J. M. Teixeira

Mitochondrial DNA phylogeography of Lissotriton boscai (Caudata, Salamandridae): evidence for old, multiple refugia in an Iberian endemic

In Europe, southern peninsulas served as refugia during cold periods in the Pleistocene, acting both as centres of origin of endemisms and as sources from which formerly glaciated areas were recolonized during interglacial periods. Previous studies have revealed that within the main refugial areas, intraspecific lineages often survived in allopatric refugia. We analysed two mitochondrial markers (nad4, control region, ∼1.4 kb) in 103 individuals representing the entire distribution of Lissotriton boscai, a newt endemic to the western Iberian Peninsula. We inferred the evolutionary history of the species through phylogenetic, phylogeographic and historical demographic analyses. The results revealed unexpected, deep levels of geographically structured genetic variability. We identified two main evolutionary lineages, each containing three well‐supported clades. The first historical split involved populations from central‐southwestern coastal Portugal and the ancestor of all the remaining populations around 5.8 million years ago. Both lineages were subsequently fragmented into different population groups between 2.5 and 1.2 million years ago. According to nested clade analysis, at lower hierarchical levels the patterns suggest restricted gene flow with isolation by distance, whereas at higher levels the clades exhibit signatures of contiguous range expansion. Bayesian Skyline Plots show recent bottlenecks, followed by demographic expansions in all lineages. The significant genetic structure found is consistent with long‐term survival of populations in allopatric refugia, supporting the ‘refugia‐within‐refugia’ scenario for southern European peninsulas. The comparison of our results with other co‐distributed species highlights the generality of this hypothesis for the Iberian herpetofauna and suggests that Mediterranean refuges had more relevance for the composition and distribution of present biodiversity patterns than currently acknowledged. We briefly discuss the taxonomic and conservation implications of our results.

Alzheimer's disease, enzyme targets and drug discovery struggles: From natural products to drug prototypes

Alzheimers disease (AD) is an incapacitating neurodegenerative disease that slowly destroys brain cells. This disease progressively compromises both memory and cognition, culminating in a state of full dependence and dementia. Currently, AD is the main cause of dementia in the elderly and its prevalence in the developed world is increasing rapidly. Classic drugs, such as acetylcholinesterase inhibitors (AChEIs), fail to decline disease progression and display several side effects that reduce patients adhesion to pharmacotherapy. The past decade has witnessed an increasing focus on the search for novel AChEIs and new putative enzymatic targets for AD, like β- and γ-secretases, sirtuins, caspase proteins and glycogen synthase kinase-3 (GSK-3). In addition, new mechanistic rationales for drug discovery in AD that include autophagy and synaptogenesis have been discovered. Herein, we describe the state-of-the-art of the development of recent enzymatic inhibitors and enhancers with therapeutic potential on the treatment of AD.

Alzheimer’s Disease, Cholesterol, and Statins: The Junctions of Important Metabolic Pathways

Recent years have seen a significant increase in published data supporting the positive effects of statins on neurodegenerative diseases, in particular on Alzheimers disease. Statins show neuroprotective activity by a combination of different cellular and systemic mechanisms that are based on the inhibition of the biosynthesis of cholesterol and isoprenoid by-products. The promising results obtained in vivo and in epidemiological studies are generally not in accordance with those of placebo-controlled randomized clinical trials. Nevertheless, these results make statins valuable assets for disease prevention rather than therapeutic agents for use when disease symptoms are already displayed. Thus, the modulation of midlife cholesterol and/or statin administration prior to the appearance of dementia or cognitive impairment may have a better long-term outcome.

Exploring nature profits: development of novel and potent lipophilic antioxidants based on galloyl-cinnamic hybrids.

Phenolic acids are ubiquitous antioxidants accounting for approximately one third of the phenolic compounds in our diet. Their importance was supported by epidemiological studies that suggest an inverse relationship between dietary intake of phenolic antioxidants and the occurrence of diseases, such as cancer and neurodegenerative disorders. However, until now, most of natural antioxidants have limited therapeutic success a fact that could be related with their limited distribution throughout the body and with the inherent difficulties to attain the target sites. The development of phenolic antioxidants based on a hybrid concept and structurally based on natural hydroxybenzoic (gallic acid) and hydroxycinnamic (caffeic acid) scaffolds seems to be a suitable solution to surpass the mentioned drawbacks. Galloyl-cinnamic hybrids were synthesized and their antioxidant activity as well as partition coefficients and redox potentials evaluated. The structure-property-activity relationship (SPAR) study revealed the existence of a correlation between the redox potentials and antioxidant activity. The galloyl-cinnamic acid hybrid stands out as the best antioxidant supplementing the effect of a blend of gallic acid plus caffeic acid endorsing the hypothesis that the whole is greater than the sum of the parts. In addition, some hybrid compounds possess an appropriate lipophilicity allowing their application as chain-breaking antioxidant in biomembranes or other type of lipidic systems. Their predicted ADME properties are also in accordance with the general requirements for drug-like compounds. Accordingly, these phenolic hybrids can be seen as potential antioxidants for tackling the oxidative status linked to the neurodegenerative, inflammatory or cancer processes.

