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By using methods of subordinacy theory, we study packing continuity properties of spectral measures of discrete one-dimensional Schrödinger operators acting on the whole line. Then we apply these methods to Sturmian operators with rotation numbers of quasibounded density to show that they have purely $\unicode[STIX]{x1D6FC}$-packing continuous spectrum. A dimensional stability result is also mentioned.

Mitochondrial metabolism is a highly orchestrated phenomenon in which many enzyme systems cooperate in a variety of pathways to dictate cellular fate. As well as its vital role in cellular energy metabolism (ATP production), mitochondria are powerful organelles that regulate reactive oxygen species production, NAD+/NADH ratio and programmed cell death. In addition, mitochondrial abnormalities have been well-recognized to contribute to degenerative diseases, like Parkinson's disease (PD). Particularly a deficiency in the mitochondrial respiratory chain complex I and cristae disruption have been consistently described in PD. Moreover, the products of PD-familial genes, including α-synuclein, Parkin, PINK1, DJ-1, LRRK2 and HTR2A, were shown to localize to the mitochondria under certain conditions. It seems that PD has a mitochondrial component so events that would modulate normal mitochondrial functions may compromise neuronal survival. However, it remains an open question whether alterations of these pathways lead to different aspects of PD or whether they converge at a point that is the common denominator of PD pathogenesis. In this review we will focus on mitochondrial metabolic control and its implications on sirtuins activation, microtubule dynamics and the autophagic-lysosomal pathway. We will address mitochondrial metabolism modulation as a new promising therapeutic tool for PD.

Alzheimer's disease (AD) is an irreversible, progressive brain disease that slowly destroys memory and thinking skills. With over 26 million patients in 2006, AD is the most prevalent neurodegenerative disease worldwide. Different hypotheses have been suggested to explain the pathogenesis of AD, like those involving inflammation, mitochondrial dysfunction or oxidative stress. Many of these studies have addressed amyloid plaque formation, tau hyperphosphorylation and apoptotic neuronal loss, the three main histopathological hallmarks of this disease. Increasing evidences, however, suggest another feature that can also be considered a neuropathological marker for AD: ectopic cell cycle re-entry. Cell cycle events have been frequently registered in the brains of AD patients. Although the exact starting point of cell cycle re-entry remains unclear, a number of subsequent cascades, which include events such as kinase upregulation, DNA replication and cytoskeletal alterations, have already been described. There are also increasing reports suggesting that cell cycle reactivation in mature neurons occurs as part of the apoptotic process. Upon a brief overview of the different theories and models addressing cell cycle reactivation in AD, we will describe possible mechanisms that trigger cell cycle re-entry, with special attention to links between this feature and the main neuropathological markers of AD. Finally, we will also analyze possible similarities between cell cycle dysregulation in AD and in other pathologies, such as Prion-Related Encephalopathies.

Amyloid β-peptide (Aβ) is widely held to be associated with Alzheimer’s disease, the insoluble aggregates of the peptide being the major constituents of senile plaques. In this study, we evaluated the effect of Zn2+(5, 50 and 200 μM) on Aβ induced toxicity using the human teratocarcinome (NT2) cell line. Our results proved that 50 and 200 μM Zn2+protected NT2 cells from Aβ 25–35 toxicity. Zinc was also shown to be effective by preventing the loss of mitochondrial membrane potential (ΔΨm) induced by Aβ 25–35, not allowing cytochromecrelease from mitochondria, and subsequently, caspase 3 activation. However, when the cells were treated with Aβ 1–40, only 5 μM Zn2+had a protective effect. We have further observed that 5 μM Zn2+prevented Aβ 1–40 aggregation into a p-sheet structure. Considering the results presented, we argue that Zn2+has a concentration-dependent protective effect.

Parkinson's disease (PD), considered one of the major neurological disorders, is characterized by the loss of dopaminergic neurons in the pars compacta of the substantia nigra and by the presence of intraneuronal cytoplasmic inclusions called Lewy bodies. The causes for degeneration of PD neurons remain unclear, however, recent findings contributed to clarify this issue. This review will discuss the current understanding of the mechanisms underlying Parkinson's disease pathogenesis, focusing on the current and potential therapeutic strategies for human treatment.

