Improving oral drug bioavailability with polycations?

The administration of drugs via the oral route is challenging due to the (bio)chemical aggressivity of the digestive system and to the presence of barriers that hinder cell uptake and access to the bloodstream. Indeed, the gastrointestinal tract is characterized by large variations of pH, the presence of enzymes and surfactants, and by absorption barriers such as mucus and the epithelium. Thus, many compounds such as proteins and nucleic acids do not reach the systemic circulation due to their premature degradation and/or large size.

Biogenesis, delivery, and function of extracellular RNA.

The Extracellular RNA (exRNA) Communication Consortium was launched by the National Institutes of Health to focus on the extent to which RNA might function in a non-cell-autonomous manner. With the availability of increasingly sensitive tools, small amounts of RNA can be detected in serum, plasma, and other bodily fluids. The exact mechanism(s) by which RNA can be secreted from cells and the mechanisms for the delivery and uptake by recipient cells remain to be determined.

A functional perspective on phenotypic heterogeneity in microorganisms.

Most microbial communities consist of a genetically diverse assembly of different organisms, and the level of genetic diversity plays an important part in community properties and functions. However, biological diversity also arises at a lower level of biological organization, between genetically identical cells that reside in the same microenvironment. In this Review, I outline the molecular mechanisms responsible for phenotypic heterogeneity and discuss how phenotypic heterogeneity allows genotypes to persist in fluctuating environments.

Alternatively Spliced EDA Domain of Fibronectin Is a Target for Pharmacodelivery Applications in Inflammatory Bowel Disease.

The antibody-based pharmacodelivery of cytokines to sites of disease has been extensively studied for various indications but not for the treatment of inflammatory bowel diseases. Here, we report that the alternatively spliced EDA domain of fibronectin, a marker of angiogenesis and of tissue remodeling, is expressed in the dextran sodium sulfate mouse model of colitis and in patients with inflammatory bowel conditions, while being virtually undetectable in most normal adult tissues. Radiolabeled preparations of the F8 antibody, specific to the EDA domain of fibronectin, were shown to selectively localize to sites of inflammation in mice with colitis, as revealed by autoradiographic analysis.

Bio-inspired wooden actuators for large scale applications.

Implementing programmable actuation into materials and structures is a major topic in the field of smart materials. In particular the bilayer principle has been employed to develop actuators that respond to various kinds of stimuli. A multitude of small scale applications down to micrometer size have been developed, but up-scaling remains challenging due to either limitations in mechanical stiffness of the material or in the manufacturing processes.

Insights into PBDE Uptake, Body Burden, and Elimination Gained from Australian Age-Concentration Trends Observed Shortly after Peak Exposure.

Background: Population pharmacokinetic models combined with multiple sets of age-concentration biomonitoring data facilitate back-calculation of chemical uptake rates from biomonitoring data.

Objectives: We back-calculated uptake rates of PBDEs for the Australian population from multiple biomonitoring surveys (top-down) and compared them with uptake rates calculated from dietary intake estimates of PBDEs and PBDE concentrations in dust (bottom-up).

Methods: Using three sets of PBDE elimination half-lives, we applied a population pharmacokinetic model to the PBDE biomonitoring data measured between 2002-2003 and 2010-2011 to derive the top-down uptake rates of four key PBDE congeners and six age groups.

The antibody-mediated targeted delivery of interleukin-13 to syngeneic murine tumors mediates a potent anticancer activity.

We describe the expression and in vivo characterization of an antibody-cytokine fusion protein, based on murine Interleukin-13 (IL13) and the monoclonal antibody F8, specific to the alternatively spliced extra domain A of fibronectin, a marker of neo-angiogenesis. The IL13 moiety was fused at the C-terminal extremity of the F8 antibody in diabody format. The resulting F8-IL13 immunocytokine retained the full binding properties of the parental antibody and cytokine bioactivity.

Semi-permeable coatings fabricated from comb-polymers efficiently protect proteins in vivo.

In comparison to neutral linear polymers, functional and architecturally complex (that is, non-linear) polymers offer distinct opportunities for enhancing the properties and performance of therapeutic proteins. However, understanding how to harness these parameters is challenging, and studies that capitalize on them in vivo are scarce. Here we present an in vivo demonstration that modification of a protein with a polymer of appropriate architecture can impart low immunogenicity, with a commensurably low loss of therapeutic activity.

