polymer obtained by the partial N -deacetylation of chitin. Chitosan microparticles can be prepared by cross-linking with tripolyphosphate (TPP) via the ionic interaction between positively charged amino groups (CS) and negatively charged counter ions (TPP). This can be controlled by the charge density of CS and TPP, which depend on the pH and ionic strength of the solution. The purpose of this study is to investigate the combined effects of three independent variables (pH, ionic strength and CS:TPP ratio) on three important physico-chemical properties (viscosity, zeta potential and particle size) during the preparation of microparticles. CS:TPP microparticles were prepared using experimental design and equations were generated and used to predict relative viscosity, zeta potential and particle size under different conditions. This gives us the ability to design tuneable CS-TPP microparticles with desired size for specific pharmaceutical or forensic applications e.g. latent fingerprint visualisation. [ABSTRACT FROM AUTHOR]

Successful culturing of tissues within polysaccharide hydrogels is reliant upon specific mechanical properties. Namely, the stiffness and elasticity of the gel have been shown to have a profound effect on cell behaviour in 3D cell cultures and correctly tuning these mechanical properties is critical to the success of culture. The usual way of tuning mechanical properties of a hydrogel to suit tissue engineering applications is to change the concentration of polymer or its cross-linking agents. In this study sonication applied at various amplitudes was used to control mechanical properties of gellan gum solutions and gels. This method enables the stiffness and elasticity of gellan gum hydrogels cross-linked with DMEM to be controlled without changing either polymer concentration or cross-linker concentration. Controlling the mechanical behaviour of gellan hydrogels impacted upon the activity of alkaline phosphatase (ALP) in encapsulated MC3T3 pre-osteoblasts. This shows the potential of applying a simple technique to generate hydrogels where tissue-specific mechanical properties can be produced that subsequently influence cell behaviour. [ABSTRACT FROM AUTHOR]

Calcium phosphate coatings have been applied to the surface of metallic prostheses to mediate hard and soft tissue attachment for more than 40 years. Most coatings are formed of high purity hydroxyapatite, and coating methods are often designed to produce highly crystalline surfaces. It is likely however, that coatings of lower crystallinity can facilitate more rapid tissue attachment since the surface will exhibit a higher specific surface area and will be considerably more reactive than a comparable highly crystalline surface. Here we test this hypothesis by growing a population of MC3T3 osteoblast-like cells on the surface of two types of hip prosthesis with similar composition, but with differing crystallinity. The surfaces with lower crystallinity facilitated more rapid cell attachment and increased proliferation rate, despite having a less heterogeneous surface topography. This work highlights that the influence of the crystallinity of HA at the nano-scale is dominant over macro-scale topography for cell adhesion and growth. Furthermore, crystallinity could be easily adjusted by without compromising coating purity. These findings could facilitate designing novel coated calcium phosphate surfaces that more rapidly bond tissue following implantation. [ABSTRACT FROM AUTHOR]

Polysaccharides have received a great deal of attention from, for example, the food, cosmetic and pharmaceutical industries. Their conformations (flexibility/stiffness) span a wide range of conformational flexibilities with large hydrated volumes, these properties are important in relation to polysaccharide structure-function relationships.Perhaps the simplest parameter available to estimate the dilute solution conformation of polysaccharides is the Smidsrød-Haug stiffness parameter (B) where the stiffness of polyelectrolytes can be estimated by measuring the intrinsic viscosity at a number of different ionic strengths.In this paper we propose an alternative method for estimating the Smidsrød-Haug stiffness parameter (B) using the ionic strength dependency of zeta potential. For this purpose we have studied a number of different polysaccharides. [ABSTRACT FROM AUTHOR]

Webcams have become popular means of showcasing beach conditions for a wide variety of beach users. However, webcams can also be a useful tool in assessing changes in coastal morphology and coastal processes. This information can be used by managers to assist in planning. A number of fixed-position beach webcams are freely available to the South African public via various tourism, surfing, weather and aviation websites, individual clubs and a cell-phone network provider. The advantages of these public networks are that the information is free and as the webcams are fixed, afford a consistent and comparable view of the beach. The disadvantage is that you are at the mercy of the provider: resolution is generally poor, downtime and communication are out of your control, and you have no influence over the positioning of the webcam or the discontinuity of service. Notwithstanding the above, the existing webcams can still provide valuable information. From the network of beach webcams available in South Africa we analyse imagery from three beach webcams located in the province of KwaZulu-Natal, at Umhlanga, Margate beach and lagoon, and Amanzimtoti beach and lagoon to examine the coastal dynamics. From these case studies we illustrate seasonal beach rotation and lagoon mouth dynamics, specifically why outlets migrate southwards in opposition to regional longshore drift. [ABSTRACT FROM AUTHOR]

Hydrogels have been widely investigated as 3D culturesubstratesbecause of their reported structural similarity to the extracellularmatrix (ECM). Limited ECM deposition, however, occurs within thesematerials, so the resulting “tissues” bear little resemblanceto those found in the body. Here matrix deposition by fibroblastsencapsulated within a calcium alginate (Ca-alg) hydrogel was investigated.Although the cells transcribed mRNA for coll Iα over a periodof 3 weeks, very little collagen protein deposition was observed withinthe gel by histology or immunohistochemistry (IHC). Although moleculardiffusion demonstrated charge dependency, this did not prevent theflux of both positively and negative charged amino acids through thegel, suggesting that the absence of ECM could not be attributed tosubstrate limitation. The flux of protein, however, was charge-dependentas proteins with a net negative charge passed quickly through theCa-alg into the medium. The minimal collagen deposition within theCa-alg was attributed to a combination of rapid movement of negativelycharged procollagen through the gel and steric hindrance of fibrilformation. [ABSTRACT FROM AUTHOR]