The characteristic hallmarks of Alzheimer's disease (AD), the most common form of dementia in the elderly, include senile plaques, mainly composed of beta-amyloid (Aβ) peptide, neurofibrillary tangles and selective synaptic and neuronal loss in brain regions involved in learning and memory. Genetic studies, together with the demonstration of Aβ neurotoxicity, led to the development of the amyloid cascade hypothesis to explain the AD-associated neurodegenerative process. However, a modified version of this hypothesis has emerged, the Aβ cascade hypothesis, which takes into account the fact that soluble oligomeric forms and protofibrils of Aβ and its intraneuronal accumulation also play a key role in the pathogenesis of the disease. Recent evidence posit that synaptic dysfunction triggered by non fibrillar Aβ species is an early event involved in memory decline in AD. The current understanding of the molecular mechanisms responsible for impaired synaptic function and cognitive deficits is outlined in this review, focusing on oxidative stress and disturbed metal ion homeostasis, Ca2+ dysregulation, mitochondria and endoplasmic reticulum dysfunction, cholesterol dyshomeostasis and impaired neurotransmission. The activation of apoptotic cell death as a mechanism of neuronal loss in AD, and the prominent role of neuroinflammation in this neurodegenerative disorder, are also reviewed herein. Furthermore, we will focus on the more relevant therapeutical strategies currently used, namely those involving antioxidants, drugs for neurotransmission improvement, hormonal replacement, γ- and β- secretase inhibitors, Aβ clearance agents (Aβ immunization, disruption of Aβ fibrils, modulation of the cholesterol-mediated Aβ transport), nonsteroidal anti-inflammatory drugs (NSAIDs), microtubules stabilizing drugs and kinase inhibitors.

Abstract Oral tolerance is an important approach in allergic diseases and murine model can provide useful information to improve its understanding and therapeutic measures. To address the influence of non-related allergen sensitization in immunized mice with the mite Blomia tropicalis (Bt) or ovalbumin (OVA) or with both Bt/OVA allergens. Furthermore, we sought to verify oral tolerance effect in the Bt/OVA co-immunization model. Mice sensitized with Bt and then exposed to OVA developed an enhanced IgE response to both allergens; contrariwise, this effect was not observed when OVA-sensitization was prior to Bt-sensitization. Co-injection of Bt and OVA led to a dominant IgE response towards OVA over Bt, which was not observed when co-immunization was performed with a 240-fold less amount of OVA. Induction of oral tolerance with OVA, prior to co-immunization, suppressed IgE response to both allergens, probably as a consequence of the increased levels of IFN-? found in these animals. The results evidenced that, depending on allergenic potential, new allergen exposure may exert an adjuvant effect to the first allergen used in the sensitization. The bystander suppression to non-related allergens through oral tolerance should be a useful mechanism to control sensitization to new allergens.

Abstract: Drugs of abuse induce the release of dopamine in the central nervous system, particularly in the mesolimbic‐mesocortical pathway. As dopamine may act as a neurotoxin, in this study, we analyzed the effects of the drugs of abuse, cocaine, heroin, and amphetamine, on the neurodegeneration of PC12 cells, a dopaminergic cell line, by evaluating the activity of caspase‐3 and mitochondrial cytochrome c release. All the drugs were shown to induce caspase‐3 activation, similarly to staurosporine, a classical inducer of apoptotic cell death. Furthermore, like staurosporine, the drugs of abuse induced a decrease in mitochondrial cytochrome c content, suggesting the involvement of the mitochondrial apoptotic pathway.

Cell death and reactive oxygen species production have been suggested to be involved in neurodegeneration induced by the drugs of abuse. In this study we analyze the toxicity of the following drugs of abuse: heroin, morphine, d-amphetamine, and cocaine in undifferentiated PC12 cells, used as dopaminergic neuronal models. Our data show that opioid drugs (heroin and morphine) are more toxic than stimulant drugs (d-amphetamine and cocaine). Toxic effects induced by heroin are associated with a decrease in intracellular dopamine, an increase in DOPAC levels, and the formation of ROS, whereas toxic effects induced by amphetamine are associated with a decrease in intracellular dopamine and in ATPADP levels. In contrast with cocaine, both amphetamine and heroin induced features of apoptosis. The data suggest that the death of cultured PC12 cells induced by the drugs of abuse is correlated with a decrease in intracellular dopamine levels, which can be associated with an increased dopamine turnover and oxidative cell injury.

