Developing methodology to evaluate the oral sensory features of pharmaceutical tablet coatings

Acceptability of medicines is critical for effective pharmacotherapy. The aim of this study was to investigate the oral sensory properties of tablet coatings to determine how mouthfeel can improve acceptability. A randomised double-blind study was performed in 84 adult volunteers (51% ≥55 years). Each participant received 4 placebo tablets (3 coated and 1 uncoated) to evaluate (i) ease of swallowing and (ii) palatability. Visual analogue scales (VAS) were used to capture sensory parameters. Acceptability was assessed using the following parameters: ease of swallowing; amount of water taken with the tablet; rank order of preference; roughness; adhesiveness and slipperiness. Ease of swallowing was determined to be the most sensitive measure of acceptance. The best coating was the one that was reported to be the most slippery and smooth. The presence of a coating improved ease of swallowing, mouthfeel and overall palatability. This study demonstrates that slippery coatings improve acceptability of tablets. The study also demonstrates the value of VAS to measure the sensory attributes of coated tablets

Hypercomplex Integrable Systems

In this paper we study hypercomplex manifolds in four dimensions. Rather than using an approach based on differential forms, we develop a dual approach using vector fields. The condition on these vector fields may then be interpreted as Lax equations, exhibiting the integrability properties of such manifolds. A number of different field equations for such hypercomplex manifolds are derived, one of which is in Cauchy-Kovaleskaya form which enables a formal general solution to be given. Various other properties of the field equations and their solutions are studied, such as their symmetry properties and the associated hierarchy of conservation laws.Comment: Latex file, 19 page

CLE Peptides can Negatively Regulate Protoxylem Vessel Formation via Cytokinin Signaling

Cell–cell communication is critical for tissue and organ development. In plants, secretory CLAVATA3/EMBRYO SURROUNDING REGION-related (CLE) peptides function as intercellular signaling molecules in various aspects of tissue development including vascular development. However, little is known about intracellular signaling pathways functioning in vascular development downstream of the CLE ligands. We show that CLE peptides including CLE10, which is preferentially expressed in the root vascular system, inhibit protoxylem vessel formation in Arabidopsis roots. GeneChip analysis displayed that CLE10 peptides repressed specifically the expression of two type-A Arabidopsis Response Regulators (ARRs), ARR5 and ARR6, whose products act as negative regulators of cytokinin signaling. The arr5 arr6 roots exhibited defective protoxylem vessel formation. These results indicate that CLE10 inhibits protoxylem vessel formation by suppressing the expression of type-A ARR genes including ARR5 and ARR6. This was supported by the finding that CLE10 did not suppress protoxylem vessel formation in a background of arr10 arr12, a double mutant of type-B ARR genes. Thus, our results revealed cross-talk between CLE signaling and cytokinin signaling in protoxylem vessel formation in roots. Taken together with the indication that cytokinin signaling functions downstream of the CLV3/WUS signaling pathway in the shoot apical meristem, the cross-talk between CLE and cytokinin signaling pathways may be a common feature in plant development

An optimized algorithm for detecting and annotating regional differential methylation

Background: DNA methylation profiling reveals important differentially methylated regions (DMRs) of the genome that are altered during development or that are perturbed by disease. To date, few programs exist for regional analysis of enriched or whole-genome bisulfate conversion sequencing data, even though such data are increasingly common. Here, we describe an open-source, optimized method for determining empirically based DMRs (eDMR) from high-throughput sequence data that is applicable to enriched whole-genome methylation profiling datasets, as well as other globally enriched epigenetic modification data. Results: Here we show that our bimodal distribution model and weighted cost function for optimized regional methylation analysis provides accurate boundaries of regions harboring significant epigenetic modifications. Our algorithm takes the spatial distribution of CpGs into account for the enrichment assay, allowing for optimization of the definition of empirical regions for differential methylation. Combined with the dependent adjustment for regional p-value combination and DMR annotation, we provide a method that may be applied to a variety of datasets for rapid DMR analysis. Our method classifies both the directionality of DMRs and their genome-wide distribution, and we have observed that shows clinical relevance through correct stratification of two Acute Myeloid Leukemia (AML) tumor sub-types. Conclusions: Our weighted optimization algorithm eDMR for calling DMRs extends an established DMR R pipeline (methylKit) and provides a needed resource in epigenomics. Our method enables an accurate and scalable way of finding DMRs in high-throughput methylation sequencing experiments. eDMR is available for download at http://code.google.com/p/edmr/.Sheng Li, Francine E Garrett-Bakelman, Altuna Akalin, Paul Zumbo, Ross Levine, Bik L To, Ian D Lewis, Anna L Brown, Richard J D’Andrea, Ari Melnick, Christopher E Maso