Abstract: Medium scale clinoforms within sandstones of the Vryheid Formation, northern KwaZulu-Natal, South Africa have in the past been interpreted as the products of Gilbert-type or river-dominated deltaic deposition. Detailed sedimentary logging of these rocks reveals a tempestite association, overlain by a series of moderate to very large scale climbing bedforms. These are intersected at various stratigraphic levels by massive sandstone filled channels, some with subordinate rippled bases, which are orthogonally orientated to the largest scale bedding surfaces (clinoforms) of the climbing bedform association. The sedimentary architecture is dominated by the south-easterly, south-westerly and north-westerly dipping clinoforms, all orientated oblique to the east–west trending palaeo-coastline. Local dip direction reversals are commonplace. This is at odds with Gilbert-type or river-dominated deltaic settings where: (1) sediment progrades normal to the shoreline; (2) distributary channels do not intersect the underlying deltaic foresets orthogonally; and (3) wave action is typically limited. We subsequently interpret the succession as a shelf sand ridge that evolved on a subaqueous delta, fed by sediment exchange from the upper to lower shoreface via a series of rippled scour depressions. To foster such thick (∼30m) shelf ridge development, it is likely that these remained attached to the shoreface for a significant period of time. In light of these findings, caution should be adopted in applying a blanket deltaic interpretation of shallow marine deposits comprising similar medium scale clinoforms. [Copyright &y& Elsevier]

Terra Nova, 23, 375-381, 2011 Abstract Calcifying tufa stromatolites are forming on a high energy coast of the South African Indian Ocean. The tufa stromatolites form in upper intertidal to supra tidal rock pools, encrust bedrock and are linked both laterally and vertically to physico-chemical properties of their pool water. Calcification only occurs in pools where dissolved carbonate-rich, spring-fed groundwater is routed, and δ18O values are consistent with calcification in a mixture of freshwater and seawater. Increasing pH and less negative isotope values away from the spring are consistent with CO2 degassing and in-stream calcification, albeit with some in-mixing of seawater. The rocky shore setting of these active tufa stromatolites is new and invites serious comparison with some Archaean rocky substrate peritidal stromatolites (e.g. the c. 3.45 Ga Strelley Pool sequences, Pilbara Craton). This new association shows that initial encrustation of rocky intertidal substrates can begin with freshwater influence in the intertidal zone, a facies detail that should be sought in ancient peritidal stromatolites. [ABSTRACT FROM AUTHOR]

Objectives Standard pharmaceutical capsules are designed to dissolve in the acidic environment of the stomach releasing the encapsulated contents for absorption. When release is required further along the gastrointestinal tract capsules can be coated with acid insoluble polymers to enable passage through the stomach and dissolution in the intestine. This paper describes formulations that have the potential to be used to produce two-piece hard capsules for post-gastric delivery without the requirement of an exterior coat. Methods The formulation uses three polysaccharides: sodium alginate, hypromellose and gellan gum to provide acid insolubility and the ability to form capsules using standard industrial equipment. Key findings The rheological profile, on cooling, of the base material, water content and thickness of the films were shown to be comparable with those of commercial capsules. The capsules remained intact for 2 h in 100 m m HCl at pH 1.2, and within 5 min of being removed from the acid and submerged in phosphate-buffered saline at pH 6.8 were ruptured. Conclusions Selected formulations from this study have potential for use as delayed release capsules. [ABSTRACT FROM AUTHOR]

Ex situ conservation is of increasing importance to prevent the extinction of endangered animals in the wild. Despite low success rates of reintroduction programs few researchers have investigated empirically the efficacy of captive breeding regimes for the release of captive-bred vertebrates. We used guppies (Poecilia reticulata ) from two populations in Trinidad to compare different conservation breeding regimes. The upper Aripo population was chosen for its small effective population size (N e≈ 100) and genetic isolation, which makes it representative of many endangered natural populations. By contrast, the lower Aripo population is a genetically diverse, much larger population (N e≈ 2400). We examined three captive-breeding regimes: (1) inbreeding fish crossed with their full siblings, (2) minimized inbreeding, no consanguineous matings, and (3) control fish crossed at random. We kept pedigree records for all regimes so that we could calculate inbreeding coefficients over four generations. The body size and fertility of guppies was significantly reduced due to inbreeding depression. The genetic load of sterile equivalents was particularly high for the lower Aripo population. Body size also declined due to breeding conditions in the captive environment. After four generations in captivity, the fish were released into a mesocosm in Trinidad. Captive-bred guppies were extremely susceptible to gyrodactylid parasites (58% survival rate) compared with their wild counterparts (96% survival). A reduced level of immunogenetic variation due to inbreeding and lack of exposure to natural parasites may have rendered captive-bred individuals more prone to infectious disease. The threat of disease outbreak is particularly high when naive captive-bred hosts are released in wild populations. Susceptible, captive-bred hosts could facilitate the transmission of parasites throughout the wild population, thus initiating an epidemic. This risk could potentially be reduced by prior exposure to parasites before release and gradual release of captive-bred individuals. [ABSTRACT FROM AUTHOR]