This paper details an approach to modelling gas–solid fluidized beds using the two‐fluid granular temperature model. Details concerning the difficulties associated with the boundary conditions, particularly for curved boundaries, are described along with a novel means of obtaining the internal stress of the solid‐phase, in part, by solving an implicit equation. This results in a scheme that is stable even when the solid volume fraction is close to maximum packing. A transient, mixed finite element discretization is used to solve the multi‐phase equations with a discontinuous finite element representation of the granular temperature and continuity equations. A new solution method is proposed to solve the coupled momentum and continuity equations based on Arnoldi iteration. Two fluidized beds are modelled, one in the bubbling regime and the other in the slugging regime. These simulations are compared with experiments. Copyright © 2001 John Wiley & Sons, Ltd.

AbstractResearch on the incorporation of compressibility effects, for both the liquid and radiolytic gas phases, into the Finite Element Transient Criticality (FETCH) coupled neutronics/computational fluid dynamics code is described. The code has been developed to simulate criticality transients in multiphase media and is applied here to fissile solution transient criticality. The predicted fission and pressure transients obtained by the enhanced numerical model are benchmarked against the results from the SILENE series of experiments on criticality transients in uranium solutions. The amplitude and the form of the first pressure peak, following a step reactivity change, are well represented, and insight is gained into the form of subsequent pressure oscillations. An explanation is given on the absence of these oscillations in more energetic transients.

A novel basic phospholipase A2(PLA2) isoform was isolated from Bothrops jararacussusnake venom and partially characterized. The venom was fractionated by HPLC ion-exchange chromatography in ammonium bicarbonate buffer, followed by reverse-phase HPLC to yield the protein Bj IV. Tricine SDS-PAGE in the presence or absence of dithiothreitol showed that Bj IV had a molecular mass of 15 and 30 kDa, respectively. This enzyme was able to form multimeric complexes (30, 45, and 60 kDa). Amino acid analysis showed a high content of hydrophobic and basic amino acids as well as 14 half-cysteine residues. The N-terminal sequence (DLWSWGQMIQETGLLPSYTTY . . .) showed a high degree of homology with basic D49 PLA2myotoxins from other Bothropsvenoms. Bj IV had high PLA2activity and produced moderate myonecrosis in skeletal muscle, but showed no neuromuscular activity in mouse phrenic nerve-diaphragm preparations. Bj IV showed allosteric enzymatic behavior, with maximal activity at pH 8.2 and 35-45°C. Full PLA2activity required Ca2+but was inhibited by Cu2+and Zn2+, and by Cu2+and Mg2+in the presence and absence of Ca2+, respectively. Crotapotins from Crotalus durissus terrificusrattlesnake venom significantly inhibited the enzymatic activity of Bj IV. The latter observation suggested that the binding site for crotapotin in this PLA2was similar to that in the basic PLA2of the crotoxin complex from C. d. terrificusvenom. The presence of crotapotin-like proteins capable of inhibiting the catalytic activity of D49 PLA2could partly explain the low PLA2activity of Bothropsvenoms.

This paper describes a neural network graph partitioning algorithm which partitions unstructured finite element/volume meshes as a precursor to a parallel domain decomposition solution method. The algorithm works by first constructing a coarse graph approximation using an automatic graph coarsening method. The coarse graph is partitioned and the results are interpolated onto the original graph to initialize an optimization of the graph partition problem. In practice, a hierarchy of (usually more than two) graphs are used to help obtain the final graph partition. A mean field theorem neural network is used to perform all partition optimization. The partitioning method is applied to graphs derived from unstructured finite element meshes and in this context it can be viewed as a multi-grid partitioning method. Copyright © 1999 John Wiley & Sons, Ltd.

