Surface and core detonations in rotating white dwarfs

The feasibility of the double detonation mechanism—surface helium detonation followed by complete carbon detonation of the core—in a rotating white dwarf with mass ;1Me is studied using three-dimensional hydrodynamic simulations. A rapid rigid rotation of the white dwarf was assumed, so that its initial spherical geometry is considerably distorted. Unlike spherically symmetric models, we found that when helium ignition is located far from the spinning axis, the detonation fronts converge asynchronically at the antipodes of the ignition point. Nevertheless, the detonation of the carbon core still remains as the most probable outcome. The detonation of the core gives rise to a strong explosion, matching many of the basic observational constraints of Type Ia supernovae (SNe Ia). We conclude that the double detonation mechanism also works when the white dwarf is rapidly rotating. These results provide further evidence for the viability of sub-Chandrasekhar-mass models as well as some double degenerate models (those having some helium fuel at the merging moment), making them appealing channels for the production of SN Ia events.Peer ReviewedPostprint (published version

Transient alteration of the vestibular calyceal junction and synapse in response to chronic ototoxic insult in rats

Aquest article conté una errata annexadaOtotoxicity is known to cause permanent loss of vestibule function through degeneration of sensory hair cells (HCs). However, functional recovery has been reported during washout after chronic ototoxicity, although the mechanisms underlying this reversible dysfunction are unknown. Here, we study this question in rats chronically exposed to the ototoxic compound 3,3′-iminodipropionitrile (IDPN). Pronounced alterations in vestibular function appeared before significant loss of HCs or stereociliary coalescence became evident by ultrastructural analyses. This early dysfunction was fully reversible if the exposure was terminated promptly. In cristae and utricles, the distinct junctions formed between type I HCs (HCI) and calyx endings were completely dismantled at these early stages of reversible dysfunction, and completely rebuilt during washout. Immunohistochemical observations revealed loss and recovery of the junction proteins CASPR1 and tenascin-C and RT-PCR indicated that their loss was not due to decreased gene expression. KCNQ4 was mislocalized during intoxication and recovered control-like localization after washout. At early stages of the intoxication, the calyces could be classified as showing intact or lost junctions, indicating that calyceal junction dismantlement is triggered on a calyx-by-calyx basis. Chronic toxicity also altered the presence of ribeye, PSD-95 and GluA2 puncta in the calyces. These synaptic alterations varied between the two types of calyx endings (formed by calyx-only or dimorphic afferents) and some persisted at the end of the washout period. The present data reveal new forms of plasticity of the calyx endings in adult mammals, including a robust capacity for rebuilding the calyceal junction. These findings contribute to a better understanding of the phenomena involved in progressive vestibular dysfunction and its potential recovery during and after ototoxic exposure

New perspectives on corpora amylacea in the human brain

Corpora amylacea are structures of unknown origin and function that appear with age in human brains and are profuse in selected brain areas in several neurodegenerative conditions. They are constituted of glucose polymers and may contain waste elements derived from different cell types. As we previously found on particular polyglucosan bodies in mouse brain, we report here that corpora amylacea present some neo-epitopes that can be recognized by natural antibodies, a certain kind of antibodies that are involved in tissue homeostasis. We hypothesize that corpora amylacea, and probably some other polyglucosan bodies, are waste containers in which deleterious or residual products are isolated to be later eliminated through the action of the innate immune system. In any case, the presence of neo-epitopes on these structures and the existence of natural antibodies directed against them could become a new focal point for the study of both age-related and degenerative brain processes