Alpha-modified minimum essential medium (αMEM) has been found to cross-link a 1% gellan gum solution, resulting in the formation of a self-supporting hydrogel in 1:1 and 5:1 ratios of polysaccharide: αMEM. Rheological data from temperature sweeps confirm that in addition to orders of magnitude differences in G' between 1% gellan and 1% gellan with αMEM, there is also a 20°C increase in the temperature at which the onset of gelation takes place when αMEM is present. Frequency sweeps confirm the formation of a true gel; mechanical spectra for mixtures of gellan and αMEM clearly demonstrate G' to be independent of frequency. It is possible to immobilize cells within a three-dimensional (3D) gellan matrix that remain viable for up to 21 days in culture by adding a suspension of rat bone marrow cells (rBMC) in αMEM to 1% gellan solution. This extremely simple approach to cell immobilization within 3D constructs, made possible by the fact that gellan solutions cross-link in the presence of millimolar concentrations of cations, poses a very low risk to a cell population immobilized within a gellan matrix and thus indicates the potential of gellan for use as a tissue engineering scaffold. [ABSTRACT FROM AUTHOR]

Abstract: In this essay we provide an interdisciplinary approach to the problem of the evolution of human cognition and suggest the theoretical framework of genetic system theory (GST) for organizing the relevant content of several disciplines. This bio-social-cultural theory is based on the assumption that organisms are dynamic systems which interact with one another and their environment and are themselves composed of dynamic internal relations at several levels. Special emphasis will be placed upon these internal cellular and molecular mechanisms underlying the physiological mechanisms of learning and memory. The human individual organism is emphasized because in its experiential activity over time it is the site of integration for social, and cultural stimuli and because of its unique properties among living things. The primary disciplines for our discussion are drawn from the biological, social, and humanistic sciences and several concrete examples are given from each science. [Copyright &y& Elsevier]

Abstract: Photoreactive liposomes have been exploited as a means of developing 3D tissue constructs. Liposomes formulated using the photosensitive lipid 1,2-bis(4-(n-butyl)phenylazo-4′-phenylbutyroyl)phosphatidylcholine (Bis Azo PC), which undergoes conformational change on stimulation with long wavelength ultraviolet light, were prepared with entrapped CaCl2 before being incorporated into a 4% alginate solution. It was shown that stimulation of the photosensitive lipid using a light emitting diode (LED) (peak emission at 385 nm, dose equivalent to 9 mJ/cm2) caused the release of liposome-entrapped CaCl2, resulting in cross-linking of the alginate solution and immobilisation of bone-derived cells over a range of seeding densities, approximately 97% of which remained viable for periods of up to 14 days in culture. Entrapment volumes of a variety of liposome types were evaluated and interdigitating fusion vesicles were identified as having the highest payload (24%), however the inclusion of cholesterol as a means of shifting Bis Azo PC sensitivity into the visible light wavelengths resulted in an approximately 10-fold reduction in calcium entrapment. This application of light-sensitised liposomes offers the potential to create complex tissue engineering substrates containing cells immobilised in precise locations, in contrast with substrates onto which cells are seeded post-production. [Copyright &y& Elsevier]

Discusses the role that gene targeting and other transgenic techniques have had in the study of mammalian learning and memory. What should be included in an explanation of learning and memory; Findings of behavioral and neuroanatomical studies of different system that process types of information in the brain; What is the relation between human and animal learning.

Subaqueous dunes are formed on the KwaZuhJ-Natal outer-shelf due to sediment transport by the Agulhas Current (geostrophic current). These dunes occur within two dune fields at depths of - 35 to - 70 m. The net sediment transport direction is south, but short-period reversals ferm northward-migrating bedforms. The dune fields are physically bounded by late Pleistocene beachrock and aeolianite ledges. A bedform hierarchy has been recognized in the dune fields comprising a system of three generations of climbing bedforrns. The outer dunefield has given rise to a sand ridge (H = 12 m; L = 4 km; W = 1.1 km; and an 8° lee slope) whereas the inner dune fields have achieved large-scale dune status. Bedload parting zones within the dune fields occur where the sediment transport direction switches from north to south due to reversals in the geostrophic flow; these zones occur at depths of - 60, -47 and - 45 m. An interpretative stratigraphic model is presented on what such geostrophite deposits would look like in the ancient sedimentary record. [ABSTRACT FROM AUTHOR]

Capsules are a widely used oral dosage form due to their simplicity and ease of manufacture. They are equally popular for both pharmaceutical and nutraceutical products and since they do not need extensive formulation development, it is a dosage form of choice for new drugs undergoing animal or clinical trials. In addition to the standard hard-gelatin or cellulose-based vegetarian capsules, functional capsules such as those with built-in gastroresistance would be of great value. In this work, commonly used enteric polymers were investigated for the production of hard-capsules. The polymers used in this study included cellulose derivatives (HPMC AS-LF and HP-55) and acrylic/methacrylic acid derivatives (EUDRAGIT L100 and S100). A range of concentrations of polymers and plasticisers were tested to optimise the formulation for the production of capsule shells with desirable physicochemical and gastroresistance characteristics. Drug release from optimised capsules produced from HPMC AS-LF, HP-55, EUDRAGIT L100 and S100 was shown to be comparable to drug release from corresponding polymer-coated tablets in both compendial and physiological bicarbonate buffer. In summary, herein we report a simple method for producing enteric capsule shells which do not need an additional coating step which, if validated at large scale, can significantly reduce the cost of manufacturing of conventional enteric coated dosage forms. These capsules are also likely to improve the inter-tablet variability in post-gastric drug release inherent in conventional dosage forms due to coating variability. [ABSTRACT FROM AUTHOR]

