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.     

Targeting O 6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy

O ⁶-methylguanine-DNA methyltransferase (MGMT) repairs the cancer chemotherapy-relevant DNA adducts, O ⁶-methylguanine and O ⁶-chloroethylguanine, induced by methylating and chloroethylating anticancer drugs, respectively. These adducts are cytotoxic, and given the overwhelming evidence that MGMT is a key factor in resistance, strategies for inactivating MGMT have been pursued. A number of drugs have been shown to inactivate MGMT in cells, human tumour models and cancer patients, and O ⁶-benzylguanine and O ⁶-[4-bromothenyl]guanine have been used in clinical trials. While these agents show no side effects per se, they also inactivate MGMT in normal tissues and hence exacerbate the toxic side effects of the alkylating drugs, requiring dose reduction. This might explain why, in any of the reported trials, the outcome has not been improved by their inclusion. It is, however, anticipated that, with the availability of tumour targeting strategies and hematopoetic stem cell protection, MGMT inactivators hold promise for enhancing the effectiveness of alkylating agent chemotherapy.     

Adaptive immunity maintains occult cancer in an equilibrium state

The capacity of immunity to control and shape cancer, that is, cancer immunoediting, is the result of three processes that function either independently or in sequence: elimination (cancer immunosurveillance, in which immunity functions as an extrinsic tumour suppressor in naive hosts); equilibrium (expansion of transformed cells is held in check by immunity); and escape (tumour cell variants with dampened immunogenicity or the capacity to attenuate immune responses grow into clinically apparent cancers). Extensive experimental support now exists for the elimination and escape processes because immunodeficient mice develop more carcinogen-induced and spontaneous cancers than wild-type mice, and tumour cells from immunodeficient mice are more immunogenic than those from immunocompetent mice. In contrast, the equilibrium process was inferred largely from clinical observations, including reports of transplantation of undetected (occult) cancer from organ donor into immunosuppressed recipients. Herein we use a mouse model of primary chemical carcinogenesis and demonstrate that equilibrium occurs, is mechanistically distinguishable from elimination and escape, and that neoplastic cells in equilibrium are transformed but proliferate poorly in vivo. We also show that tumour cells in equilibrium are unedited but become edited when they spontaneously escape immune control and grow into clinically apparent tumours. These results reveal that, in addition to destroying tumour cells and sculpting tumour immunogenicity, the immune system of a naive mouse can also restrain cancer growth for extended time periods.     

A closely packed system of low-mass, low-density planets transiting Kepler-11

When an extrasolar planet passes in front of (transits) its star, its radius can be measured from the decrease in starlight and its orbital period from the time between transits. Multiple planets transiting the same star reveal much more: period ratios determine stability and dynamics, mutual gravitational interactions reflect planet masses and orbital shapes, and the fraction of transiting planets observed as multiples has implications for the planarity of planetary systems. But few stars have more than one known transiting planet, and none has more than three. Here we report Kepler spacecraft observations of a single Sun-like star, which we call Kepler-11, that reveal six transiting planets, five with orbital periods between 10 and 47?days and a sixth planet with a longer period. The five inner planets are among the smallest for which mass and size have both been measured, and these measurements imply substantial envelopes of light gases. The degree of coplanarity and proximity of the planetary orbits imply energy dissipation near the end of planet formation.     

Leibniz's Observations on Hydrology: An Unpublished Letter on the Great Lombardy Flood of 1705

Although the historical reputation of Gottfried Wilhelm Leibniz (1646–1716) largely rests on his philosophical and mathematical work, it is widely known that he made important contributions to many of the emerging but still inchoate branches of natural science of his day. Among the many scientific papers Leibniz published during his lifetime are ones on the nascent science we now know as hydrology. While Leibniz's other scientific work has become of increasing interest to scholars in recent years, his thinking about hydrology has been neglected, despite being relatively broad in extent, including as it does papers on the ‘raising of vapours’ and the formation of ice, as well as the separation of salt and fresh water. That list can now be extended still further following the discovery of a previously unpublished letter of Leibniz's on the causes of the devastating Lombardy flood of October and November 1705. This letter, which will be the focus of our paper, reveals the depth of Leibniz's understanding of key hydrological processes. In it, he considers various mechanisms for the flood, such as heavy rains on high ground, underwater earthquakes, and a mountain collapse. Over the course of the paper we examine each of these mechanisms in depth, and show that Leibniz was in the vanguard of hydrological thinking. We also show that the letter contains one of the first scholarly attempts to apply aspects of the still-forming notion of the hydrological cycle to account for a flood event.     

Common variation at 10p12.31 near MLLT10 influences meningioma risk

To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 × 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.     

Effects of elevation on litter-size variation among lizard populations in the Sceloporus grammicus complex (Phrynosomatidae) in Mexico

We examined the effect of elevation on litter-size variation in viviparous lizards of the Sceloporus grammicus complex in 10 states of Mexico. Female snout–vent length (SVL) decreased with increasing elevation, and absolute litter size based on embryos also tended to de crease with increasing elevation. However, after controlling for variation in female body size, we found that litter sizes tended to be relatively larger at higher elevation. Elevation therefore appears to influence litter size in these lizards; however, relatively little of the variation is explained by elevation; thus, other factors are likely making substantial contributions to the observed litter-size variation. The S. grammicus complex appears to be a good model system for examining the underlying causes of geographic and elevational variation in lizard life histories. Examinamos el efecto del altitud en la variación del tamaño de camada de las lagartijas vivíparas del complejo Sceloporus grammicus en 10 estados de México. La LHC de las hembras disminuyó con la altitud, y el tamaño absoluto de camada, calculado con base en el número de embriones, también tendió a disminuir. No obstante, después de controlar la variación en el tamaño corporal de las hembras, encontramos que los tamaños de camada tendieron a ser relativamente más grandes en altitudes mayores. La altitud, por tanto, parece influir en el tamaño de camada de estas lagartijas; sin embargo, la altitud explica relativamente poco de la variación, por lo que, es probable que otros factores contribuyan substancialmente a la variación observada en el tamaño de camada. El complejo S. grammicus parece ser un buen sistema para estudiar las causas fundamentales de la variación geográfica y altitudinal en la historia de vida de las lagartijas.