Methylxanthines and Neurodegenerative Diseases: An Update

Methylxanthines (MTX) are purine derived xanthine derivatives. Whereas naturally occurring methylxanthines like caffeine, theophylline or theobromine are widely consumed in food, several synthetic but also non-synthetic methylxanthines are used as pharmaceuticals, in particular in treating airway constrictions. Besides the well-established bronchoprotective effects, methylxanthines are also known to have anti-inflammatory and anti-oxidative properties, mediate changes in lipid homeostasis and have neuroprotective effects. Known molecular mechanisms include adenosine receptor antagonism, phosphodiesterase inhibition, effects on the cholinergic system, wnt signaling, histone deacetylase activation and gene regulation. By affecting several pathways associated with neurodegenerative diseases via different pleiotropic mechanisms and due to its moderate side effects, intake of methylxanthines have been suggested to be an interesting approach in dealing with neurodegeneration. Especially in the past years, the impact of methylxanthines in neurodegenerative diseases has been extensively studied and several new aspects have been elucidated. In this review we summarize the findings of methylxanthines linked to Alzheimer´s disease, Parkinson’s disease and Multiple Sclerosis since 2017, focusing on epidemiological and clinical studies and addressing the underlying molecular mechanisms in cell culture experiments and animal studies in order to assess the neuroprotective potential of methylxanthines in these diseases

Very long storage times and evaporative cooling of cesium atoms in a quasi-electrostatic dipole trap

We have trapped cesium atoms over many minutes in the focus of a CO$_2$-laser beam employing an extremely simple laser system. Collisional properties of the unpolarized atoms in their electronic ground state are investigated. Inelastic binary collisions changing the hyperfine state lead to trap loss which is quantitatively analyzed. Elastic collisions result in evaporative cooling of the trapped gas from 25 $\mu$K to 10 $\mu$K over a time scale of about 150 s.Comment: 5 pages, 3 figure

Unique Role of Caffeine Compared to Other Methylxanthines (Theobromine, Theophylline, Pentoxifylline, Propentofylline) in Regulation of AD Relevant Genes in Neuroblastoma SH-SY5Y Wild Type Cells

Methylxanthines are a group of substances derived from the purine base xanthine with a methyl group at the nitrogen on position 3 and different residues at the nitrogen on position 1 and 7. They are widely consumed in nutrition and used as pharmaceuticals. Here we investigate the transcriptional regulation of 83 genes linked to Alzheimer’s disease in the presence of five methylxanthines, including the most prominent naturally occurring methylxanthines—caffeine, theophylline and theobromine—and the synthetic methylxanthines pentoxifylline and propentofylline. Methylxanthine-regulated genes were found in pathways involved in processes including oxidative stress, lipid homeostasis, signal transduction, transcriptional regulation, as well as pathways involved in neuronal function. Interestingly, multivariate analysis revealed different or inverse effects on gene regulation for caffeine compared to the other methylxanthines, which was further substantiated by multiple comparison analysis, pointing out a distinct role for caffeine in gene regulation. Our results not only underline the beneficial effects of methylxanthines in the regulation of genes in neuroblastoma wild-type cells linked to neurodegenerative diseases in general, but also demonstrate that individual methylxanthines like caffeine mediate unique or inverse expression patterns. This suggests that the replacement of single methylxanthines by others could result in unexpected effects, which could not be anticipated by the comparison to other substances in this substance class

Anomaly Cancelation in Field Theory and F-theory on a Circle

We study the manifestation of local gauge anomalies of four- and six-dimensional field theories in the lower-dimensional Kaluza-Klein theory obtained after circle compactification. We identify a convenient set of transformations acting on the whole tower of massless and massive states and investigate their action on the low-energy effective theories in the Coulomb branch. The maps employ higher-dimensional large gauge transformations and precisely yield the anomaly cancelation conditions when acting on the one-loop induced Chern-Simons terms in the three- and five-dimensional effective theory. The arising symmetries are argued to play a key role in the study of the M-theory to F-theory limit on Calabi-Yau manifolds. For example, using the fact that all fully resolved F-theory geometries inducing multiple Abelian gauge groups or non-Abelian groups admit a certain set of symmetries, we are able to generally show the cancelation of pure Abelian or pure non-Abelian anomalies in these models.Comment: 48 pages, 2 figures; v2: typos corrected, comments on circle fluxes adde

Coexistence and critical behaviour in a lattice model of competing species

In the present paper we study a lattice model of two species competing for the same resources. Monte Carlo simulations for d=1, 2, and 3 show that when resources are easily available both species coexist. However, when the supply of resources is on an intermediate level, the species with slower metabolism becomes extinct. On the other hand, when resources are scarce it is the species with faster metabolism that becomes extinct. The range of coexistence of the two species increases with dimension. We suggest that our model might describe some aspects of the competition between normal and tumor cells. With such an interpretation, examples of tumor remission, recurrence and of different morphologies are presented. In the d=1 and d=2 models, we analyse the nature of phase transitions: they are either discontinuous or belong to the directed-percolation universality class, and in some cases they have an active subcritical phase. In the d=2 case, one of the transitions seems to be characterized by critical exponents different than directed-percolation ones, but this transition could be also weakly discontinuous. In the d=3 version, Monte Carlo simulations are in a good agreement with the solution of the mean-field approximation. This approximation predicts that oscillatory behaviour occurs in the present model, but only for d>2. For d>=2, a steady state depends on the initial configuration in some cases.Comment: 11 pages, 14 figure