Vestibular damage in chronic ototoxicity: a mini-review

Ototoxicity is a major cause of the loss of hearing and balance in humans. Ototoxic compounds include pharmaceuticals such as aminoglycoside antibiotics, anti-malarial drugs, loop diuretics and chemotherapeutic platinum agents, and industrial chemicals including several solvents and nitriles. Human and rodent data indicate that the main target of toxicity is hair cells (HCs), which are the mechanosensory cells responsible for sensory transduction in both the auditory and the vestibular system. Nevertheless, the compounds may also affect the auditory and vestibular ganglion neurons. Exposure to ototoxic compounds has been found to cause HC apoptosis, HC necrosis, and damage to the afferent terminals, of differing severity depending on the ototoxicity model. One major pathway frequently involved in HC apoptosis is the c-jun N-terminal kinase (JNK) signaling pathway activated by reactive oxygen species, but other apoptotic pathways can also play a role in ototoxicity. Moreover, little is known about the effects of chronic low-dose exposure. In rodent vestibular epithelia, extrusion of live HCs from the sensory epithelium may be the predominant form of cell demise during chronic ototoxicity. In addition, greater involvement of the afferent terminals may occur, particularly the calyx units contacting type I vestibular HCs. As glutamate is the neurotransmitter in this synapse, excitotoxic phenomena may participate in afferent and ganglion neuron damage. Better knowledge of the events that take place in chronic ototoxicity is of great interest, as it will increase understanding of the sensory loss associated with chronic exposure and ageing

Cisplatin-induced ototoxicity: effects, mechanisms and protection strategies

Cisplatin is a highly effective chemotherapeutic agent that is widely used to treat solid organ malignancies. However, serious side effects have been associated with its use, such as bilateral, progressive, irreversible, dose-dependent neurosensory hearing loss. Current evidence indicates that cisplatin triggers the production of reactive oxygen species in target tissues in the inner ear. A variety of agents that protect against cisplatin-induced ototoxicity have been successfully tested in cell culture and animal models. However, many of them interfere with the therapeutic effect of cisplatin, and therefore are not suitable for systemic administration in clinical practice. Consequently, local administration strategies, namely intratympanic adminis- tration, have been developed to achieve otoprotection, without reducing the antitumoral effect of cisplatin. While a considerable amount of pre-clinical information is available, clinical data on treatments to prevent cisplatin ototoxicity are only just beginning to appear. This review summarizes clinical and experimental studies of cisplatin ototoxicity, and focuses on understanding its toxicity mechanisms, clinical repercussions and prevention strategies

Study of the transport of substances across the blood-brain barrier with the 8D3 anti-transferrin receptor antibody

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/128014Numerous strategies have been proposed to overcome the blood-brain barrier (BBB) and efficiently deliver therapeutic agents to the brain. One of these strategies consists of linking the pharmacologically active substance to a molecular vector that acts as a molecular Trojan Horse and is capable of crossing the BBB using a receptor-mediated transcellular transport system of the brain capillary endothelial cells (BCECs). The transferrin receptor (TfR) is related to a transcytosis process in these cells, and the 8D3 monoclonal antibody (mAb), directed against the mouse TfR, is able to induce a receptor response. Thus, the 8D3 antibody could be a potential molecular Trojan Horse to transport pharmacologically active substances across the BBB. On these bases, a series of experiments were performed where the 8D3 antibody was conjugated to different cargoes, the resulting constructs were administered in vivo to mice, and the distribution and intracellular mechanisms that these constructs undergo at the BBB were studied. Our results indicated a TfR-mediated and clathrin-dependent internalization process by which the 8D3-cargo constructs enters the BCEC. The resulting endocytic vesicles follow at least two different routes. On one hand, most vesicles enter intracellular processes of vesicular fusion and rearrangement in which the cargo is guided to late endosomes, multivesicular bodies or lysosomes. On the other hand, a small but not negligible percentage of the vesicles follow a different route in which they fuse with the abluminal membrane and open towards the basal lamina, indicating a potential route for the delivery of therapeutic substances. In this route, however, the 8D3−cargo remain fixed to the abluminal membrane, indicating that the 8D3 is maintained linked to the TfR, and the cargo does not go beyond the basal membrane. Altogether, different optimization approaches need to be developed for efficient drug delivery, but receptor-mediated transport (RMT) continues to be one of the most promising strategies to overcome the BBB

Neo-epitopes emerging in the degenerative hippocampal granules of aged mice can be recognized by natural IgM autoantibodies

