Design of Lipid-Based Nanocarriers via Cation Modulation of Ethanol-Interdigitated Lipid Membranes

Short-chain alcohols (i.e., ethanol) can induce membrane interdigitation in saturated-chain phosphatidylcholines (PCs). In this process, alcohol molecules intercalate between phosphate heads, increasing lateral separation and favoring hydrophobic interactions between opposing acyl chains, which interpenetrate forming an interdigitated phase. Unraveling mechanisms underlying the interactions between ethanol and model lipid membranes has implications for cell biology, biochemistry, and for the formulation of lipid-based nanocarriers. However, investigations of ethanol–lipid membrane systems have been carried out in deionized water, which limits their applicability. Here, using a combination of small- and wide-angle X-ray scattering, small-angle neutron scattering, and all-atom molecular dynamics simulations, we analyzed the effect of varying CaCl2 and NaCl concentrations on ethanol-induced interdigitation. We observed that while ethanol addition leads to the interdigitation of bulk phase 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayers in the presence of CaCl2 and NaCl regardless of the salt concentration, the ethanol-induced interdigitation of vesicular DPPC depends on the choice of cation and its concentration. These findings unravel a key role for cations in the ethanol-induced interdigitation of lipid membranes in either bulk phase or vesicular form

Fluoxetine: a case history of its discovery and preclinical development

Introduction: Depression is a multifactorial mood disorder with a high prevalence worldwide. Until now, treatments for depression have focused on the inhibition of monoaminergic reuptake sites, which augment the bioavailability of monoamines in the CNS. Advances in drug discovery have widened the therapeutic options with the synthesis of so-called selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine. Areas covered: The aim of this case history is to describe and discuss the pharmacokinetic and pharmacodynamic profiles of fluoxetine, including its acute effects and the adaptive changes induced after long-term treatment. Furthermore, the authors review the effect of fluoxetine on neuroplasticity and adult neurogenesis. In addition, the article summarises the preclinical behavioural data available on fluoxetine’s effects on depressive-like behaviour, anxiety and cognition as well as its effects on other diseases. Finally, the article describes the seminal studies validating the antidepressant effects of fluoxetine. Expert opinion: Fluoxetine is the first selective SSRI that has a recognised clinical efficacy and safety profile. Since its discovery, other molecules that mimic its mechanism of action have been developed, commencing a new age in the treatment of depression. Fluoxetine has also demonstrated utility in the treatment of other disorders for which its prescription has now been approved

Stalking influenza by vaccination with pre-fusion headless HA mini-stem.

Inaccuracies in prediction of circulating viral strain genotypes and the possibility of novel reassortants causing a pandemic outbreak necessitate the development of an anti-influenza vaccine with increased breadth of protection and potential for rapid production and deployment. The hemagglutinin (HA) stem is a promising target for universal influenza vaccine as stem-specific antibodies have the potential to be broadly cross-reactive towards different HA subtypes. Here, we report the design of a bacterially expressed polypeptide that mimics a H5 HA stem by protein minimization to focus the antibody response towards the HA stem. The HA mini-stem folds as a trimer mimicking the HA prefusion conformation. It is resistant to thermal/chemical stress, and it binds to conformation-specific, HA stem-directed broadly neutralizing antibodies with high affinity. Mice vaccinated with the group 1 HA mini-stems are protected from morbidity and mortality against lethal challenge by both group 1 (H5 and H1) and group 2 (H3) influenza viruses, the first report of cross-group protection. Passive transfer of immune serum demonstrates the protection is mediated by stem-specific antibodies. Furthermore, antibodies indudced by these HA stems have broad HA reactivity, yet they do not have antibody-dependent enhancement activity

Signal Propagation in Feedforward Neuronal Networks with Unreliable Synapses

In this paper, we systematically investigate both the synfire propagation and firing rate propagation in feedforward neuronal network coupled in an all-to-all fashion. In contrast to most earlier work, where only reliable synaptic connections are considered, we mainly examine the effects of unreliable synapses on both types of neural activity propagation in this work. We first study networks composed of purely excitatory neurons. Our results show that both the successful transmission probability and excitatory synaptic strength largely influence the propagation of these two types of neural activities, and better tuning of these synaptic parameters makes the considered network support stable signal propagation. It is also found that noise has significant but different impacts on these two types of propagation. The additive Gaussian white noise has the tendency to reduce the precision of the synfire activity, whereas noise with appropriate intensity can enhance the performance of firing rate propagation. Further simulations indicate that the propagation dynamics of the considered neuronal network is not simply determined by the average amount of received neurotransmitter for each neuron in a time instant, but also largely influenced by the stochastic effect of neurotransmitter release. Second, we compare our results with those obtained in corresponding feedforward neuronal networks connected with reliable synapses but in a random coupling fashion. We confirm that some differences can be observed in these two different feedforward neuronal network models. Finally, we study the signal propagation in feedforward neuronal networks consisting of both excitatory and inhibitory neurons, and demonstrate that inhibition also plays an important role in signal propagation in the considered networks.Comment: 33pages, 16 figures; Journal of Computational Neuroscience (published

Historical translocations and stocking alter the genetic structure of a Mediterranean lobster fishery