LCAA, a Novel Factor Required for Magnesium Protoporphyrin Monomethylester Cyclase Accumulation and Feedback Control of Aminolevulinic Acid Biosynthesis in Tobacco

Low Chlorophyll Accumulation A (LCAA) antisense plants were obtained from a screen for genes whose partial down-regulation results in a strong chlorophyll deficiency in tobacco (Nicotiana tabacum). The LCAA mutants are affected in a plastid-localized protein of unknown function, which is conserved in cyanobacteria and all photosynthetic eukaryotes. They suffer from drastically reduced light-harvesting complex (LHC) contents, while the accumulation of all other photosynthetic complexes per leaf area is less affected. As the disturbed accumulation of LHC proteins could be either attributable to a defect in LHC biogenesis itself or to a bottleneck in chlorophyll biosynthesis, chlorophyll synthesis rates and chlorophyll synthesis intermediates were measured. LCAA antisense plants accumulate magnesium (Mg) protoporphyrin monomethylester and contain reduced protochlorophyllide levels and a reduced content of CHL27, a subunit of the Mg protoporphyrin monomethylester cyclase. Bimolecular fluorescence complementation assays confirm a direct interaction between LCAA and CHL27. 5-Aminolevulinic acid synthesis rates are increased and correlate with an increased content of glutamyl-transfer RNA reductase. We suggest that LCAA encodes an additional subunit of the Mg protoporphyrin monomethylester cyclase, is required for the stability of CHL27, and contributes to feedback-control of 5-aminolevulinic acid biosynthesis, the rate-limiting step of chlorophyll biosynthesis

The Influence of Acitretin on Brain Lipidomics in Adolescent Mice : Implications for Pediatric and Adolescent Dermatological Therapy

Administration of systemic retinoids such as acitretin has not been approved yet for pediatric patients. An adverse event of retinoid-therapy that occurs with lower prevalence in children than in adults is hyperlipidemia. This might be based on the lack of comorbidities in young patients, but must not be neglected. Especially for the development of the human brain up to young adulthood, dysbalance of lipids might be deleterious. Here, we provide for the first time an in-depth analysis of the influence of subchronic acitretin-administration on lipid composition of brain parenchyma of young wild type mice. For comparison and to evaluate the systemic effect of the treatment, liver lipids were analogously investigated. As expected, triglycerides increased in liver as well as in brain and a non-significant increase in cholesterol was observed. However, specifically brain showed an increase in lyso-phosphatidylcholine and carnitine as well as in sphingomyelin. Group analysis of lipid classes revealed no statistical effects, while single species were tissue-dependently changed: effects in brain were in general more subtly as compared to those in liver regarding the mere number of changed lipid species. Thus, while the overall impact of acitretin seems comparably small regarding brain, the change in individual species and their role in brain development and maturation has to be considered

Quantum gases in trimerized kagom\'e lattices

We study low temperature properties of atomic gases in trimerized optical kagom\'{e} lattices. The laser arrangements that can be used to create these lattices are briefly described. We also present explicit results for the coupling constants of the generalized Hubbard models that can be realized in such lattices. In the case of a single component Bose gas the existence of a Mott insulator phase with fractional numbers of particles per trimer is verified in a mean field approach. The main emphasis of the paper is on an atomic spinless interacting Fermi gas in the trimerized kagom\'{e} lattice with two fermions per site. This system is shown to be described by a quantum spin 1/2 model on the triangular lattice with couplings that depend on the bond directions. We investigate this model by means of exact diagonalization. Our key finding is that the system exhibits non-standard properties of a quantum spin-liquid crystal: it combines planar antiferromagnetic order in the ground state with an exceptionally large number of low energy excitations. The possibilities of experimental verification of our theoretical results are critically discussed.Comment: 19 pages/14 figures, version to appear in Phys. Rev. A., numerous minor corrections with respect to former lanl submissio

Quasi-2D Confinement of a BEC in a Combined Optical and Magnetic Potential

We have added an optical potential to a conventional Time-averaged Orbiting Potential (TOP) trap to create a highly anisotropic hybrid trap for ultracold atoms. Axial confinement is provided by the optical potential; the maximum frequency currently obtainable in this direction is 2.2 kHz for rubidium. The radial confinement is independently controlled by the magnetic trap and can be a factor of 700 times smaller than in the axial direction. This large anisotropy is more than sufficient to confine condensates with ~10^5 atoms in a Quasi-2D (Q2D) regime, and we have verified this by measuring a change in the free expansion of the condensate; our results agree with a variational model.Comment: 11 pages, 10 figur