Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1.

Neurofibromatosis type I (NF1) is one of the most common single-gene disorders that causes learning deficits in humans. Mice carrying a heterozygous null mutation of the Nfl gene (Nfl(+/-) show important features of the learning deficits associated with NF1 (ref. 2). Although neurofibromin has several known properties and functions, including Ras GTPase-activating protein activity, adenylyl cyclase modulation and microtubule binding, it is unclear which of these are essential for learning in mice and humans. Here we show that the learning deficits of Nf1(+/-) mice can be rescued by genetic and pharmacological manipulations that decrease Ras function. We also show that the Nf1(+/-) mice have increased GABA (gamma-amino butyric acid)-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Our results indicate that the learning deficits associated with NF1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. Our findings have implications for the development of treatments for learning deficits associated with NF1.     

The detection of superoxide anion from the reaction of oxyhemoglobin and phenylhydrazine using EPR spectroscopy

Summary The low temperature EPR spectrum of a quickly reacted mixture of oxyhemoglobin and phenylhydrazine was studied. With the use of a computer, the spectral contribution of methemoglobin in the region of g=2 was subtracted. The remaining spectrum was that of an axial free radical (g=2.00, g=2.06) having the magnetic parameters of superoxide anion. In the presence of superoxide dismutase, this axial radical was not seen, confirming that superoxide anion is indeed generated by the reaction.The portion of this investigation carried out at the Albert Einstein College of Medicine was supported in part by US Public Health Service Research Grant HL-93399 from the Heart and Lung Institute and by National Institute Contract Nol-CP-55606 to J.P. This is communication No. 378 from the Joan and Lester Avnet Institute of Molecular Biology.Predoctoral fellow in the Medical Scientist Training Program (United States Public Health Service Grant 5-TO-5-GM 01669-12) at the New York University School of Medicine.Recipient of a grant-in-aid from the New York Heart Association.     

Morphological evolution through multiple cis-regulatory mutations at a single gene

One central, and yet unsolved, question in evolutionary biology is the relationship between the genetic variants segregating within species and the causes of morphological differences between species. The classic neo-darwinian view postulates that species differences result from the accumulation of small-effect changes at multiple loci. However, many examples support the possible role of larger abrupt changes in the expression of developmental genes in morphological evolution. Although this evidence might be considered a challenge to a neo-darwinian micromutationist view of evolution, there are currently few examples of the actual genes causing morphological differences between species. Here we examine the genetic basis of a trichome pattern difference between Drosophila species, previously shown to result from the evolution of a single gene, shavenbaby (svb), probably through cis-regulatory changes. We first identified three distinct svb enhancers from D. melanogaster driving reporter gene expression in partly overlapping patterns that together recapitulate endogenous svb expression. All three homologous enhancers from D. sechellia drive expression in modified patterns, in a direction consistent with the evolved svb expression pattern. To test the influence of these enhancers on the actual phenotypic difference, we conducted interspecific genetic mapping at a resolution sufficient to recover multiple intragenic recombinants. This functional analysis revealed that independent genetic regions upstream of svb that overlap the three identified enhancers are collectively required to generate the D. sechellia trichome pattern. Our results demonstrate that the accumulation of multiple small-effect changes at a single locus underlies the evolution of a morphological difference between species. These data support the view that alleles of large effect that distinguish species may sometimes reflect the accumulation of multiple mutations of small effect at select genes.     

RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease

Receptor for AGE (RAGE) is a member of the immunoglobulin superfamily that engages distinct classes of ligands. The biology of RAGE is driven by the settings in which these ligands accumulate, such as diabetes, inflammation, neurodegenerative disorders and tumors. In this review, we discuss the context of each of these classes of ligands, including advance glycation end-products, amyloid beta peptide and the family of beta sheet fibrils, S100/calgranulins and amphoterin. Implications for the role of these ligands interacting with RAGE in homeostasis and disease will be considered.     

Rapid collisional evolution of comets during the formation of the Oort cloud

The Oort cloud of comets was formed by the ejection of icy planetesimals from the region of giant planets--Jupiter, Saturn, Uranus and Neptune--during their formation. Dynamical simulations have previously shown that comets reach the Oort cloud only after being perturbed into eccentric orbits that result in close encounters with the giant planets, which then eject them to distant orbits about 10(4) to 10(5) AU from the Sun (1 AU is the average Earth-Sun distance). All of the Oort cloud models constructed until now simulate its formation using only gravitational effects; these include the influence of the Sun, the planets and external perturbers such as passing stars and Galactic tides. Here we show that physical collisions between comets and small debris play a fundamental and hitherto unexplored role throughout most of the ejection process. For standard models of the protosolar nebula (starting with a minimum-mass nebula) we find that collisional evolution of comets is so severe that their erosional lifetimes are much shorter than the timescale for dynamical ejection. It therefore appears that collisions will prevent most comets escaping from most locations in the region of the giant planets until the disk mass there declines sufficiently that the dynamical ejection timescale is shorter than the collisional lifetime. One consequence is that the total mass of comets in the Oort cloud may be less than currently believed.     

Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo

Do changes in neuronal structure underlie cortical plasticity? Here we used time-lapse two-photon microscopy of pyramidal neurons in layer 2/3 of developing rat barrel cortex to image the structural dynamics of dendritic spines and filopodia. We found that these protrusions were highly motile: spines and filopodia appeared, disappeared or changed shape over tens of minutes. To test whether sensory experience drives this motility we trimmed whiskers one to three days before imaging. Sensory deprivation markedly (approximately 40%) reduced protrusive motility in deprived regions of the barrel cortex during a critical period around postnatal days (P)11-13, but had no effect in younger (P8-10) or older (P14-16) animals. Unexpectedly, whisker trimming did not change the density, length or shape of spines and filopodia. However, sensory deprivation during the critical period degraded the tuning of layer 2/3 receptive fields. Thus sensory experience drives structural plasticity in dendrites, which may underlie the reorganization of neural circuits.     

Hidden symmetries in the energy levels of excitonic 'artificial atoms'

Quantum dots or 'artificial atoms' are of fundamental and technological interest--for example, quantum dots may form the basis of new generations of lasers. The emission in quantum-dot lasers originates from the recombination of excitonic complexes, so it is important to understand the dot's internal electronic structure (and of fundamental interest to compare this to real atomic structure). Here we investigate artificial electronic structure by injecting optically a controlled number of electrons and holes into an isolated single quantum dot. The charge carriers form complexes that are artificial analogues of hydrogen, helium, lithium, beryllium, boron and carbon excitonic atoms. We observe that electrons and holes occupy the confined electronic shells in characteristic numbers according to the Pauli exclusion principle. In each degenerate shell, collective condensation of the electrons and holes into coherent many-exciton ground states takes place; this phenomenon results from hidden symmetries (the analogue of Hund's rules for real atoms) in the energy function that describes the multi-particle system. Breaking of the hidden symmetries leads to unusual quantum interferences in emission involving excited states.     

When and how did plate tectonics begin？ Theoretical and empirical considerations

Plate tectonics is the horizontal motion of Earth’s thermal boundary layer (lithosphere) over the convecting mantle (asthenosphere) and is mostly driven by lithosphere sinking in subduction zones. Plate tectonics is an outstanding example of a self organizing, far from equilibrium complex system (SOFFECS), driven by the negative buoyancy of the thermal boundary layer and controlled by dissipation in the bending lithosphere and viscous mantle. Plate tectonics is an unusual way for a silicate planet to lose heat, as it exists on only one of the large five silicate bodies in the inner solar system. It is not known when this mode of tectonic activity and heat loss began on Earth. All silicate planets probably experienced a short-lived magma ocean stage. After this solidified, stagnant lid behavior is the common mode of planetary heat loss, with interior heat being lost by delamination and “hot spot” volcanism and shallow intrusions. Decompression melting in the hotter early Earth generated a different lithosphere than today, with thicker oceanic crust and thinner mantle lithosphere; such lithosphere would take much longer than at present to become negatively buoyant, suggesting that plate tectonics on the early Earth occurred sporadically if at all. Plate tectonics became sustainable (the modern style) when Earth cooled sufficiently that decompression melting beneath spreading ridges made thin oceanic crust, allowing oceanic lithosphere to become negatively buoyant after a few tens of millions of years. Ultimately the question of when plate tectonics began must be answered by informa- tion retrieved from the geologic record. Criteria for the operation of plate tectonics includes ophiolites, blueschist and ultra-high pressure metamorphic belts, eclogites, passive margins, transform faults, paleomagnetic demonstration of different motions of different cratons, and the presence of diagnostic geochemical and isotopic indicators in igneous rocks. This record must be interpreted individually; I interpret the record to indicate a progression of tectonic styles from active Archean tectonics and magmatism to something similar to plate tectonics at ~1.9 Ga to sustained, modern style plate tectonics with deep subduction——and powerful slab pull——beginning in Neoproterozoic time.