Background: Antimicrobial resistance (AMR) is a growing problem worldwide, with differences in regional resistance patterns partially driven by local variance in antibiotic stewardship. Trauma patients transferring from Mexico have more AMR than those injured in the United States; we hypothesized a similar pattern would be present for burn patients. Patients and Methods: The registry of an American Burn Association (ABA)-verified burn center was queried for all admissions for burn injury January 2015 through December 2019 with hospital length-of-stay (LOS) longer than seven days. Patients were divided into two groups based upon burn location: United States (USA) or Mexico (MEX). All bacterial infections were analyzed. Results: A total of 73 MEX and 826 USA patients were included. Patients had a similar mean age (40.4 years MEX vs. 42.2 USA) and gender distribution (69.6% male vs. 64.4%). The MEX patients had larger median percent total body surface area burned (%TBSA; 11.1% vs. 4.3%; p ≤ 0.001) and longer hospital LOS (18.0 vs. 13.0 days; p = 0.028). The MEX patients more often had respiratory infections (16.4% vs. 7.4%; p = 0.046), whereas rates of other infections were similar. The MEX patients had higher rates of any resistant organism (47.2% of organisms MEX vs. 28.1% USA; p = 0.013), and were more likely to have resistant infections on univariable analysis; however, on multivariable analysis country of burn was no longer significant. Conclusions: Antimicrobial resistance is more common in burn patients initially burned in Mexico than those burned in the United States, but location was not a predictor of resistance compared to other traditional burn-related factors. Continuing to monitor for AMR regardless of country of burn remains critical. [ABSTRACT FROM AUTHOR]

The article focuses on Cape Morgan peritidal stromalites in South Africa. The Cape Morgan stromalites occupy a unique niche within the supratidal and upper intertidal zones on a high-energy rocky headland. The combination of cyanobacterial mats, widely fluctuating salinities and temperatures in the rock pools promotes the formation of stromatolites, which consist of alternating thick and thin laminar "couplets". The thicker layers comprise densely packed vertical filaments forming radiating fans, interpreted as a pioneer community. The thinner laminae are made up of horizontal filaments that typically contain trapped sand and diatoms.We suggest that the couplets are annual growth forms representing seasonal environmental fluctuations.

Chitosan (CS) is a cationic polymer with excellent film, gel and particle-forming properties. This polymer has been investigated widely for its potential in the development of food and drug delivery systems and pharmaceutical applications, however it has not generally been considered in forensic applications for example fingerprints (fingermarks). Fingerprints are a very common form of physical evidence. The most commonly used procedure for revealing the ridge pattern is powder dusting, which relies on the mechanical adherence of fingerprint formulation to the fatty components of the skin deposit that are secreted by sweat pores that exist on friction ridges. Cross-linking between oppositely charged molecules can be used to prepare chitosan microparticles. Tripolyphosphate (TPP) is a nontoxic polyanion; it can form particles by ionic interaction between positively charged amino groups of CS and negatively charged counter ions of TPP. In the present study chitosan microparticles (CSMPs) were prepared under four different processing/formulation conditions. The development of latent fingermarks using CSMPs was analysed by using a 2 3 factorial design, which considered simultaneously three main factors: pH, ionic strength and CS: TPP (v/v) ratio. In this study CS: TPP ratio has the strongest effect on fingerprint quality. The best conditions for fingerprint visualisation were pH 4.8, CS: TPP of 2:1 and 0.2 M of ionic strength in buffer (AB-12). [ABSTRACT FROM AUTHOR]

The functionality of plant-resourced biopolymers depends on their physicochemical properties. In addition, the extraction protocol and further processing conditions can significantly affect the effectiveness of biopolymer in diverse industrial applications. Therefore, the objective of this study was to investigate the impact of purification on chemical composition, molecular arrangement, solubility, swelling, erosion, wettability, quantitative wetting kinetics, surface energy and three-dimensional (3D) surface texture properties of okra biopolymer and its compacted form. FTIR and XRD results confirmed that the purification process had no effect on the molecular structural arrangement. The highest purity grade (bi-purified okra biopolymer) had the highest sugar content, solubility, matrix tablet swelling, wettability and surface energy, although the surface porosity and roughness of matrix tablet were low. Okra biopolymer showed pH-dependent solubility and the maximum solubility was achieved at pH 7.4. The mechanism of swelling of less-purified matrices was anomalous, where the rate of water diffusion and polymer relaxation was of the same magnitude, whereas bi-purified matrices showed diffusion-controlled swelling. Wetting was absorption-controlled and the bi-purified biopolymer had a high degree of wetting and surface energy. The extraction method, therefore, has a major influence on the properties and the subsequent drug delivery, biotechnology and food science applications for the biopolymer. [ABSTRACT FROM AUTHOR]

