Search

We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, brains had 20 to 60 detectable single-nucleotide mutations, but ~6% of brains harbored hundreds of somatic mutations. Hypermutability was associated with age and damaging mutations in genes implicated in cancers and, in some brains, reflected in vivo clonal expansions. Somatic duplications, likely arising during development, were found in ~5% of normal and diseased brains, reflecting background mutagenesis. Brains with autism were associated with mutations creating putative transcription factor binding motifs in enhancer-like regions in the developing brain. The top-ranked affected motifs corresponded to MEIS (myeloid ectopic viral integration site) transcription factors, suggesting a potential link between their involvement in gene regulation and autism.

Yu et al. suggested calculating precisely the size ranges of the three parts of our figure 3A, adjusting the free-energy levels in figure 3B, and considering the shape effect in the first-principles calculation. The first and second suggestions raise strong concerns for misinterpretation and overinterpretation of our experiments. The original calculation is sufficient to support our claim about crystalline-to-disordered transformations.

Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell-induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. These hotspots are enriched with histone H2A isoforms and RNA binding proteins and are associated with evolutionarily conserved elements of the human genome. These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system.

Nucleation in atomic crystallization remains poorly understood, despite advances in classical nucleation theory. The nucleation process has been described to involve a nonclassical mechanism that includes a spontaneous transition from disordered to crystalline states, but a detailed understanding of dynamics requires further investigation. In situ electron microscopy of heterogeneous nucleation of individual gold nanocrystals with millisecond temporal resolution shows that the early stage of atomic crystallization proceeds through dynamic structural fluctuations between disordered and crystalline states, rather than through a single irreversible transition. Our experimental and theoretical analyses support the idea that structural fluctuations originate from size-dependent thermodynamic stability of the two states in atomic clusters. These findings, based on dynamics in a real atomic system, reshape and improve our understanding of nucleation mechanisms in atomic crystallization.

An ever-present limitation of transmission electron microscopy is the damage caused by high-energy electrons interacting with any sample. By reconsidering the fundamentals of imaging, we demonstrate an event-responsive approach to electron microscopy that delivers more information about the sample for a given beam current. Measuring the time to achieve an electron count threshold rather than waiting a predefined constant time improves the information obtained per electron. The microscope was made to respond to these events by blanking the beam, thus reducing the overall dose required. This approach automatically apportions dose to achieve a given signal-to-noise ratio in each pixel, eliminating excess dose that is associated with diminishing returns of information. We demonstrate the wide applicability of our approach to beam-sensitive materials by imaging biological tissue and zeolite. [ABSTRACT FROM AUTHOR]

Intratumoral heterogeneity contributes to cancer drug resistance, but the underlying mechanisms are not understood. Single-cell analyses of patient-derived models and clinical samples from glioblastoma patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate that tumor cells reversibly up-regulate or suppress mutant EGFR expression, conferring distinct cellular phenotypes to reach an optimal equilibrium for growth. Resistance to EGFR TKIs is shown to occur by elimination of mutant EGFR from extrachromosomal DNA. After drug withdrawal, reemergence of clonal EGFR mutations on extrachromosomal DNA follows. These results indicate a highly specific, dynamic, and adaptive route by which cancers can evade therapies that target oncogenes maintained on extrachromosomal DNA.

Evidence for a three-coordinate silyl cation is provided by the crystal structure of [(Mes)3Si][H-CB11Me5Br6].C6H6 (where Mes is 2,4,6-trimethylphenyl). Free (Mes)3Si+ cations are well separated from the carborane anions and benzene solvate molecules. Ortho-methyl groups of the mesityl substituents shield the silicon atom from the close approach of nucleophiles, while remaining innocent as significant ligands themselves. The silicon center is three-coordinate and planar. The downfield 29Si nuclear magnetic resonance chemical shift in the solid state (226.7 parts per million) is almost identical to that in benzene solution and in "gas phase" calculations, indicating that three-coordination can be preserved in all phases.

A new superacid, H(CB11H6X6) (where X = chlorine or bromine), whose conjugate base is the exceptionally inert CB11H6X6- carborane anion, separates Bronsted acidity from oxidizing capacity and anion nucleophilicity in a manner not previously achieved. Reaction of this superacid with C60 gives HC60+ as a stable ion in solution and in the solid state. In a separate experiment, an oxidant was developed such that the long-sought C60.+ ion can be synthesized in solution. The preparation of these two fullerene carbocations is a notable departure from the prevalent chemistry of C60, which is dominated by the formation of anions or the addition of nucleophiles. The H(CB11H6X6) superacid overcomes the major limitations of presently known superacids and has potentially wide application.

