Self-assembly of polyphosphazene immunoadjuvant with poly(ethylene oxide) enables advanced nanoscale delivery modalities and regulated pH-dependent cellular membrane activity

AbstractWater-soluble polyphosphazene polyacids, such as poly[di(carboxylatophenoxy)phosphazene] (PCPP), have been of significant interest due to their unique immunoadjuvant and vaccine delivery properties. We report that PCPP can spontaneously self-assemble into intermolecular complexes with common formulation excipients − polyethers in aqueous solutions at neutral pH through the establishment of hydrogen bonds. The resulting advanced PCPP delivery modalities can range from macromolecular assemblies at the nanoscale level to physically cross-linked hydrogels and the physical state can be modulated through varying polymer ratios and molecular weight of polyether. It has been demonstrated that such macromolecular complexes maintain protein-binding ability − a key characteristics of the delivery system. Importantly, the non-covalent modification of PCPP immunoadjuvant with polyethers introduces pH dependent membrane disruptive activity, which is not characteristic for PCPP itself, and is typically correlated to the ability of macromolecular carrier to facilitate endosomal escape. This can potentially affect the mechanism of immunoadjuvant action displayed by PCPP, afford means for its fine-tuning, as well as provide important insights for understanding the relationship between fundamental physico-chemical characteristics of polyphosphazene immunoadjuvants and their activity in vivo

Capital trading, stock trading, and the inflation tax on equity: a note

The authors show that there is more responsiveness of consumption and output to changes in the money supply than exists in the standard neoclassical growth models.Capital investments

Haemanthus coccineus extract and its main bioactive component narciclasine display profound anti-inflammatory activities in vitro and in vivo

Haemanthus coccineus extracts (HCE) have traditionally been used to treat a variety of diseases, like febrile colds or asthma. Since new therapeutic options against inflammatory processes are still urgently needed, we aimed to pharmacologically characterise the anti-inflammatory potential of HCEin vitro and in vivo and to identify the underlying bioactive component(s). The action of HCE on oedema formation and leucocyte infiltration were analysed in two murine models of inflammation (dermal oedema induced by arachidonic acid and croton oil;kidney injury caused by unilateral ureteral obstruction). The interaction of leucocytes with endothelial cells (ECs) as well as the activation parameters of these two cell types were analysed. Moreover, the nuclear factor B (NFB) pathway was investigated in detail in ECs. Using different fractions of HCE, the bioactive principle was identified. In vivo, HCE (450mg/kg orally or 2mg/kg intraperitoneally) inhibited oedema formation, leucocyte infiltration and cytokine synthesis. In vitro, HCE (100-300ng/ml) blocked leucocyte-EC interaction as well as the activation of isolated leucocytes (cytokine synthesis and proliferation) and of primary ECs (adhesion molecule expression). HCE suppressed NFB-dependent gene transcription in the endothelium, but did not interfere with the NFB activation cascade (IB degradation, p65 nuclear translocation and NFB DNA-binding activity). The alkaloid narciclasine was elucidated as the bioactive compound responsible for the anti-inflammatory action of HCE. Our study highlights HCE and its main alkaloid narciclasine as novel interesting approach for the treatment of inflammation-related disorders

Haemanthus coccineus extract and its main bioactive component narciclasine display profound anti-inflammatory activities in vitro and in vivo