The nasal mucosa provides a potentially good route for local and systemic drug delivery. However, the protective feature of the nasal cavity make intranasal delivery challenging. The application of mucoadhesive polymers in nasal drug delivery systems enhances the retention of the dosage form in the nasal cavity. Several groups have investigated using low acyl gellan as a drug delivery vehicle but only limited research however, has been performed on high acyl gellan for this purpose, despite its properties being more conducive to mucoadhesion. High acyl gellan produces highly elastic gels below 60 °C which make it difficult to spray using a mechanical spray device. Therefore, in this study we have tried to address this problem by making fluid gels by introducing a shear force during gelation of the gellan polymer. These fluid gel systems contain gelled micro-particles suspended in a solution of un-gelled polymer. These systems can therefore behave as pourable viscoelastic fluids. In this study we have investigated the rheological behavior and mucoadhesion of fluid gels of two different types of gellan (high and low acyl) and fluid gels prepared from blends of high and low acyl gellan at a 50:50 ratio. The results demonstrated that by preparing fluid gels of high acyl gellan, the rheological properties were sufficient to spray through a standard nasal spray device. Moreover fluid gels also significantly enhance both high acyl and low acyl gellan mucoadhesion properties. [ABSTRACT FROM AUTHOR]

The potential of okra extract was evaluated for uses in pharmaceutical and food applications. Okra polysaccharides were extracted and dried using different drying procedures (oven drying and freeze-drying). The extracts were examined by means of measurement of swelling and dissolution behaviour of okra extract-based hydrophilic matrices for controlled drug release and emulsification capacity of n -hexadecane. Drying technique and solubility of drugs used were shown to have a significant impact on the swelling and dissolution of the hydrophilic matrix tablets prepared. It was shown that the oven-dried extracts increased swelling of the matrices by approximately 20% compared with freeze dried extracts, resulting in slower drug release. The relative drug solubility also contributed to the extent of swelling and drug release with poorly soluble flurbiprofen reducing the swelling and the release rate when compared with freely soluble theophylline. The emulsification capacity of the okra extracts was also investigated and they were found to emulsify n -hexadecane at pH 3.0. The emulsions produced had an average droplet size of ∼6 μm rising to ∼23 μm after 5 days then remaining relatively constant following 30 days of storage. These results highlight the potential of okra polysaccharide as an alternative sources to fabricate hydrophilic matrix tablets or as stabilisers of emulsions that can be used to deliver drugs or nutrients. [ABSTRACT FROM AUTHOR]

Oral liquids are often preferred for drug administration to patients for whom swallowing is difficult, however, formulating modified release versions can be challenging. A potential route to achieve modified release in oral liquids is by using fluid (sheared) gels formed by introducing a shear field during gelation in gel-forming biopolymers. These fluid gels can act as pourable viscoelastic fluids but retain true gel micro/nano structure. Here, we have demonstrated that fluid gels have potential as paediatric oral liquids preventing release of ibuprofen in simulated gastric fluid. Subsequent release at pH 7.4 was affected by the duration of exposure and magnitude of acid pH with a linear relationship between onset of release and the preceding acidic exposure duration. Delayed release was a result of increasing gel stiffness, a consequence of the acidity of the initial release media and exposure time. A much faster release rate was measured when exposure time in acid was 10 min compared with 60 min. This study highlights the potential to design fluid gels that are tuned to have a specified stiffness at a particular pH and exposure time. This could enable the preparation oral liquids with modified release behaviour. [ABSTRACT FROM AUTHOR]

Abstract: Hypromellose, HPMC, is frequently used to control drug release from matrix tablet formulations. Drug is released by a combination of diffusion through and erosion of, the matrix and is usually measured in vitro by separate dissolution and swelling/erosion studies. The present study was designed to measure matrix erosion, polymer dissolution and drug release kinetics and their inter-relationship in a single experiment using a phenol-sulphuric acid assay to quantify dissolved HPMC alongside spectrophotometrical analysis of drug release. HPMC-based matrix tablets were manufactured containing two drugs at various drug:HPMC ratios. Drug release was determined and the degree of erosion was calculated by gravimetry. Results showed the matrix erosion rate and drug release were dependent on HPMC content and drug solubility, as expected. It was also apparent that the erosion rate was directly related to the drug release kinetics and comparative analysis of both matrix erosion techniques showed a high level of correlation. The findings show that a simple and inexpensive assay can be utilised not only to quantify HPMC but can also be used to calculate the degree of erosion of tablet matrices, negating the need for a separate study and providing a simplified practical approach that may be of use during product optimization. [Copyright &y& Elsevier]

Abstract: Teratogens, substances that may cause fetal abnormalities during development, are responsible for a significant number of birth defects. Animal models used to predict teratogenicity often do not faithfully correlate to human response. Here, we seek to develop a more predictive developmental toxicity model based on an in vitro method that utilizes both human embryonic stem (hES) cells and metabolomics to discover biomarkers of developmental toxicity. We developed a method where hES cells were dosed with several drugs of known teratogenicity then LC–MS analysis was performed to measure changes in abundance levels of small molecules in response to drug dosing. Statistical analysis was employed to select for specific mass features that can provide a prediction of the developmental toxicity of a substance. These molecules can serve as biomarkers of developmental toxicity, leading to better prediction of teratogenicity. In particular, our work shows a correlation between teratogenicity and changes of greater than 10% in the ratio of arginine to asymmetric dimethylarginine levels. In addition, this study resulted in the establishment of a predictive model based on the most informative mass features. This model was subsequently tested for its predictive accuracy in two blinded studies using eight drugs of known teratogenicity, where it correctly predicted the teratogenicity for seven of the eight drugs. Thus, our initial data shows that this platform is a robust alternative to animal and other in vitro models for the prediction of the developmental toxicity of chemicals that may also provide invaluable information about the underlying biochemical pathways. [Copyright &y& Elsevier]