Silica nanoparticles induce endoplasmic reticulum stress response, oxidative stress and activate the mitogen-activated protein kinase (MAPK) signaling pathway.

Application of silica nanoparticles (SiO-NPs) may result in human exposure. Here we investigate unexplored modes of action by which SiO-NPs with average size of 225 nm act on human hepatoma cells (Huh7). We focused on the endoplasmic (ER) stress response and on mitogen-activated protein kinase (MAPK) signaling pathways.

Evaluation of antibody-chemokine fusion proteins for tumor-targeting applications.

There is an increasing biotechnological interest in the 'arming' of therapeutic antibodies with bioactive payloads. While many antibody-cytokine fusion proteins have been extensively investigated in preclinical and clinical studies, there are only few reports related to antibody-chemokine fusion proteins ('immunochemokines'). Here, we describe the cloning, expression, and characterization of 10 immunochemokines based on the monoclonal antibody F8, specific to the alternatively spliced extra domain A (EDA) of fibronectin, a marker of angiogenesis.

Tumor-targeting properties of novel immunocytokines based on murine IL1β and IL6.

There is an increasing biotechnological interest in 'arming' therapeutic antibodies with bioactive payloads. Many antibody-cytokine fusion proteins (immunocytokines) have been described and some of these biopharmaceuticals have progressed to clinical studies. Here, we describe for the first time the expression and in vivo characterization of immunocytokines based on murine IL1β and IL6.

Targeting of injectable drug nanocrystals.

"Nano" drug delivery carriers are established technologies for improving the therapeutic index of chemotherapeutic drugs and overcoming formulation challenges of poorly water-soluble compounds. Two important remaining challenges, however, are the need to formulate drugs on a case-by-case basis (due to the specific chemistry of each drug) and the difficulty associated with transporting large amounts of drug specifically to the site of the tumor (in part because of moderate to poor drug loadings). One of the most valuable "nano" opportunities in this field is to address these challenges by creating nanocarriers composed of the drug itself, in the form of so-called nanocrystals.

Tissue-, sex- and development-specific transcription profiles of eight UDP-glucuronosyltransferase genes in zebrafish (Danio rerio) and their regulation by activator of aryl hydrocarbon receptor.

UDP-Glucuronosyltransferases (Ugts) are phase II biotransformation enzymes that glucuronidate numerous endogenous and xenobiotic substrates. Based on the reported zebrafish Ugt gene repertoire, primers for the Ugt1a and Ugt1b family and for individual Ugt5a1, Ugt5a3, Ugt5a4, Ugt5a5, Ugt5c2 and Ugt5c3 were designed and applied in RT-qPCR analyses. Transcriptional expression profiles of these Ugts were analyzed in intestine, liver, gonad and brain of female and male adult zebrafish and at different embryonic developmental stages.

Circulating glucagon-like peptide-1 (GLP-1) inhibits eating in male rats by acting in the hindbrain and without inducing avoidance.

To address the neural mediation of the eating-inhibitory effect of circulating glucagon-like peptide-1 (GLP-1), we investigated the effects of 1) intra-fourth ventricular infusion of the GLP-1 receptor antagonist exendin-9 or 2) area postrema lesion on the eating-inhibitory effect of intrameal hepatic portal vein (HPV) GLP-1 infusion in adult male rats. To evaluate the physiological relevance of the observed effect we examined 3) the influence of GLP-1 on flavor acceptance in a 2-bottle conditioned flavor avoidance test, and 4) measured active GLP-1 in the HPV and vena cava (VC) in relation to a meal and in the VC after HPV GLP-1 infusion. Intrameal HPV GLP-1 infusion (1 nmol/kg body weight-5 min) specifically reduced ongoing meal size by almost 40% (P < .

Explaining microbial genomic diversity in light of evolutionary ecology.