Highly purified 3'-arylazido-ATP (aATP) was obtained by high performance liquid chromatography. In the dark, this photoactivatable ATP analog was a competitive inhibitor of ATP hydrolysis catalyzed by purified sarcoplasmic reticulum (SR) ATPase with a Ki of 10 microM. The analog itself was hydrolyzed by the enzyme in the dark. A biphasic curve of velocity of hydrolysis of the analog versus aATP concentration was obtained, indicating the presence of high and low affinity sites with K0.5 of approximately 10 microM and 300 microM, respectively. Upon irradiation with visible light, a biphasic curve was obtained for the level of covalent photolabeling of the enzyme versus [beta-32P]aATP concentrations. Levels of 6.5-9 nmol of analog/mg of protein and 20-22 nmol of analog/mg of protein were obtained when labeling with 20-30 or with 400 microM aATP, respectively, showing the existence of 1 mol of high affinity sites/mol of ATPase and 1-1.5 mol of low affinity sites/mol of enzyme. The rate of light-dependent incorporation of [beta-32P]aATP was decreased by the presence of ATP, Pi, 2',3'-O-(2,4,6-trinitrocyclohexadienylidene-ATP, or Ca2+ in the illumination media. Photolabeling of the high affinity sites had little effect on the velocity of ATP hydrolysis but significantly inhibited the splitting of additional aATP added in the dark. Photolabeling the low affinity sites caused irreversible inhibition of the ATPase activity. The inhibition was prevented by having ATP in the illumination medium, which protected it from labeling. Gel filtration chromatography in the presence of detergent showed that radioactive photolabel was incorporated in the SR ATPase protein. The results indicate that aATP is a useful tool for stoichiometrically labeling and probing the nucleotide binding domains of the SR ATPase.

The effect of central injection of selective kinin B1and B2receptor antagonists on the febrile response induced by endotoxin (E. colilipopolysaccharide, LPS) in rats was investigated.Intracerebroventricular (i.c.v.) injection of a selective B2receptor antagonist (Hoe‐140, 8 nmol) reduced the early (0–2 h), but increased the late phase (4–6 h) of the febrile response induced by intravenous (i.v.) injection of LPS (0.5 μg kg−1).Co‐administration of Hoe‐140 (8 nmol, i.c.v.) with LPS (0.5 μg kg−1, i.v.), followed 2.5 h later by the i.c.v. injection of a selective B1receptor antagonist [des‐Arg9‐Leu8]‐bradykinin (BK, 8 nmol), significantly reduced the febrile response induced by LPS throughout the whole experimental period.Intravenous injection of Hoe‐140 (1 mg kg−1) significantly reduced the febrile response induced by LPS (0.5 μg kg−1, i.p.).Pretreatment (24 h) with LPS (0.5 μg kg−1, i.v.) reduced the febrile response induced by BK or [Tyr8]‐BK (both, 5 nmol, i.c.v.), but markedly increased the febrile response induced by [des‐Arg9]‐BK (5 nmol, i.c.v.). The response induced by [des‐Arg9]‐BK in LPS‐pretreated rats was significantly inhibited by co‐injection of [des‐Arg9‐Leu8]‐BK (15 nmol, i.c.v.).The results suggest that kinins are involved in the induction of LPS‐induced fever and that central B2and B1receptors are activated during the initial and late phase of this response, respectively. The results also suggest that downregulation and/or desensitization of B2receptors and induction and/or upregulation of B1receptors in LPS‐pretreated animals may have a significant pathophysiologcal role in the induction and maintenance of fever. These observations may be specifically important in the case of chronic inflammatory conditions, because the BK metabolite [des‐Arg9]‐BK, so far considered an inactive metabolite, acquires an active and relevant role with the progressive expression of B1receptors that occurs in such states.

This paper reports numerical simulation of the flow past a heated/cooled sphere. A Galerkin finite element method is used to solve the 3D incompressible Boussinesq equations in primitive variable form. Numerical simulations of flow around the sphere for a range of Grashof numbers and moderate Reynolds numbers, were conducted. The drag coefficient for adiabatic flow shows good agreement with standard correlations over the range of the Reynolds numbers investigated. It is shown that the drag can vary considerably with heating of the sphere and that computational fluid dynamics methods can be used to derive constitutive laws for macroscopic momentum and heat exchange in multiphase flow. © 1998 John Wiley & Sons, Ltd.