Haemanthus coccineus extracts (HCE) have traditionally been used to treat a variety of diseases, like febrile colds or asthma. Since new therapeutic options against inflammatory processes are still urgently needed, we aimed to pharmacologically characterise the anti-inflammatory potential of HCEin vitro and in vivo and to identify the underlying bioactive component(s). The action of HCE on oedema formation and leucocyte infiltration were analysed in two murine models of inflammation (dermal oedema induced by arachidonic acid and croton oil;kidney injury caused by unilateral ureteral obstruction). The interaction of leucocytes with endothelial cells (ECs) as well as the activation parameters of these two cell types were analysed. Moreover, the nuclear factor B (NFB) pathway was investigated in detail in ECs. Using different fractions of HCE, the bioactive principle was identified. In vivo, HCE (450mg/kg orally or 2mg/kg intraperitoneally) inhibited oedema formation, leucocyte infiltration and cytokine synthesis. In vitro, HCE (100-300ng/ml) blocked leucocyte-EC interaction as well as the activation of isolated leucocytes (cytokine synthesis and proliferation) and of primary ECs (adhesion molecule expression). HCE suppressed NFB-dependent gene transcription in the endothelium, but did not interfere with the NFB activation cascade (IB degradation, p65 nuclear translocation and NFB DNA-binding activity). The alkaloid narciclasine was elucidated as the bioactive compound responsible for the anti-inflammatory action of HCE. Our study highlights HCE and its main alkaloid narciclasine as novel interesting approach for the treatment of inflammation-related disorders

Guidance on terminology, application, and reporting of citation searching: the TARCiS statement

Evidence syntheses adhering to systematic literature searching techniques are a cornerstone of evidence based healthcare. Beyond term based searching in electronic databases, citation searching is a prevalent search technique to identify relevant sources of evidence. However, for decades, citation searching methodology and terminology has not been standardised. An evidence guided, four round Delphi consensus study was conducted with 27 international methodological experts in order to develop the Terminology, Application, and Reporting of Citation Searching (TARCiS) statement. TARCiS comprises 10 specific recommendations, each with a rationale and explanation on when and how to conduct and report citation searching in the context of systematic literature searches. The statement also presents four research priorities, and it is hoped that systematic review teams are encouraged to incorporate TARCiS into standardised workflows

Acidification increases abundances of Vibrionales and Planctomycetia associated to a seaweed-grazer system: potential consequences for disease and prey digestion efficiency

Ocean acidification significantly affects marine organisms in several ways, with complex interactions. Seaweeds might benefit from rising CO2 through increased photosynthesis and carbon acquisition, with subsequent higher growth rates. However, changes in seaweed chemistry due to increased CO2 may change the nutritional quality of tissue for grazers. In addition, organisms live in close association with a diverse microbiota, which can also be influenced by environmental changes, with feedback effects. As gut microbiomes are often linked to diet, changes in seaweed characteristics and associated microbiome can affect the gut microbiome of the grazer, with possible fitness consequences. In this study, we experimentally investigated the effects of acidification on the microbiome of the invasive brown seaweed Sargassum muticum and a native isopod consumer Synisoma nadejda. Both were exposed to ambient CO2 conditions (380 ppm, pH 8.16) and an acidification treatment (1,000 ppm, pH 7.86) for three weeks. Microbiome diversity and composition were determined using high-throughput sequencing of the variable regions V5-7 of 16S rRNA. We anticipated that as a result of acidification, the seaweed-associated bacterial community would change, leading to further changes in the gut microbiome of grazers. However, no significant effects of elevated CO2 on the overall bacterial community structure and composition were revealed in the seaweed. In contrast, significant changes were observed in the bacterial community of the grazer gut. Although the bacterial community of S. muticum as whole did not change, Oceanospirillales and Vibrionales (mainly Pseudoalteromonas) significantly increased their abundance in acidified conditions. The former, which uses organic matter compounds as its main source, may have opportunistically taken advantage of the possible increase of the C/N ratio in the seaweed under acidified conditions. Pseudoalteromonas, commonly associated to diseased seaweeds, suggesting that acidification may facilitate opportunistic/pathogenic bacteria. In the gut of S. nadejda, the bacterial genus Planctomycetia increased abundance under elevated CO2. This shift might be associated to changes in food (S. muticum) quality under acidification. Planctomycetia are slow-acting decomposers of algal polymers that could be providing the isopod with an elevated algal digestion and availability of inorganic compounds to compensate the shifted C/N ratio under acidification in their food. In conclusion, our results indicate that even after only three weeks of acidified conditions, bacterial communities associated to ungrazed seaweed and to an isopod grazer show specific, differential shifts in associated bacterial community. These have potential consequences for seaweed health (as shown in corals) and isopod food digestion. The observed changes in the gut microbiome of the grazer seem to reflect changes in the seaweed chemistry rather than its microbial composition.Erasmus Mundus Doctoral Programme MARES on Marine Ecosystem Health Conservation [MARES_13_08]; FCT (Foundation for Science and Technology, Portugal) [SFRH/BPD/63703/2009, SFRH/BPD/107878/2015, SFRH/BPD/116774/2016]; EU SEAS-ERA project INVASIVES [SEAS-ERA/0001/2012]; [CCMAR/Multi/04326/2013