Death from choking is the fourth most common cause of unintentional-injury mortality, but little data are published on causes or locations of these episodes. These deaths typically are peaked at the extremes of age, with young children and the elderly having the greatest rate of fatal choking. Our objective was to characterize the causes of fatal airway obstruction in adults. The San Diego County Medical Examiner's database was searched for deaths attributed to choking in decedents 18 years and older during the 10-year period from 1994 to 2004. Data were abstracted regarding the underlying medical conditions, items choked on, location of the choking, and treatments involved in the individual cases. We found 133 victims who died from choking, with 14% having using alcohol or other sedatives and 55% having a documented neurological deficit or anatomic difficulty with swallowing. The most common specified food objects that victims choked on were meat products, and 45% occurred at home, followed by 26% at supervised facilities, and 14% at restaurants. Of the 19 choking episodes occurring in restaurants, only one employee was documented to attempt a resuscitative effort. Most victims who choked to death had an underlying neurological deficit, and occurred at home or supervised facilities appear to have an appropriate initial-response intervention. [ABSTRACT FROM AUTHOR]

To evaluate pediatric endotracheal intubations by our paramedics, we performed a retrospective review of a prehospital computer database, quality assurance reviews, and prehospital run sheets for all patients under 15 years of age who had an endotracheal tube (ETT) placed. During the 4.5-year study period, 324 pediatric patients had intubation attempts by field paramedics, of which 264 (82%) were successful and three were reported esophageal and unrecognized by the paramedic. Two of these esophageal placements were noted on arrival at the hospital, and one upon turn-over of patient care to a nurse of an aeromedical service. All three intubations were deemed esophageal with direct laryngoscopy, and the patients had been in cardiopulmonary arrest status prior to the intubation. Of the 264 patients who had ETT placed, 99% were endotracheal, while only 1% were unrecognized esophageal. We conclude that pediatric endotracheal intubation by out-of-hospital paramedics in an established EMS system has a low occurrence of unrecognized esophageal placements. [Copyright &y& Elsevier]

Invasive freshwater fishes are known to readily hybridize with indigenous congeneric species, driving loss of unique and irreplaceable genetic resources. Here we reveal that newly discovered (2013–2016) evolutionarily significant populations of Korogwe tilapia (Oreochromis korogwe) from southern Tanzania are threatened by hybridization with the larger invasive Nile tilapia (Oreochromis niloticus). We use a combination of morphology, microsatellite allele frequencies and whole genome sequences to show that O. korogwe from southern lakes (Nambawala, Rutamba and Mitupa) are distinct from geographically disjunct populations in northern Tanzania (Zigi River and Mlingano Dam). We also provide genetic evidence of O. korogwe × niloticus hybrids in three southern lakes and demonstrate heterogeneity in the extent of admixture across the genome. Finally, using the least admixed genomic regions we estimate that the northern and southern O. korogwe populations most plausibly diverged ~140,000 years ago, suggesting that the geographical separation of the northern and southern groups is not a result of a recent translocation, and instead these populations represent independent evolutionarily significant units. We conclude that these newly discovered and phenotypically unique cichlid populations are already threatened by hybridization with an invasive species, and propose that these irreplaceable genetic resources would benefit from conservation interventions. see also the Perspective by Iva Popovic and Louis Bernatchez. [ABSTRACT FROM AUTHOR]

Tibia fractures are common after trauma. Prior studies have shown that delays in treatment are associated with poor outcomes. A subpopulation of our patients are transported from Mexico, adding barriers to prompt care. We hypothesized that patients with tibia fractures crossing from Mexico would have delays in treatment and subsequently worse outcomes. The trauma registry of an American College of Surgeons-verified level 1 trauma center was retrospectively reviewed for all tibia fractures admitted from 2010 to 2015. Data collection included demographics, country of injury, characterization of injuries, interventions, complications, and outcomes. Patients were subdivided into those injured in the United States and in Mexico, and the two groups were compared. A total of 498 patients were identified, 440 from the United States and 58 from Mexico. Mexico patients were more severely injured overall, with higher injury severity scores and a higher percentage of patients with abbreviated injury scale scores ≥3 for both head and chest regions. Mexico patients had longer times from injury to admission, as well as increased times to both debridement of open fractures and operative fixation after admission. On subgroup analysis of patients with isolated tibia fractures (other system abbreviated injury scale < 3), times from arrival to treatment and injury severity score were no longer statistically different. Patients crossing the border from Mexico with tibia fractures have delays in time to admission and from admission to operative management, although this is primarily due to other severe injuries. Ongoing systems development is required to minimize delays in care and optimize outcomes. [ABSTRACT FROM AUTHOR]