Antioxidant therapy: Still in search of the 'magic bullet'

The therapeutic potential of natural phenolic antioxidants in human diseases associated with oxidative damage has received great attention to date. Appraisal of literature evidences that, in general, antioxidant therapy has enjoyed relative successes in preclinical studies but little benefits in human intervention studies or clinical trials. In fact, despite the huge, largely untapped potential therapeutic benefit of natural phenolic antioxidants, such as vitamins, non-flavonoid and flavonoid compounds, they appear not to be suitable drug candidates. The problem may be related, among others, to their non-drug-likeness properties. Though controversial the results obtained so far confirm the importance of exploring phenolic natural systems as safe templates for the design of new antioxidants. To support the assumption an outlook of the lead structural optimization process to improve ADME properties was given by means of natural hydroxycinnamic acids as a case study. The optimization of drug physicochemical properties and the development of appropriate delivery antioxidant systems can provide in the next future a way out to attain effective therapeutic antioxidant agents.

Alzheimer's disease and antioxidant therapy: how long how far?

Alzheimers disease (AD) has become a health problem to societies worldwide affecting millions of people. AD normally ensues in middle and late life but its specific cause remains unknown. Besides amyloid-β deposition and hyperphosphorylated tau protein, increased production of reactive species (RS) has also been described to be a hallmark in early steps of this disorder. Antioxidant therapy has received considerable attention over the last years as a promising approach to delay or slow the neurodegeneration progression in AD either by boosting the pool of endogenous antioxidants (e.g.vitamins, coenzyme Q10 or melatonin) or by the intake of dietary antioxidants, such as phenolic compounds of flavonoid or non-flavonoid type. However, the majority of antioxidants studied so far have limited success in clinical trials, a fact that could be related to their poor distribution and with the inherent difficulties to cross the blood brain barrier and attain the target sites. Despite the evidence that different classes of antioxidants are neuroprotectants in vitro, the clinical data is not consistent. Alzheimers disease and antioxidant therapy is still an open question: the research is far from the end but the success may not be so time-consuming if the data obtained so far are gathered and rationally analyzed either by checking new targets or by the obtention of new and effective compounds, for instance by the rational modification of the previous ones.

Electroforming, magnetic and resistive switching in MgO-based tunnel junctions

Magnetic tunnel junctions (MTJs) are under investigation since they offer great potential for applications in magnetic memories. An interesting effect in TJs concerns non-volatile resistive switching of non-magnetic origin. We report magnetic (magnetoresistance) and structural (resistive; R) switching in MgO-based MTJs (barrier thicknesses t = 0.75, 1.35 nm). As-grown MTJs display R-switching only in the thinnest series, while thicker barrier samples need an electroforming step for R-switching to occur. Forming changes the electrical resistance temperature dependence, from tunnel- to metallic-like, revealing the formation of conductive bridges across the barrier which, leading to local high electrical fields and temperatures, are essential for resistive switching.

Resistive switching and activity-dependent modifications in Ni-doped graphene oxide thin films

The resistive switching (RS) mechanism in Ni-doped graphene oxide (GO) devices is studied. We found that RS depends strongly on the fabrication method of the GO sheet and on the electrode material. Resistive switching in GO-devices can be caused by the diffusion of ions from metallic electrode or by the migration of oxygen groups, depending on the fabrication process. We also show that GO-based structures possess activity-dependent modification capabilities, emphasized by the increase/decrease of device conductance after consecutive voltage sweeps of opposite polarity. Our results allow a better understanding of bipolar RS, towards future non-volatile memories and neuromorphic systems.

Versatile, high sensitivity, and automatized angular dependent vectorial Kerr magnetometer for the analysis of nanostructured materials

Magneto-optical Kerr effect (MOKE) magnetometry is an indispensable, reliable, and one of the most widely used techniques for the characterization of nanostructured magnetic materials. Information, such as the magnitude of coercive fields or anisotropy strengths, can be readily obtained from MOKE measurements. We present a description of our state-of-the-art vectorial MOKE magnetometer, being an extremely versatile, accurate, and sensitivity unit with a low cost and comparatively simple setup. The unit includes focusing lenses and an automatized stepper motor stage for angular dependent measurements. The performance of the magnetometer is demonstrated by hysteresis loops of Co thin films displaying uniaxial anisotropy induced on growth, MnIr/CoFe structures exhibiting the so called exchange bias effect, spin valves, and microfabricated flux guides produced by optical lithography.

Tailoring the physical properties of thin nanohole arrays grown on flat anodic aluminum oxide templates.

The introduction of voids in a magnetic thin-film alters the stray field distribution and enables the tailoring of the corresponding physical properties. Here we present a detailed study on thin magnetic nanohole arrays (NhAs) grown on top of hexagonally-ordered anodic aluminum oxide (AAO) substrates. We address the effect of AAO topography on the corresponding electrical and magneto-transport properties. Optimization of the AAO topography led to NhAs with improved resistance and magnetoresistance responses, while retaining their most important feature of enhanced coercivity. This opens new pathways for the growth of more complex structures on AAO substrates, a crucial aspect for their technological viability.