Femoral and vertebral strength improvements in postmenopausal women with osteoporosis treated with denosumab

In the randomized, placebo-controlled FREEDOM study of women aged 60 to 90 years with postmenopausal osteoporosis, treatment with denosumab once every 6 months for 36 months significantly reduced hip and new vertebral fracture risk by 40% and 68%, respectively. To gain further insight into this efficacy, we performed a nonlinear finite element analysis (FEA) of hip and spine quantitative computed tomography (QCT) scans to estimate hip and spine strength in a subset of FREEDOM subjects (n=48 placebo; n=51 denosumab) at baseline, 12, 24, and 36 months. We found that, compared with baseline, the finite element estimates of hip strength increased from 12 months (5.3%; p<0.0001) and through 36 months (8.6%; p<0.0001) in the denosumab group. For the placebo group, hip strength did not change at 12 months and decreased at 36 months (-5.6%; p<0.0001). Similar changes were observed at the spine: strength increased by 18.2% at 36 months for the denosumab group (p<0.0001) and decreased by -4.2% for the placebo group (p=0.002). At 36 months, hip and spine strength increased for the denosumab group compared with the placebo group by 14.3% (p<0.0001) and 22.4% (p<0.0001), respectively. Further analysis of the finite element models indicated that strength associated with the trabecular bone was lost at the hip and spine in the placebo group, whereas strength associated with both the trabecular and cortical bone improved in the denosumab group. In conclusion, treatment with denosumab increased hip and spine strength as estimated by FEA of QCT scans compared with both baseline and placebo owing to positive treatment effects in both the trabecular and cortical bone compartments. These findings provide insight into the mechanism by which denosumab reduces fracture risk for postmenopausal women with osteoporosis

A simple approach for detecting HLA-A02 alleles in archival formalin-fixed paraffin-embedded tissue samples and an application example for studying cancer immunoediting

The HLA system represents a central component of the antigen presentation machinery. As every patient possesses a defined set of HLA molecules, only certain antigens can be presented on the cell surface. Thus, studying HLA type-dependent antigen presentation can improve the understanding of variation in susceptibility to various diseases, including infectious diseases and cancer. In archival formalin-fixed paraffin-embedded (FFPE) tissue, the HLA type is difficult to analyze because of fragmentation of DNA, hindering the application of commonly used assays that rely on long DNA stretches. Addressing these difficulties, we present a refined approach for characterizing presence or absence of HLA-A*02, the most common HLA-A allele in the Caucasian population, in archival samples. We validated our genotyping strategy in a cohort of 90 samples with HLA status obtained by an NGS-based method. 90% (n = 81) of the samples could be analyzed with the approach. For all of them, the presence or absence of HLA-A*02 alleles was correctly determined with the method, demonstrating 100% sensitivity and specificity (95% CI: 91.40%-100% and 91.19%-100%). Furthermore, we provide an example of application in an independent cohort of 73 FFPE microsatellite-unstable (MSI) colorectal cancer samples. As MSI cancer cells encompass a high number of mutations in coding microsatellites, leading to the generation of highly immunogenic frameshift peptide antigens, they are ideally suited for studying relations between the mutational landscape of tumor cells and interindividual differences in the immune system, including the HLA genotype. Overall, our method can help to promote studying HLA type-dependency during the pathogenesis of a wide range of diseases, making archival and historic tissue samples accessible for identifying HLA-A*02 alleles.Peer reviewe