The Permian-aged coal-bearing Vryheid Formation is the central stratigraphic unit of the Ecca Group within the Karoo Supergroup. In the main Vryheid Formation basin the succession comprises upward coarsening deltaic fan sediments followed by upward fining fluvial sequences. A narrow belt of the Vryheid Formation crops out along the KwaZulu-Natal (KZN) north coast, approximately ∼200 km south of the main Vryheid depocentre. The outcrops consist mainly of cliffs and rugged terrain in which predominantly fluvio-deltaic sedimentary sequences occur, along with highly carbonaceous and lower delta front sediments. Interpretation of detailed sedimentary logs suggests northward deepening of the succession, along with southerly-directed palaeocurrents in the shallower, coarse-grained and immature sediments. Broadly northerly-directed palaeocurrents are recorded in the lower delta front sediments. While the sedimentary record in this area might be discounted as merely a distal portion of the main Vryheid Formation basin, we contend that there is inconsistency relative to the main basin, and that there is a linked history in the pre-, syn- and post-Ecca depositional record. The syn-Ecca record we present from the eastern margin of the Vryheid basin, along with pre- and post-Ecca records and an appraisal of the incumbent tectonics, suggests that there was a relatively persistent control on sediment sourcing which existed to the southeast of the current KZN coastline. This region was most likely an uplifted area of the Maurice-Ewing Bank, which lay immediately offshore of what is now the KZN coast in a tight refit between Antarctica and Africa. • The Vryheid Formation along the east coast of South Africa comprises deltaic and fluvial sequences. • Coarse-grained, immature sediments were derived from the north, delta front deposits from the south. • Southerly sediment source and northward deepening of delta front deposits conflicts with main Vryheid Basin. • Synthesis of literature reveals continental assembly likely controlled local depositional setting. [ABSTRACT FROM AUTHOR]

From the 1950s onwards, programmes to promote aquaculture and improve capture fisheries in East Africa have relied heavily on the promise held by introduced species. In Tanzania these introductions have been poorly documented. Here we report the findings of surveys of inland water bodies across Tanzania between 2011 and 2017 that clarify distributions of tilapiine cichlids of the genus Oreochromis. We identified Oreochromis from 123 sampling locations, including 14 taxa restricted to their native range and three species that have established populations beyond their native range. Of these three species, the only exotic species found was blue-spotted tilapia (Oreochromis leucostictus), while Nile tilapia (Oreochromis niloticus) and Singida tilapia (Oreochromis esculentus), which are both naturally found within the country of Tanzania, have been translocated beyond their native range. Using our records, we developed models of suitable habitat for the introduced species based on recent (1960-1990) and projected (2050, 2070) East African climate. These models indicated that presence of suitable habitat for these introduced species will persist and potentially expand across the region. The clarification of distributions provided here can help inform the monitoring and management of biodiversity, and inform policy related to the future role of introduced species in fisheries and aquaculture. [ABSTRACT FROM AUTHOR]

Heparin, a major anticoagulant drug, comprises a complex mixture of motifs. Heparin is isolated from natural sources while being subjected to a variety of conditions but the detailed effects of these on heparin structure have not been studied in depth. Therefore, the result of exposing heparin to a range of buffered environments, ranging pH values from 7 to 12, and temperatures of 40, 60 and 80 °C were examined. There was no evidence of significant N-desulfation or 6-O-desulfation in glucosamine residues, nor of chain scission, however, stereochemical re-arrangement of α-L-iduronate 2-O-sulfate to α-L-galacturonate residues occurred in 0.1 M phosphate buffer at pH 12/80 °C. The results confirm the relative stability of heparin in environments like those during extraction and purification processes; on the other hand, the sensitivity of heparin to pH 12 in buffered solution at high temperature is highlighted, providing an important insight for heparin manufacturers. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: The impact of different physiological fluids on the rheological properties of gellan gum is investigated using a commercially available rheometer with a modified lower plate. The power of this method is demonstrated by measuring in real time, the rapid gelation kinetics, and gel strength of gellan gum exposed to simulated gastric fluid, lacrimal fluid, saliva, and wound fluid (all having a different ionic composition), highlighting potential use in the intelligent design of in situ gelling delivery systems. Changes in rheological behavior are examined in situ, gelation kinetics are modeled, and microstructure analyzed in the different simulated physiological environments. [ABSTRACT FROM AUTHOR]

Diclofenac topical formulations are often preferred for drug administration to patients who experience serious GIT problems. Absorption of the drug through the skin, however, can be challenging due to the natural protective feature of the stratum corneum (SC). In this article, fluid gels prepared from gellan gum were explored as a topical drug delivery vehicle. Rheological analysis of the formulations showed that it was possible to produce a topical gel with a viscosity and the mechanical strength similar to that of the commercially available Voltaren ® gel using 1% w/w of a 50:50 low acyl/high acyl (LA/HA) gellan blend. Soft-tribology was used to assess the lubrication properties of gellan fluid gels. The lubrication of the gellan gum fluid gel formulations at high rubbing speeds was similar to the lubrication of the Voltaren ® gel. The use of gellan gum dramatically increased skin permeation of diclofenac when compared with the commercially available formulation and could be controlled by changing the gellan gum concentration and/or sodium ion concentration in the formulation. This study highlights the potential use of fluid gels that can be easily tuned to have physical properties suitable for topical formulations with the added advantage of increasing drug permeation. [ABSTRACT FROM AUTHOR]