Electrons in graphene behave like Dirac fermions, permitting phenomena from high-energy physics to be studied in a solid-state setting. A key question is whether or not these fermions are critically influenced by Coulomb correlations. We performed inelastic x-ray scattering experiments on crystals of graphite and applied reconstruction algorithms to image the dynamical screening of charge in a freestanding graphene sheet. We found that the polarizability of the Dirac fermions is amplified by excitonic effects, improving screening of interactions between quasiparticles. The strength of interactions is characterized by a scale-dependent, effective fine-structure constant, [[alpha].sup.*.sub.g] (k, [omega]), the value of which approaches 0.14 [+ or -] 0.092 ~ 1/7 at tow energy and Large distances. This value is substantially smaller than the nominal [[alpha].sub.g] = 2.2, suggesting that, on the whole, graphene is more weakly interacting than previously believed. 10.1126/science.1190920

Tool use is so rare in the animal kingdom that its evolutionary origins cannot be traced with comparative analyses. Valuable insights can be gained from investigating the ecological context and adaptive significance of tool use under contemporary conditions, but obtaining robust observational data is challenging. We assayed individual-level tool-use dependence in wild New Caledonian crows by analyzing stable isotope profiles of the birds' feathers, blood, and putative food sources. Bayesian diet-mixing models revealed that a substantial amount of the crows' protein and lipid intake comes from prey obtained with stick tools--wood-boring beetle larvae. Our calculations provide estimates of larva-intake rates and show that just a few larvae can satisfy a crow's daily energy requirements, highlighting the substantial rewards available to competent tool users. 10.1126/science.1192053

Africa is the source of all modern humans, but characterization of genetic variation and of relationships among populations across the continent has been enigmatic. We studied 121 African populations, four African American populations, and 60 non-African populations for patterns of variation at 1337 nuclear microsatellite and insertion/deletion markers. We identified 14 ancestral population dusters in Africa that correlate with self-described ethnicity and shared cultural and/or linguistic properties. We observed high levels of mixed ancestry in most populations, reflecting historical migration events across the continent. Our data also provide evidence for shared ancestry among geographically diverse hunter-gatherer populations (Khoesan speakers and Pygmies). The ancestry of African Americans is predominantly from Niger-Kordofanian (~71%), European (~13%), and other African (~8%) populations, although admixture levels varied considerably among individuals. This study helps tease apart the complex evolutionary history of Africans and African Americans, aiding both anthropotogical and genetic epidemioiogic studies.

An organic material composed of neutral free radicals based on the spirobiphenalenyl system exhibits a room temperature conductivity of 0.3 siemens per centimeter and a high-symmetry crystal structure. It displays the temperature-independent Pauli pararnagnetism characteristic of a metal with a magnetic susceptibility that implies a density of states at the Fermi level of 15.5 states per electron volt per mole. Extended Huckel calculations indicate that the solid is a three-dimensional organic metal with a band width of ~0.5 electron volts. However, the compound shows activated conductivity (activation energy, 0.054 electron volts) and an optical energy gap of 0.34 electron volts. We argue that these apparently contradictory properties are best resolved in terms of the resonating valence-bond ground state originally suggested by Pauling, but with the modifications introduced by Anderson., The familiar properties of inorganic metals, such as the inverse temperature dependence of their conductivity, are well understood in terms of band theory, in which valence electrons populate delocalized states [...]

We generated mice lacking Cks2, one of two mammalian homologs of the yeast Cdk1-binding proteins, Sue1 and Cks1, and found them to be viable but sterile in both sexes. Sterility is due to failure of both male and female germ cells to progress past the first meiotic metaphase. The chromosomal events up through the end of prophase I are normal in both [CKS2.sup.-/-] males and females, suggesting that the phenotype is due directly to failure to enter anaphase and not a consequence of a checkpoint-mediated metaphase I arrest., Like the mitotic cell cycle, the meiotic cell cycle is controlled by regulating the activity of maturation promoting factor (MPF), the complex of cyclin B and Cdk1. But the need [...]

Heteromultimeric cyclic nucleotide-gated (CNG) channels play a central role in the transduction of odorant signals and subsequent adaptation. The contributions of individual subunits to native channel function in olfactory receptor neurons remain unclear. Here, we show that the targeted deletion of the mouse CNGA4 gene, which encodes a modulatory CNG subunit, results in a defect in odorant-dependent adaptation. Channels in excised membrane patches from the CNGA4 null mouse exhibited slower [Ca.sup.2+]-calmodulin-mediated channel desensitization. Thus, the CNGA4 subunit accelerates the [Ca.sup.2+]-mediated negative feedback in olfactory signaling and allows rapid adaptation in this sensory system., Olfactory receptor neurons (ORNs) respond to odorant stimulation with a receptor-mediated increase in intracellular cyclic adenosine 3',5'-monophosphate (cAMP), which directly activates a cyclic nucleotide-gated (CNG) channel in the plasma membrane [...]