Conjugation with L, L-diphenylalanine Self-Assemblies Enhances In Vitro Antitumor Activity of Phthalocyanine Photosensitizer

We present the synthesis and characterization of new peptide conjugates obtained by hierarchical co-assembly of L,L-diphenylalanine (FF) and zinc phthalocyanine complexes (ZnPc) in water. Self-assembly capabilities under defined conditions were investigated by scanning electron microscopy, and photophysical properties were evaluated using UV-Vis and fluorescence spectroscopy. AFM observations demonstrated that these ZnPcs form different highly ordered arrays on the crystalline faces of the FF microplates and that surface roughness significantly changes with the presence of differently substituted phthalocyanine units. XRD assays showed that the overall molecular packing of the conjugates is organized according to a hexagonal symmetry, with ZnPcs hosted in the interstices of the peptide phase. In vitro photodynamic studies were conducted on human breast cancer MCF-7 cells to investigate both cellular uptake and cytotoxicity. It was shown that FF self-assemblies are not toxicity and enhance accumulation of ZnPc in MCF-7 cells, improving apoptotic cell death upon irradiation. Our findings demonstrate enhancement of ZnPc antitumor efficiency by FF conjugates and a proof-of-concept for new photosensitizer carriers based on peptide conjugates

Scientific Opinion on the safety and efficacy of niacin (nicotinic acid and nicotinamide) as a feed additive for all animal species based on a dossier submitted by Lonza Benelux BV

<p>The term ‘niacin’ is used as a generic description of nicotinic acid and nicotinamide with pyridine as the basic structure. Nicotinic acid and nicotinamide function mainly as precursors of the co-enzymes NAD and NADP. Thus, nicotinamide has physiologically critical roles in mitochondrial respiration and in the metabolism of carbohydrates, lipids, and amino acids. Oral administration routes of nicotinic acid and nicotinamide via feed or water for drinking were considered bioequivalent. Niacin is safe for the target animals with a margin of safety that is at least ten times the requirements and use levels. The FEEDAP Panel assumes that exposure figures for a population already include the contribution of edible tissues and products of animals fed niacin-supplemented diets. Information on niacin metabolism and the limited data available on retention in edible tissues and products indicate that supplemental levels in feeds even far higher than the requirements (1–35 mg/kg feed) are highly unlikely to lead the tolerable upper intake level being exceeded. The FEEDAP Panel considers that the use of niacin in animal nutrition is not of safety concern for consumers. Nicotinic acid and nicotinamide are not irritant to skin, but can cause irritancy to eyes and mucous membranes. They are unlikely to cause skin sensitisation. Workers might be exposed to a respirable dust when handling nicotinic acid, which should be regarded as being potentially harmful to their health. Nicotinamide is considered to be of no concern for inhalation exposure. The use of nicotinic acid and nicotinamide in animal nutrition does not pose a risk to the environment. Nicotinic acid and nicotinamide are regarded as effective sources of niacin in animal nutrition.</p&gt

South Asia as a Reservoir for the Global Spread of Ciprofloxacin-Resistant Shigella sonnei: A Cross-Sectional Study.

BACKGROUND: Antimicrobial resistance is a major issue in the Shigellae, particularly as a specific multidrug-resistant (MDR) lineage of Shigella sonnei (lineage III) is becoming globally dominant. Ciprofloxacin is a recommended treatment for Shigella infections. However, ciprofloxacin-resistant S. sonnei are being increasingly isolated in Asia and sporadically reported on other continents. We hypothesized that Asia is a primary hub for the recent international spread of ciprofloxacin-resistant S. sonnei. METHODS AND FINDINGS: We performed whole-genome sequencing on a collection of 60 contemporaneous ciprofloxacin-resistant S. sonnei isolated in four countries within Asia (Vietnam, n = 11; Bhutan, n = 12; Thailand, n = 1; Cambodia, n = 1) and two outside of Asia (Australia, n = 19; Ireland, n = 16). We reconstructed the recent evolutionary history of these organisms and combined these data with their geographical location of isolation. Placing these sequences into a global phylogeny, we found that all ciprofloxacin-resistant S. sonnei formed a single clade within a Central Asian expansion of lineage III. Furthermore, our data show that resistance to ciprofloxacin within S. sonnei may be globally attributed to a single clonal emergence event, encompassing sequential gyrA-S83L, parC-S80I, and gyrA-D87G mutations. Geographical data predict that South Asia is the likely primary source of these organisms, which are being regularly exported across Asia and intercontinentally into Australia, the United States and Europe. Our analysis was limited by the number of S. sonnei sequences available from diverse geographical areas and time periods, and we cannot discount the potential existence of other unsampled reservoir populations of antimicrobial-resistant S. sonnei. CONCLUSIONS: This study suggests that a single clone, which is widespread in South Asia, is likely driving the current intercontinental surge of ciprofloxacin-resistant S. sonnei and is capable of establishing endemic transmission in new locations. Despite being limited in geographical scope, our work has major implications for understanding the international transfer of antimicrobial-resistant pathogens, with S. sonnei acting as a tractable model for studying how antimicrobial-resistant Gram-negative bacteria spread globally

