Edar/Eda interactions regulate enamel knot formation in tooth morphogenesis.

tabby and downless mutant mice have apparently identical defects in teeth, hair and sweat glands. Recently, genes responsible for these spontaneous mutations have been identified. downless (Dl) encodes Edar, a novel member of the tumour necrosis factor (TNF) receptor family, containing the characteristic extracellular cysteine rich fold, a single transmembrane region and a death homology domain close to the C terminus. tabby (Ta) encodes ectodysplasin-A (Eda) a type II membrane protein of the TNF ligand family containing an internal collagen-like domain. As predicted by the similarity in adult mutant phenotype and the structure of the proteins, we demonstrate that Eda and Edar specifically interact in vitro. We have compared the expression pattern of Dl and Ta in mouse development, taking the tooth as our model system, and find that they are not expressed in adjacent cells as would have been expected. Teeth develop by a well recorded series of epithelial-mesenchymal interactions, similar to those in hair follicle and sweat gland development, the structures found to be defective in tabby and downless mice. We have analysed the downless mutant teeth in detail, and have traced the defect in cusp morphology back to initial defects in the structure of the tooth enamel knot at E13. Significantly, the defect is distinct from that of the tabby mutant. In the tabby mutant, there is a recognisable but small enamel knot, whereas in the downless mutant the knot is absent, but enamel knot cells are organised into a different shape, the enamel rope, showing altered expression of signalling factors (Shh, Fgf4, Bmp4 and Wnt10b). By adding a soluble form of Edar to tooth germs, we were able to mimic the tabby enamel knot phenotype, demonstrating the involvement of endogenous Eda in tooth development. We could not, however, reproduce the downless phenotype, suggesting the existence of yet another ligand or receptor, or of ligand-independent activation mechanisms for Edar. Changes in the structure of the enamel knot signalling centre in downless tooth germs provide functional data directly linking the enamel knot with tooth cusp morphogenesis. We also show that the Lef1 pathway, thought to be involved in these mutants, functions independently in a parallel pathway.

Geochemical and H-O-Sr-Nd isotope evidence for magmatic processes and meteoric-water interactions in the basal complex of La Gomera, Canary Islands

The plutonic rocks of the Basal Complex of La Gomera, Canary Islands, Spain, were studied by means of major and trace element contents and by H-O-Sr-Nd isotope compositions in order to distinguish primary magmatic characteristics and late-stage alteration products. Deciphering the effects of alteration allowed us to determine primary, plume-related compositions that indicated D- and (18)O-depletion relative to normal upper mantle, supporting the conclusions of earlier studies on the plutonic rocks of Fuerteventura and La Palma. Late-stage alteration took place during the formation of the intrusive series induced by interaction with meteoric water. Inferred isotopic compositions of the meteoric water indicate that the water infiltrated into the rock edifice at a height of about 1500 m above sea level, suggesting the existence of a subaerial volcano which was active during the intrusive activity and that it has been either distroyed or remain buried by later volcanic and landslide events.

Stable alpha-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones.

α-Synuclein aggregation and accumulation in Lewy bodies are implicated in progressive loss of dopaminergic neurons in Parkinson disease and related disorders. In neurons, the Hsp70s and their Hsp40-like J-domain co-chaperones are the only known components of chaperone network that can use ATP to convert cytotoxic protein aggregates into harmless natively refolded polypeptides. Here we developed a protocol for preparing a homogeneous population of highly stable β-sheet enriched toroid-shaped α-Syn oligomers with a diameter typical of toxic pore-forming oligomers. These oligomers were partially resistant to in vitro unfolding by the bacterial Hsp70 chaperone system (DnaK, DnaJ, GrpE). Moreover, both bacterial and human Hsp70/Hsp40 unfolding/refolding activities of model chaperone substrates were strongly inhibited by the oligomers but, remarkably, not by unstructured α-Syn monomers even in large excess. The oligomers acted as a specific competitive inhibitor of the J-domain co-chaperones, indicating that J-domain co-chaperones may preferably bind to exposed bulky misfolded structures in misfolded proteins and, thus, complement Hsp70s that bind to extended segments. Together, our findings suggest that inhibition of the Hsp70/Hsp40 chaperone system by α-Syn oligomers may contribute to the disruption of protein homeostasis in dopaminergic neurons, leading to apoptosis and tissue loss in Parkinson disease and related neurodegenerative diseases.

Tuning the immune response of dendritic cells to surface-assembled poly(I:C) on microspheres through synergistic interactions between phagocytic and TLR3 signaling.

The artificial dsRNA polyriboinosinic acid-polyribocytidylic acid, poly(I:C), is a potent adjuvant candidate for vaccination, as it strongly drives cell-mediated immunity. However, because of its effects on non-immune bystander cells, poly(I:C) administration may bear danger for the development of autoimmune diseases. Thus poly(I:C) should be applied in the lowest dose possible. We investigated microspheres carrying surface-assembled poly(I:C) as a two-in-one adjuvant formulation to stimulate maturation of monocyte-derived dendritic cells (MoDCs). Negatively charged polystyrene microspheres were equipped with a poly(ethylene glycol) corona through electrostatically driven surface assembly of a library of polycationic poly(l-lysine)-graft-poly(ethylene glycol) copolymers, PLL-g-PEG. Stable surface assembly of poly(I:C) was achieved by incubation of polymer-coated microspheres in an aqueous poly(I:C) solution. Surface-assembled poly(I:C) exhibited a strongly enhanced efficacy to stimulate maturation of MoDCs by up to two orders of magnitude, as compared to free poly(I:C). Multiple phagocytosis events were the key factor to enhance the efficacy. The cytokine secretion pattern of MoDCs after exposure to surface-assembled poly(I:C) differed from that of free poly(I:C), while their ability to stimulate T cell proliferation was similar. Overall, phagocytic signaling plays an important role in defining the resulting immune response to such two-in-one adjuvant formulations.

