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\"This award-winning science book uses the latest findings from neuroscience research and brain-imaging technology to take you on a journey into the human brain.\"-- Publisher's description.

MEMBERS of the nerve growth factor (NGF) family promote the survival of neurons during development 1 . NGF specifically acti-vates the receptor trkA, initiating a signal transduction cascade which ultimately blocks cell death. Here we show that NGF can have the opposite effect, inducing the death of mature oligodendrocytes cultured from postnatal rat cerebral cortex. This effect was highly specific, because NGF had no effect on oligodendrocyte precursors and astrocytes. Other neurotrophins such as brain-derived neurotrophin factor (BDNF) and neurotrophin-3 (NT-3) did not induce cell death. NGF binding to mature oligodendrocytes expressing the p75 neurotrophin receptor, but not trkA, resulted in a sustained increase of intracellular ceramide and c-Jun amino-terminal kinase (JNK) activity, which are thought to participate in a signal transduction pathway leading to cell death. Taken together, these results indicate that NGF has the ability to promote cell death in specific cell types through a ligand-dependent signalling mechanism involving the p75 neurotrophin receptor.

Over the past three decades, we have witnessed one of the great revolutions in our understanding of the cosmos-the dawn of the Exoplanet Era. Where once we knew of just one planetary system (the solar system), we now know of thousands, with new systems being announced on a weekly basis. Of the thousands of planetary systems we have found to date, however, there is only one that we can study up-close and personal-the solar system. In this review, we describe our current understanding of the solar system for the exoplanetary science community-with a focus on the processes thought to have shaped the system we see today. In section one, we introduce the solar system as a single well studied example of the many planetary systems now observed. In section two, we describe the solar system's small body populations as we know them today-from the two hundred and five known planetary satellites to the various populations of small bodies that serve as a reminder of the system's formation and early evolution. In section three, we consider our current knowledge of the solar system's planets, as physical bodies. In section four we discuss the research that has been carried out into the solar system's formation and evolution, with a focus on the information gleaned as a result of detailed studies of the system's small body populations. In section five, we discuss our current knowledge of planetary systems beyond our own-both in terms of the planets they host, and in terms of the debris that we observe orbiting their host stars. As we learn ever more about the diversity and ubiquity of other planetary systems, our solar system will remain the key touchstone that facilitates our understanding and modeling of those newly found systems, and we finish section five with a discussion of the future surveys that will further expand that knowledge.

Mutations in the gene encoding the amyloid protein precursor (APP) cause autosomal dominant Alzheimer's disease 1 , 2 , 3 . Cleavage of APP by unidentified proteases, referred to as β- and γ-secretases 4 , 5 , 6 , 7 , generates the amyloid β-peptide, the main component of the amyloid plaques found in Alzheimer's disease patients 8 . The disease-causing mutations flank the protease cleavage sites in APP and facilitate its cleavage. Here we identify a new membrane-bound aspartyl protease (Asp2) with β-secretase activity. The Asp2 gene is expressed widely in brain and other tissues. Decreasing the expression of Asp2 in cells reduces amyloid β-peptide production and blocks the accumulation of the carboxy-terminal APP fragment that is created by β-secretase cleavage. Solubilized Asp2 protein cleaves a synthetic APP peptide substrate at the β-secretase site, and the rate of cleavage is increased tenfold by a mutation associated with early-onset Alzheimer's disease in Sweden 3 . Thus, Asp2 is a new protein target for drugs that are designed to block the production of amyloid β-peptide peptide and the consequent formation of amyloid plaque in Alzheimer's disease.

Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) selectively bind to distinct members of the Trk family of tyrosine kinase receptors, but all three bind with similar affinities to the neurotrophin receptor p75 (p75$^{NTR}$). The biological significance of neurotrophin binding to p75$^{NTR}$ in cells that also express Trk receptors has been difficult to ascertain. In the absence of TrkA, NGF binding to p75$^{NTR}$ activated the transcription factor nuclear factor kappa B (NF-κB) in rat Schwann cells. This activation was not observed in Schwann cells isolated from mice that lacked p75$^{NTR}$. The effect was selective for NGF; NF-κB was not activated by BDNF or NT-3.