Background: Degenerative granular structures appear progressively with age in the hippocampus of most mouse strains. We recently reported that these granules contain a neo-epitope that is recognised by IgM antibodies present as contaminants in many commercial antibodies obtained from mouse ascites and mouse or rabbit serum. We hypothesise that these anti-neo-epitope IgMs are in fact natural auto-antibodies that are generated spontaneously during the foetal stage without previous contact with external antigens and whose repertoire and reactivity pattern have been determined through evolution, being remarkably stable within species and even between species. Findings: In the present work we found that mice from the ICR-CD1, BALB/C and SAMP8 strains have anti-neoepitope IgM antibodies in their plasma at all ages tested and even when maintained under specific opportunistic pathogen-free conditions. Moreover, we determined that these anti-neo-epitope IgMs are also present in rabbit, goat and rat serum. We also found that, in each mouse that presented hippocampal granules, the anti-neo-epitope IgMs contained in its plasma recognised the neo-epitopes in its own granules. Conclusions: This study led to the conclusion that anti-neo-epitope IgMs are widespread natural auto-antibodies contained in the plasma of mice and other species. The presence of these natural auto-antibodies not only explains why they are frequently found as contaminants in commercial antibodies, but also paves the way for a new approach to a treatment and diagnosis of pathological brain processes based on natural IgMs and neo-epitopes

Genuine multipartite entanglement of quantum states in the multiple-copy scenario

Genuine multipartite entanglement (GME) is considered a powerful form of entanglement since it corresponds to those states that are not biseparable, i.e. a mixture of partially separable states across different bipartitions of the parties. In this work we study this phenomenon in the multiple-copy regime, where many perfect copies of a given state can be produced and controlled. In this scenario the above definition leads to subtle intricacies as biseparable states can be GME-activatable, i.e. several copies of a biseparable state can display GME. We show that the set of GMEactivatable states admits a simple characterization: a state is GME-activatable if and only if it is not partially separable across one bipartition of the parties. This leads to the second question of whether there is a general upper bound in the number of copies that needs to be considered in order to observe the activation of GME, which we answer in the negative. In particular, by providing an explicit construction, we prove that for any number of parties and any number k 2 N there exist GME-activatable multipartite states of fixed (i.e. independent of k) local dimensions such that k copies of them remain biseparable

Trafficking of Gold Nanoparticles Coated with the 8D3 Anti-Transferrin Receptor Antibody at the Mouse Blood-Brain Barrier

Receptor-mediated transcytosis has been widely studied as a possible strategy to transport neurotherapeutics across the blood-brain barrier (BBB). Monoclonal antibodies directed against the transferrin receptor (TfR) have been proposed as potential carrier candidates. A better understanding of the mechanisms involved in their cellular uptake and intracellular trafficking is required and could critically contribute to the improvement of delivery methods. Accordingly, we studied here the trafficking of gold nanoparticles (AuNPs) coated with the 8D3 anti-transferrin receptor antibody at the mouse BBB. 8D3-AuNPs were intravenously administered to mice and allowed to recirculate for a range of times, from 10 min to 24 h, before brain extraction and analysis by transmission electron microscope techniques. Our results indicated a TfR-mediated and clathrin-dependent internalization process by which 8D3-AuNPs internalize individually in vesicles. These vesicles then follow at least two different routes. On one hand, most vesicles enter intracellular processes of vesicular fusion and rearrangement in which the AuNPs end up accumulating in late endosomes, multivesicular bodies or lysosomes, which present a high AuNP content. On the other hand, a small percentage of the vesicles follow a different route in which they fuse with the abluminal membrane and open to the basal membrane. In these cases, the 8D3-AuNPs remain attached to the abluminal membrane, which suggests an endosomal escape, but not dissociation from TfR. Altogether, although receptor-mediated transport continues to be one of the most promising strategies to overcome the BBB, different optimization approaches need to be developed for efficient drug delivery. Keywords: blood−brain barrier; drug delivery; electron microscopy; monoclonal antibodies; receptor-mediated transport; transferrin receptor