Harmonising data collection from osteoarthritis studies to enable stratification: recommendations on core data collection from an Arthritis Research UK clinical studies group

Objective. Treatment of OA by stratifying for commonly used and novel therapies will likely improve the range of effective therapy options and their rational deployment in this undertreated, chronic disease. In order to develop appropriate datasets for conducting post hoc analyses to inform approaches to stratification for OA, our aim was to develop recommendations on the minimum data that should be recorded at baseline in all future OA interventional and observational studies.Methods. An Arthritis Research UK study group comprised of 32 experts used a Delphi-style approach supported by a literature review of systematic reviews to come to a consensus on core data collection for OA studies.Results. Thirty-five systematic reviews were used as the basis for the consensus group discussion. For studies with a primary structural endpoint, core domains for collection were defined as BMI, age, gender, racial origin, comorbidities, baseline OA pain, pain in other joints and occupation. In addition to the items generalizable to all anatomical sites, joint-specific domains included radiographic measures, surgical history and anatomical factors, including alignment. To demonstrate clinical relevance for symptom studies, the collection of mental health score, self-efficacy and depression scales were advised in addition to the above.Conclusions. Currently it is not possible to stratify patients with OA into therapeutic groups. A list of core and optional data to be collected in all OA interventional and observational studies was developed, providing a basis for future analyses to identify predictors of progression or response to treatment

Dynamic evolution of clonal epialleles revealed by methclone

We describe methclone, a novel method to identify epigenetic loci that harbor large changes in the clonality of their epialleles (epigenetic alleles). Methclone efficiently analyzes genome-wide DNA methylation sequencing data. We quantify the changes using a composition entropy difference calculation and also introduce a new measure of global clonality shift, loci with epiallele shift per million loci covered, which enables comparisons between different samples to gauge overall epiallelic dynamics. Finally, we demonstrate the utility of methclone in capturing functional epiallele shifts in leukemia patients from diagnosis to relapse. Methclone is open-source and freely available at https://code.google.com/p/methclone.Sheng Li, Francine Garrett-Bakelman, Alexander E Perl, Selina M Luger, Chao Zhang, Bik L To, Ian D Lewis, Anna L Brown, Richard J D’Andrea, M Elizabeth Ross, Ross Levine, Martin Carroll, Ari Melnick, and Christopher E Maso

Two-Component Elements Mediate Interactions between Cytokinin and Salicylic Acid in Plant Immunity

Recent studies have revealed an important role for hormones in plant immunity. We are now beginning to understand the contribution of crosstalk among different hormone signaling networks to the outcome of plant–pathogen interactions. Cytokinins are plant hormones that regulate development and responses to the environment. Cytokinin signaling involves a phosphorelay circuitry similar to two-component systems used by bacteria and fungi to perceive and react to various environmental stimuli. In this study, we asked whether cytokinin and components of cytokinin signaling contribute to plant immunity. We demonstrate that cytokinin levels in Arabidopsis are important in determining the amplitude of immune responses, ultimately influencing the outcome of plant–pathogen interactions. We show that high concentrations of cytokinin lead to increased defense responses to a virulent oomycete pathogen, through a process that is dependent on salicylic acid (SA) accumulation and activation of defense gene expression. Surprisingly, treatment with lower concentrations of cytokinin results in increased susceptibility. These functions for cytokinin in plant immunity require a host phosphorelay system and are mediated in part by type-A response regulators, which act as negative regulators of basal and pathogen-induced SA–dependent gene expression. Our results support a model in which cytokinin up-regulates plant immunity via an elevation of SA–dependent defense responses and in which SA in turn feedback-inhibits cytokinin signaling. The crosstalk between cytokinin and SA signaling networks may help plants fine-tune defense responses against pathogens