Cationic carbosilane dendrimers and oligonucleotide binding: an energetic affair

GENERATION 2 CATIONIC CARBOSILANE DENDRIMERS HOLD GREAT PROMISE AS INTERNALIZING AGENTS FOR GENE THERAPY AS THEY PRESENT LOW TOXICITY AND RETAIN AND INTERNALIZE GENETIC MATERIAL AS OLIGONUCLEOTIDE OR SIRNA. IN THIS WORK WE CARRIED OUT A COMPLETE IN SILICO STRUCTURAL AND ENERGETICAL CHARACTERIZATION OF THE INTERACTIONS OF A SET OF 2G CARBOSILANE DENDRIMERS, SHOWING DIFFERENT AFFINITY TOWARDS TWO SINGLE STRAND OLIGONUCLEOTIDE (ODN) SEQUENCES IN VITRO. OUR SIMULATIONS PREDICT THAT THESE FOUR DENDRIMERS AND THE RELEVANT ODN COMPLEXES ARE CHARACTERIZED BY SIMILAR SIZE AND SHAPE, AND THAT THE MOLECULE-SPECIFIC ODN BINDING ABILITY CAN BE RATIONALIZED ONLY CONSIDERING A CRITICAL MOLECULAR DESIGN PARAMETER: THE NORMALIZED EFFECTIVE BINDING ENERGY \u394GBIND,EFF/NEFF I.E., THE PERFORMANCE OF EACH ACTIVE INDIVIDUAL DENDRIMER BRANCH DIRECTLY INVOLVED IN A BINDING INTERACTIO

Against extraction in Guatemala: multispecies strategies in vampiric times

In this article, we develop a speculative analysis of the agential modalities connected to the extractive industries that dominate the present history of Guatemala. We focus on appropriation, extraction and the destruction of places of refuge for humans and non-humans, as well as on the strategies and responses that emerge for thinking and doing ‘in the ruins’ (Tsing 2015) in seemingly apocalyptic conditions. We mobilize technoscience, multispecies thinking and Indigenous epistemologies to develop a decolonial theorization of the multiple agential modalities in play in these contemporary dynamics. More specifically, through the figures of the vampire and the snail, we explore structures of terror in the colonial order, multispecies strategies against capture, and the colonial matrix underpinning different planes and scales of mining of territory, bodies and substance. Contemporary forms of extraction are the manifestation of colonial practices, but are also tied to strategies of resistance to colonial machines and sex/race dispositifs (AVANCSO 2015) by Indigenous, poor and marginal constituencies organizing in defense of the commons. The article deploys decolonial knowledge practices and epistemologies for an analysis of the material-semiotic dimensions of extraction and racism in contemporary Guatemala

Light driven water oxidation by a single site cobalt salophen catalyst

A salophen cobalt(II) complex enables water oxidation at neutral pH in photoactivated sacrificial cycles under visible light, thus confirming the high appeal of earth abundant single site catalysis for artificial photosynthesis

Electrostatic binding of polyanions using self-assembled multivalent (SAMul) ligand displays-structure-activity effects on DNA/heparin binding

This paper reports that modifying the ligands in self-assembled multivalent (SAMul) displays has an impact on apparent binding selectivity towards two nanoscale biological polyanions-heparin and DNA. For the nanostructures assayed here, spermidine ligands are optimal for heparin binding but spermine ligands are preferred for DNA. Probing subtle differences in such nanoscale binding interfaces is a significant challenge, and as such, several experimental binding assays-competition assays and isothermal calorimetry-are employed to confirm differences in affinity and provide thermodynamic insights. Given the dynamic nature and hierarchical binding processes involved in SAMul systems, we employed multiscale modelling to propose reasons for the origins of polyanion selectivity differences. The modelling results, when expressed in thermodynamic terms and compared with the experimental data, suggest that DNA is a shape-persistent polyanion, and selectivity originates only from ligand preferences, whereas heparin is more flexible and adaptive, and as such, actively reinforces ligand preferences. As such, this study suggests that inherent differences between polyanions may underpin subtle binding selectivity differences, and that even simple electrostatic interfaces such as these can have a degree of tunability, which has implications for biological control and regulation on the nanoscale