Comparisons of closely related microorganisms have shown that individual genomes can be highly diverse in terms of gene content. In this Review, we discuss several studies showing that much of this variation is associated with social and ecological interactions, which have an important role in the population biology of wild populations of bacteria and archaea. These interactions create frequency-dependent selective pressures that can either stabilize gene frequencies at intermediate levels in populations or promote fast gene turnover, which presents as low gene frequencies in genome surveys.

RNA silencing suppression by plant pathogens: defence, counter-defence and counter-counter-defence.

RNA silencing is a central regulator of gene expression in most eukaryotes and acts both at the transcriptional level through DNA methylation and at the post-transcriptional level through direct mRNA interference mediated by small RNAs. In plants and invertebrates, the same pathways also function directly in host defence against viruses by targeting viral RNA for degradation. Successful viruses have consequently evolved diverse mechanisms to avoid silencing, most notably through the expression of viral suppressors of RNA silencing.

Modular design of redox-responsive stabilizers for nanocrystals.

Many potent drugs are difficult to administer intravenously due to poor aqueous solubility. A common approach for addressing this issue is to process them into colloidal dispersions known as "nanocrystals" (NCs). However, NCs possess high-energy surfaces that must be stabilized with surfactants to prevent aggregation.

A Safer Formulation Concept for Flame-Generated Engineered Nanomaterials.

The likely success or failure of the nanotechnology industry depends on the environmental health and safety of engineered nanomaterials (ENMs). While efforts toward engineering safer ENMs are sparse, such efforts are considered crucial to the sustainability of the nanotech industry. A promising approach in this regard is to coat potentially toxic nanomaterials with a biologically inert layer of amorphous SiO.

Enhanced cellulose orientation analysis in complex model plant tissues.

The orientation distribution of cellulose microfibrils in the plant cell wall is a key parameter for understanding anisotropic plant growth and mechanical behavior. However, precisely visualizing cellulose orientation in the plant cell wall has ever been a challenge due to the small size of the cellulose microfibrils and the complex network of polymers in the plant cell wall. X-ray diffraction is one of the most frequently used methods for analyzing cellulose orientation in single cells and plant tissues, but the interpretation of the diffraction images is complex.

Drought-adaptation potential in Fagus sylvatica: linking moisture availability with genetic diversity and dendrochronology.

Background: Microevolution is essential for species persistence especially under anticipated climate change scenarios. Species distribution projection models suggested that the dominant tree species of lowland forests in Switzerland, European beech (Fagus sylvatica L.), might disappear from most areas due to expected longer dry periods.

Occurrence and stability of inorganic and organic arsenic species in wines, rice wines and beers from Central European market.

We investigated in total 80 wine samples of different types and seven grape juice and 23 beer samples purchased from markets in Central Europe in order to understand the arsenic (As) speciation and help assess the potential As toxicity via intake of alcoholic beverages. Generally, total As concentrations in most samples investigated were below the drinking water limit 10 µg l(-1) published by the World Health Organization (WHO); ranging from 0.46 to 21.

MK2-dependent p38b signalling protects Drosophila hindgut enterocytes against JNK-induced apoptosis under chronic stress.

The integrity of the intestinal epithelium is crucial for the barrier function of the gut. Replenishment of the gut epithelium by intestinal stem cells contributes to gut homeostasis, but how the differentiated enterocytes are protected against stressors is less well understood. Here we use the Drosophila larval hindgut as a model system in which damaged enterocytes are not replaced by stem cell descendants.

A novel platform for pulmonary and cardiovascular toxicological characterization of inhaled engineered nanomaterials.

A novel method is presented which is suitable for assessing in vivo the link between the physicochemical properties of engineered nanomaterials (ENM) and their biological outcomes. The ability of the technique to generate a variety of industry-relevant, property-controlled ENM exposure atmospheres for inhalation studies was systematically investigated. The primary particle size for Fe(2)O(3), SiO(2), Ag and Ag/SiO(2) was controlled from 4 to 25 nm, while the corresponding agglomerate mobility diameter of the aerosol was also controlled and varied from 40 to 120 nm.

General practitioners are the future intermediaries.

Rationale, Aims And Objectives: Technological changes will have a large influence on medical practice. This article discusses the influences of technology and innovation on the role of general practitioners.

Methods: This conceptual paper is based on a triangulation of expert discussions and literature studies.