This is the final version. Available on open access from Wiley via the DOI in this recordStocking is often used to supplement wild populations that are overexploited or have collapsed, yet it is unclear how this affects the genetic diversity of marine invertebrate populations. During the 1970s, a lobster stock enhancement program was carried out around the island of Corsica in the Mediterranean using individuals translocated from the Atlantic coast of France. This included the release of thousands of hatchery-reared postlarval lobsters and several adult individuals, but no monitoring plan was established to assess whether these animals survived and recruited to the population. In this study, we sampled European lobster (Homarus gammarus) individuals caught around Corsica and tested whether they showed Atlantic ancestry. Due to a natural marked phylogeographic break between Atlantic and Mediterranean lobsters, we hypothesized that lobsters with dominant (>0.50) Atlantic ancestry were descended from historical stocking releases. Twenty Corsican lobsters were genotyped at 79 single nucleotide polymorphisms, and assignment analysis showed that the majority (13) had dominant Atlantic ancestry. This suggests that the hatchery stocking program carried out in Corsica during the 1970s, using individuals translocated from the Atlantic coast of France, has likely augmented local recruitment but at a cost of altering the genetic structure of the Corsican lobster population.EU Agri‐tech CornwallBiotechnology and Biological Sciences Research Council (BBSRC)Natural Environment Research Council (NERC

Controlled dendrimersome nanoreactor system for localised hypochlorite-induced killing of bacteria

Antibiotic resistance is a serious global health problem necessitating new bactericidal approaches such as nanomedicines. Dendrimersomes (DSs) have recently become a valuable alternative nanocarrier to polymersomes and liposomes due to their molecular definition and synthetic versatility. Despite this, their biomedical application is still in its infancy. Inspired by the localized antimicrobial function of neutrophil phagosomes and the versatility of DSs, a simple three-component DS-based nanoreactor with broad-spectrum bactericidal activity is presented. This was achieved by encapsulation of glucose oxidase (GOX) and myeloperoxidase (MPO) within DSs (GOX-MPO-DSs), self-assembled from an amphiphilic Janus dendrimer, that possesses a semipermeable membrane. By external addition of glucose to GOX-MPO-DS, the production of hypochlorite (−OCl), a highly potent antimicrobial, by the enzymatic cascade was demonstrated. This cascade nanoreactor yielded a potent bactericidal effect against two important multidrug resistant pathogens, Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa), not observed for H2O2 producing nanoreactors, GOX-DS. The production of highly reactive species such as –OCl represents a harsh bactericidal approach that could also be cytotoxic to mammalian cells. This necessitates the development of strategies for activating –OCl production in a localized manner in response to a bacterial stimulus. One option of locally releasing sufficient amounts of substrate using a bacterial trigger (released toxins) was demonstrated with lipidic glucose-loaded giant unilamellar vesicles (GUVs), envisioning, e.g., implant surface modification with nanoreactors and GUVs for localized production of bactericidal agents in the presence of bacterial growth

Metabolic effects of diets differing in glycaemic index depend on age and endogenous GIP

Aims/hypothesis High- vs low-glycaemic index (GI) diets unfavourably affect body fat mass and metabolic markers in rodents. Different effects of these diets could be age-dependent, as well as mediated, in part, by carbohydrate-induced stimulation of glucose-dependent insulinotrophic polypeptide (GIP) signalling. Methods Young-adult (16 weeks) and aged (44 weeks) male wild-type (C57BL/6J) and GIP-receptor knockout (Gipr −/− ) mice were exposed to otherwise identical high-carbohydrate diets differing only in GI (20–26 weeks of intervention, n = 8–10 per group). Diet-induced changes in body fat distribution, liver fat, locomotor activity, markers of insulin sensitivity and substrate oxidation were investigated, as well as changes in the gene expression of anorexigenic and orexigenic hypothalamic factors related to food intake. Results Body weight significantly increased in young-adult high- vs low-GI fed mice (two-way ANOVA, p < 0.001), regardless of the Gipr genotype. The high-GI diet in young-adult mice also led to significantly increased fat mass and changes in metabolic markers that indicate reduced insulin sensitivity. Even though body fat mass also slightly increased in high- vs low-GI fed aged wild-type mice (p < 0.05), there were no significant changes in body weight and estimated insulin sensitivity in these animals. However, aged Gipr −/− vs wild-type mice on high-GI diet showed significantly lower cumulative net energy intake, increased locomotor activity and improved markers of insulin sensitivity. Conclusions/interpretation The metabolic benefits of a low-GI diet appear to be more pronounced in younger animals, regardless of the Gipr genotype. Inactivation of GIP signalling in aged animals on a high-GI diet, however, could be beneficial

Theories of behaviour change synthesised into a set of theoretical groupings: Introducing a thematic series on the Theoretical Domains Framework

Behaviour change is key to increasing the uptake of evidence into healthcare practice. Designing behaviour-change interventions first requires problem analysis, ideally informed by theory. Yet the large number of partly overlapping theories of behaviour makes it difficult to select the most appropriate theory. The need for an overarching theoretical framework of behaviour change was addressed in research in which 128 explanatory constructs from 33 theories of behaviour were identified and grouped. The resulting Theoretical Domains Framework (TDF) appears to be a helpful basis for investigating implementation problems. Research groups in several countries have conducted TDF-based studies. It seems timely to bring together the experience of these teams in a thematic series to demonstrate further applications and to report key developments. This overview article describes the TDF, provides a brief critique of the framework, and introduces this thematic series. In a brief review to assess the extent of TDF-based research, we identified 133 papers that cite the framework. Of these, 17 used the TDF as the basis for empirical studies to explore health professionals’ behaviour. The identified papers provide evidence of the impact of the TDF on implementation research. Two major strengths of the framework are its theoretical coverage and its capacity to elicit beliefs that could signify key mediators of behaviour change. The TDF provides a useful conceptual basis for assessing implementation problems, designing interventions to enhance healthcare practice, and understanding behaviour-change processes. We discuss limitations and research challenges and introduce papers in this series