Emergence of highly-ordered hierarchical nanoscale aggregates on electrostatic binding of self-assembled multivalent (SAMul) cationic micelles with polyanionic heparin

We report three surfactants, with cationic N,N-di-(3-aminopropyl)-N-methylamine (DAPMA) head groups and aliphatic chains connected via an amide linkage, and investigate their ability to self-assemble and bind polyanionic heparin – a process of potential clinical importance in coagulation control. Modifying the hydrophobic chain length tunes the self-assembly event, with C16-DAPMA having the lowest critical micelle concentration and also being the optimal heparin binder. Remarkably highly structured hierarchical nanoscale aggregates are formed on binding between the spherical cationic micelles and linear polyanionic heparin. C14-DAPMA and C16-DAPMA yield organized polycrystalline assemblies as observed by transmission electron microscopy (TEM), predicted in solution by mesoscale simulations and characterized by small-angle X-ray scattering (SAXS). This confirms that the micelles remain intact during the hierarchical assembly process and become packed in a face-centered cubic manner. The nanoscale assembly formed by C16-DAPMA showed the highest degree of order. Importantly, these studies indicate the impact of hydrophobic modification on self-assembly and heparin binding, demonstrate remarkably high stability of these self-assembled micelles even when forming strong electrostatic interactions with heparin, and provide structural insights into nanoscale hierarchical electrostatic assemblies

An Integrated Pharmacological Counselling Approach to Guide Decision-Making in the Treatment with CDK4/6 Inhibitors for Metastatic Breast Cancer

A wide inter-individual variability in the therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) has been reported. We herein present a case series of five patients treated with either palbociclib or ribociclib referred to our clinical pharmacological counselling, including therapeutic drug monitoring (TDM), pharmacogenetics, and drug–drug interaction analysis to support clinicians in the management of CDKis treatment for metastatic breast cancer. Patients’ plasma samples for TDM analysis were collected at steady state and analyzed by an LC-MS/MS method for minimum plasma concentration (Cmin) evaluation. Under and overexposure to the drug were defined based on the mean Cmin values observed in population pharmacokinetic studies. Polymorphisms in selected genes encoding for proteins involved in drug absorption, distribution, metabolism, and elimination were analyzed (CYP3A4, CYP3A5, ABCB1, SLCO1B1, and ABCG2). Three of the five reported cases presented a CDKi plasma level above the population mean value and were referred for toxicity. One of them presented a low function ABCB1 haplotype (ABCB1-rs1128503, rs1045642, and rs2032582), possibly causative of both increased drug oral absorption and plasmatic concentration. Two patients showed underexposure to CDKis, and one of them was referred for early progression. In one patient, a CYP3A5*1/*3 genotype was found to be potentially responsible for more efficient drug metabolism and lower drug plasma concentration. This intensified pharmacological approach in clinical practice has been shown to be potentially effective in supporting prescribing oncologists with dose and drug selection and could be ultimately useful for increasing both the safety and efficacy profiles of CDKi treatment

Population pharmacokinetic modelling of imatinib in healthy subjects receiving a single dose of 400 mg