Purpose Ataxia–Telangiectasia Mutated ( ATM ) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. Methods From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. Results LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56–4.11, p  < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p  < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6–5.09, p  < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p  < 0.01). In a case–control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases ( p  = 0.027, p  = 0.018). Conclusion This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.

Hyperacute rejection of porcine organs by old world primate recipients is mediated through preformed antibodies against galactosyl-α-1,3-galactose (Galα-1,3-Gal) epitopes expressed on the pig cell surface. Previously, we generated inbred miniature swine with a null allele of the α-1,3-galactosyltransferase locus (GGTA1) by nuclear transfer (NT) with gene-targeted fibroblasts. To expedite the generation of GGTA1 null pigs, we selected spontaneous null mutant cells from fibroblast cultures of heterozygous animals for use in another round of NT. An unexpectedly high rate of spontaneous loss of GGTA1 function was observed, with the vast majority of null cells resulting from loss of the WT allele. Healthy piglets, hemizygous and homozygous for the gene-targeted allele, were produced by NT by using fibroblasts that had undergone deletional and crossover/gene conversion events, respectively. Aside from loss of Galα-1,3-Gal epitopes, there were no obvious phenotypic differences between these null piglets and WT piglets from the same inbred lines. In fact, congenital abnormalities observed in the heterozygous NT animals did not reappear in the serially produced null animals.

NRAGE (also known as Maged1, Dlxin ) is a member of the MAGE gene family that may play a role in the neuronal apoptosis that is regulated by the p75 neurotrophin receptor (p75NTR). To test this hypothesis in vivo , we generated NRAGE knockout mice and found that NRAGE deletion caused a defect in developmental apoptosis of sympathetic neurons of the superior cervical ganglia, similar to that observed in p75NTR knockout mice. Primary sympathetic neurons derived from NRAGE knockout mice were resistant to apoptosis induced by brain-derived neurotrophic factor (BDNF), a pro-apoptotic p75NTR ligand, and NRAGE-deficient sympathetic neurons show attenuated BDNF-dependent JNK activation. Hair follicle catagen is an apoptosis-like process that is dependent on p75NTR signaling; we show that NRAGE and p75NTR show regulated co-expression in the hair follicle and that identical defects in hair follicle catagen are present in NRAGE and p75NTR knockout mice. Interestingly, NRAGE knockout mice have severe defects in motoneuron apoptosis that are not observed in p75NTR knockout animals, raising the possibility that NRAGE may facilitate apoptosis induced by receptors other than p75NTR. Together, these studies demonstrate that NRAGE plays an important role in apoptotic-signaling in vivo .

ABSTRACT To understand the frequency, and thus the formation and evolution, of planetary systems like our own solar system, it is critical to detect Jupiter-like planets in Jupiter-like orbits. For long-term radial-velocity monitoring, it is useful to estimate the observational effort required to reliably detect such objects, particularly in light of severe competition for limited telescope time. We perform detailed simulations of observational campaigns, maximizing the realism of the sampling of a set of simulated observations. We then compute the detection limits for each campaign to quantify the effect of increasing the number of observational epochs and varying their time coverage. We show that once there is sufficient time baseline to detect a given orbital period, it becomes less effective to add further time coverage-rather, the detectability of a planet scales roughly as the square root of the number of observations, independently of the number of orbital cycles included in the data string. We also show that no noise floor is reached, with a continuing improvement in detectability at the maximum number of observations N = 500 tested here.

Peripheral myelin formation is initiated by axonal cues that trigger a differentiation program in associated Schwann cells. Here, we define one essential differentiation signal: activation of the transcription factor NF-κB. In rat sciatic nerves, NF-κB was highly upregulated in pre-myelinating Schwann cells, and then its expression progressively declined until it was nearly absent in adults. Similarly, in co-cultures of Schwann cells and sensory neurons, NF-κB activation paralleled myelination, and blocking its activity or using cells from mice lacking the NF-κB subunit p65 markedly attenuated myelination. Inhibiting NF-κB also prevented activation of Oct-6, a transcription factor induced by axonal contact and required for proper myelin formation. These results show that the activation of NF-κB is an essential signal for the progression of axon-associated Schwann cells into a myelinating phenotype.