Stochastic generation of homogeneous isotropic turbulence with well-defined-spectra

A precise and simple computational model to generate well-behaved two-dimensional turbulent flows is presented. The whole approach rests on the use of stochastic differential equations and is general enough to reproduce a variety of energy spectra and spatiotemporal correlation functions. Analytical expressions for both the continuous and the discrete versions, together with simulation algorithms, are derived. Results for two relevant spectra, covering distinct ranges of wave numbers, are given.

Inertial effects on reactive particles advected by turbulence

We study the problem of the advection of passive particles with inertia in a two-dimensional, synthetic, and stationary turbulent flow. The asymptotic analytical result and numerical simulations show the importance of inertial bias in collecting the particles preferentially in certain regions of the flow, depending on their density relative to that of the flow. We also study how these aggregates are affected when a simple chemical reaction mechanism is introduced through a Eulerian scheme. We find that inertia can be responsible for maintaining a stationary concentration pattern even under nonfavorable reactive conditions or destroying it under favorable ones.

Suppression of scroll wave turbulence by noise

Rotating scroll waves are dynamical spatiotemporal structures characteristic of three-dimensional active media. It is well known that, under low excitability conditions, scroll waves develop an intrinsically unstable dynamical regime that leads to a highly disorganized pattern of wave propagation. Such a ¿turbulent¿ state bears some resemblance to fibrillation states in cardiac tissue. We show here that this unstable regime can be controlled by using a spatially distributed random forcing superimposed on a control parameter of the system. Our results are obtained from numerical simulations but an explicit analytical argument that rationalizes our observations is also presented.

Expanding scroll rings and negative tension turbulence in a model of excitable media

Scroll waves in excitable media, described by the Barkley model, are studied. In the parameter region of weak excitability, negative tension of wave filaments is found. It leads to expansion of scroll rings and instability of wave filaments. A circular filament tends to stretch, bend, loop, and produce an expanding tangle that fills up the volume. The filament does not undergo fragmentation before it touches the boundaries. Statistical properties of such Winfree turbulence of scroll waves are numerically investigated.

Periodic forcing of scroll rings and control of Winfree turbulence in excitable media

By simulations of the Barkley model, action of uniform periodic nonresonant forcing on scroll rings and wave turbulence in three-dimensional excitable media is investigated. Sufficiently strong rapid forcing converts expanding scroll rings into the collapsing ones and suppresses the Winfree turbulence caused by the negative tension of wave filaments. Slow strong forcing has an opposite effect, leading to expansion of scroll rings and induction of the turbulence. These effects are explained in the framework of the phenomenological kinematic theory of scroll waves.

Ab Initio study of magnetic interactions in the KCuF3 and K2CuF4 low-dimensional Systems

The ab initio cluster model approach has been used to study the electronic structure and magnetic coupling of KCuF3 and K2CuF4 in their various ordered polytype crystal forms. Due to a cooperative Jahn-Teller distortion these systems exhibit strong anisotropies. In particular, the magnetic properties strongly differ from those of isomorphic compounds. Hence, KCuF3 is a quasi-one-dimensional (1D) nearest neighbor Heisenberg antiferromagnet whereas K2CuF4 is the only ferromagnet among the K2MF4 series of compounds (M=Mn, Fe, Co, Ni, and Cu) behaving all as quasi-2D nearest neighbor Heisenberg systems. Different ab initio techniques are used to explore the magnetic coupling in these systems. All methods, including unrestricted Hartree-Fock, are able to explain the magnetic ordering. However, quantitative agreement with experiment is reached only when using a state-of-the-art configuration interaction approach. Finally, an analysis of the dependence of the magnetic coupling constant with respect to distortion parameters is presented.

Electronic structure and magnetic interactions of the spin-chain compounds Ca2CuO3 and Sr2CuO3

The results are presented of a combined periodic and cluster model approach to the electronic structure and magnetic interactions in the spin-chain compounds Ca2CuO3 and Sr2CuO3. An extended t-J model is presented that includes in-chain and interchain hopping and magnetic interaction processes with parameters extracted from ab initio calculations. For both compounds, the in-chain magnetic interaction is found to be around -240 meV, larger than in any of the other cuprates reported in the literature. The interchain magnetic coupling is found to be weakly antiferromagnetic, -1 meV. The effective in-chain hopping parameters are estimated to be ~650 meV for both compounds, whereas the value of the interchain hopping parameter is 30 meV for Sr2CuO3 and 40 meV for Ca2CuO3, in line with the larger interchain distance in the former compound. These effective parameters are shown to be consistent with expressions recently suggested for the Néel temperature and the magnetic moments, and with relations that emerge from the t-J model Hamiltonian. Next, we investigate the physical nature of the band gap. Periodic calculations indicate that an interpretation in terms of a charge-transfer insulator is the most appropriate one, in contrast to the suggestion of a covalent correlated insulator recently reported in the literature.