Purpose: Imatinib is indicated for treatment of CML, GIST, etc. The population pharmacokinetics (popPK) of imatinib in patients under long-term treatment are reported in literature. Data obtained from bioequivalence trials for healthy subjects were used to evaluate the influence of demographic and pharmacogenetic factors on imatinib pharmacokinetics (PK) in a collective without concurrent drugs, organ dysfunction, inflammation etc. In addition, the differences in PK between the healthy subjects and a patient cohort was examined to identify possible disease effects. Methods: 26 volunteers were administered orally with single dose of 400 mg imatinib. 16–19 plasma samples per volunteer were collected from 0.5 up to 72 h post-dose. The popPK was built and post hoc estimates were compared with previously published PK parameters evaluated by non-compartmental analysis in the same cohort. The predictivity of the model for data collected from 40 patients with gastrointestinal stromal tumors at steady state was evaluated. Results: The popPK was best described by a two-compartment transit model with first-order elimination. No significant covariates were identified, probably due to the small cohort and the narrow range of demographic covariates; CYP3A5 phenotypes appeared to have some influence on the clearance of imatinib. Good agreement between non-compartment and popPK analyses was observed with the differences of the geometric means/ median of PK estimates below 10%. The model indicated lower clearance for patients compared to healthy volunteers (p value < 0.01). Conclusion: The two-compartment transit model adequately describes the absorption and distribution of imatinib in healthy volunteers. For patients, a lower clearance of imatinib compared to healthy volunteer was estimated by the model. The model can be applied for dose individualization based on trough concentrations assuming no significant differences in absorption between patients and healthy volunteersThis work was part of the master these of Yi-Han Chien. There was no funding for this work. P. Zubiaur’s contract with CIBERehd is fnanced by the “Infraestructura de Medicina de Precisión asociada a la Ciencia y Tecnología (IMPaCT, IMP/00009)”, Instituto de Salud Carlos III (ISCIII

Adverse psychiatric effects associated with herbal weight-loss products

Date of Acceptance: 02/08/2015. Copyright © 2015 F. Saverio Bersani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly citedObesity and overeating are among the most prevalent health concerns worldwide and individuals are increasingly using performance and image-enhancing drugs (PIEDs) as an easy and fast way to control their weight. Among these, herbal weight-loss products (HWLPs) often attract users due to their health claims, assumed safety, easy availability, affordable price, extensive marketing, and the perceived lack of need for professional oversight. Reports suggest that certain HWLPs may lead to onset or exacerbation of psychiatric disturbances. Here we review the available evidence on psychiatric adverse effects of HWLPs due to their intrinsic toxicity and potential for interaction with psychiatric medicationsPeer reviewe

CYP2D6 and CYP2C8 pharmacogenetics and pharmacological interactions to predict imatinib plasmatic exposure in GIST patients

Patients on treatment with oral fixed dose imatinib are frequently under- or overexposed to the drug. We investigated the association between the gene activity score (GAS) of imatinib-metabolizing cytochromes (CYP3A4, CYP3A5, CYP2D6, CYP2C9, CYP2C19, CYP2C8) and imatinib and nor-imatinib exposure. We also investigated the impact of concurrent drug-drug-interactions (DDIs) on the association between GAS and imatinib exposure

Introduction: anthropology's queer sensibilities

This special issue addresses vital epistemological, methodological, ethical and political issues at the intersections of queer theory and anthropology as they speak to the study of sexual and gender diversity in the contemporary world. The special issue centres on explorations of anthropology’s queer sensibilities, that is, experimental thinking in ethnographically informed investigations of gender and sexual difference, and related connections, disjunctures and tensions in their situated and abstract dimensions. The articles consider the possibilities and challenges of anthropology’s queer sensibilities that anthropologise queer theory whilst queering anthropology in ethnographically informed analyses. Contributors focus on anthropologising queer theory in research on same-sex desire in the Congo; LGBT migrant and asylum experience in the UK and France; same-sex intimacies within opposite gender oriented sexualities in Kenya and Ghana; secret and ambiguous intimacies and sensibilities beyond an identifiable ‘queer subject’ of rights and recognition in India; migrant imaginings of home in Indonesian lesbian relationships in Hong Kong; and cross-generational perspectives on ‘coming out’ in Taiwan and their implications for theories of kinship and relatedness. An extensive interview with Esther Newton, the prominent figure in gay and lesbian and queer anthropology concludes the collection