Mucins are the main macromolecular components of the mucus secretions that cover the oral cavity, gastrointestinal and urogenital tracts of animals. The properties of the mucus secretions are therefore directly correlated with the physicochemical properties of mucin glycoproteins. In this study, mucins were obtained from pig gastric mucous after digestion with pepsin at 37 °C for 4 h, these mucins were characterised in terms of compositional and hydrodynamic properties. Compositional analysis showed that this mucin contains protein (15%), carbohydrates (55%) of which the constituents are: fucose (4%), galactose (9%), glucosamine (55%), glucosamine (33%) and sialic acid (2%). The latter component gives the mucin polymer a pH-dependant negative charge, with a ζ-potential of −3 mV at pH 1.2 up to −11 mV at pH 7.4. The weight average molar mass was ∼1 × 10 6 g/mol and intrinsic viscosity was ∼0.42 dL/g although there was a small pH dependency due to the polyelectrolyte behavior of the polymer. The measurements of viscosity versus shear rate showed shear thinning behavior and the critical overlap concentration was determined to be 10–11% w/v indicating a compact structure. Knowledge of these properties is fundamental to the understanding interactions of mucins, with for example, novel drug delivery systems. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of autism spectrum disorder (ASD) at the earliest age possible is important for initiating optimally effective intervention. In the United States the average age of diagnosis is 4 years. Identifying metabolic biomarker signatures of ASD from blood samples offers an opportunity for development of diagnostic tests for detection of ASD at an early age. Objectives: To discover metabolic features present in plasma samples that can discriminate children with ASD from typically developing (TD) children. The ultimate goal is to identify and develop blood-based ASD biomarkers that can be validated in larger clinical trials and deployed to guide individualized therapy and treatment. Methods: Blood plasma was obtained from children aged 4 to 6, 52 with ASD and 30 age-matched TD children. Samples were analyzed using 5 mass spectrometry-based methods designed to orthogonally measure a broad range of metabolites. Univariate, multivariate and machine learning methods were used to develop models to rank the importance of features that could distinguish ASD from TD. Results: A set of 179 statistically significant features resulting from univariate analysis were used for multivariate modeling. Subsets of these features properly classified the ASD and TD samples in the 61-sample training set with average accuracies of 84% and 86%, and with a maximum accuracy of 81% in an independent 21-sample validation set. Conclusions: This analysis of blood plasma metabolites resulted in the discovery of biomarkers that may be valuable in the diagnosis of young children with ASD. The results will form the basis for additional discovery and validation research for 1) determining biomarkers to develop diagnostic tests to detect ASD earlier and improve patient outcomes, 2) gaining new insight into the biochemical mechanisms of various subtypes of ASD 3) identifying biomolecular targets for new modes of therapy, and 4) providing the basis for individualized treatment recommendations. [ABSTRACT FROM AUTHOR]

Titanium alloy (Ti6Al4V) is one of the most prominent biomaterials for bone contact because of its ability to bear mechanical loading and resist corrosion. The success of Ti6Al4V implants depends on bone formation on the implant surface. Hence, implant coatings which promote adhesion, proliferation and differentiation of bone-forming cells are desirable. One coating strategy is by adsorption of biomacromolecules. In this study, Ti6Al4V substrates produced by additive manufacturing (AM) were coated with whey protein isolate (WPI) fibrils, obtained at pH 2, and heparin or tinzaparin (a low molecular weight heparin LMWH) in order to improve the proliferation and differentiation of bone-forming cells. WPI fibrils proved to be an excellent support for the growth of human bone marrow stromal cells (hBMSC). Indeed, WPI fibrils were resistant to sterilization and were stable during storage. This WPI-heparin-enriched coating, especially the LMWH, enhanced the differentiation of hBMSC by increasing tissue non-specific alkaline phosphatase (TNAP) activity. Finally, the coating increased the hydrophilicity of the material. The results confirmed that WPI fibrils are an excellent biomaterial which can be used for biomedical coatings, as they are easily modifiable and resistant to heat treatments. Indeed, the already known positive effect on osteogenic integration of WPI-only coated substrates has been further enhanced by a simple adsorption procedure. [ABSTRACT FROM AUTHOR]

Both inter- and intrasexual selection have been implicated in the origin and maintenance of species-rich taxa with diverse sexual traits. Simultaneous disruptive selection by female mate choice and male-male competition can, in theory, lead to speciation without geographical isolation if both act on the same male trait. Female mate choice can generate discontinuities in gene flow, while male-male competition can generate negative frequency-dependent selection stabilizing the male trait polymorphism. Speciation may be facilitated when mating preference and/or aggression bias are physically linked to the trait they operate on. We tested for genetic associations among female mating preference, male aggression bias and male coloration in the Lake Victoria cichlid Pundamilia. We crossed females from a phenotypically variable population with males from both extreme ends of the phenotype distribution in the same population (blue or red). Male offspring of a red sire were significantly redder than males of a blue sire, indicating that intra-population variation in male coloration is heritable. We tested mating preferences of female offspring and aggression biases of male offspring using binary choice tests. There was no evidence for associations at the family level between female mating preferences and coloration of sires, but dam identity had a significant effect on female mate preference. Sons of the red sire directed significantly more aggression to red than blue males, whereas sons of the blue sire did not show any bias. There was a positive correlation among individuals between male aggression bias and body coloration, possibly due to pleiotropy or physical linkage, which could facilitate the maintenance of color polymorphism [ABSTRACT FROM AUTHOR]