Quantum Holographic Encoding in a Two-dimensional Electron Gas

The advent of bottom-up atomic manipulation heralded a new horizon for attainable information density, as it allowed a bit of information to be represented by a single atom. The discrete spacing between atoms in condensed matter has thus set a rigid limit on the maximum possible information density. While modern technologies are still far from this scale, all theoretical downscaling of devices terminates at this spatial limit. Here, however, we break this barrier with electronic quantum encoding scaled to subatomic densities. We use atomic manipulation to first construct open nanostructures--"molecular holograms"--which in turn concentrate information into a medium free of lattice constraints: the quantum states of a two-dimensional degenerate Fermi gas of electrons. The information embedded in the holograms is transcoded at even smaller length scales into an atomically uniform area of a copper surface, where it is densely projected into both two spatial degrees of freedom and a third holographic dimension mapped to energy. In analogy to optical volume holography, this requires precise amplitude and phase engineering of electron wavefunctions to assemble pages of information volumetrically. This data is read out by mapping the energy-resolved electron density of states with a scanning tunnelling microscope. As the projection and readout are both extremely near-field, and because we use native quantum states rather than an external beam, we are not limited by lensing or collimation and can create electronically projected objects with features as small as ~0.3 nm. These techniques reach unprecedented densities exceeding 20 bits/nm2 and place tens of bits into a single fermionic state.Comment: Published online 25 January 2009 in Nature Nanotechnology; 12 page manuscript (including 4 figures) + 2 page supplement (including 1 figure); supplementary movie available at http://mota.stanford.ed

Virtue perspectivism, externalism, and epistemic circularity

Virtue perspectivism is a bi-level epistemology according to which there are two grades of knowledge: animal and reflective. The exercise of reliable competences suffices to give us animal knowledge; but we can then use these same competences to gain a second-order assuring perspective, one through which we may appreciate those faculties as reliable and in doing so place our first-order (animal) knowledge in a competent second-order perspective. Virtue perspectivism has considerable theoretical power, especially when it comes to vindicating our external world knowledge against threats of scepticism and regress. Prominent critics, however, doubt whether the view ultimately hangs together without succumbing to vicious circularity. In this paper, I am going to focus on circularity-based criticisms of virtue perspectivism raised in various places by Barry Stroud, Baron Reed and Richard Fumerton, and I will argue that virtue perspectivism can ultimately withstand each of them

Improved annotation of 3' untranslated regions and complex loci by combination of strand-specific direct RNA sequencing, RNA-seq and ESTs

The reference annotations made for a genome sequence provide the framework for all subsequent analyses of the genome. Correct annotation is particularly important when interpreting the results of RNA-seq experiments where short sequence reads are mapped against the genome and assigned to genes according to the annotation. Inconsistencies in annotations between the reference and the experimental system can lead to incorrect interpretation of the effect on RNA expression of an experimental treatment or mutation in the system under study. Until recently, the genome-wide annotation of 3-prime untranslated regions received less attention than coding regions and the delineation of intron/exon boundaries. In this paper, data produced for samples in Human, Chicken and A. thaliana by the novel single-molecule, strand-specific, Direct RNA Sequencing technology from Helicos Biosciences which locates 3-prime polyadenylation sites to within +/- 2 nt, were combined with archival EST and RNA-Seq data. Nine examples are illustrated where this combination of data allowed: (1) gene and 3-prime UTR re-annotation (including extension of one 3-prime UTR by 5.9 kb); (2) disentangling of gene expression in complex regions; (3) clearer interpretation of small RNA expression and (4) identification of novel genes. While the specific examples displayed here may become obsolete as genome sequences and their annotations are refined, the principles laid out in this paper will be of general use both to those annotating genomes and those seeking to interpret existing publically available annotations in the context of their own experimental dataComment: 44 pages, 9 figure

X-ray Structures of the Signal Recognition Particle Receptor Reveal Targeting Cycle Intermediates

The signal recognition particle (SRP) and its conjugate receptor (SR) mediate cotranslational targeting of a subclass of proteins destined for secretion to the endoplasmic reticulum membrane in eukaryotes or to the plasma membrane in prokaryotes. Conserved active site residues in the GTPase domains of both SRP and SR mediate discrete conformational changes during formation and dissociation of the SRP·SR complex. Here, we describe structures of the prokaryotic SR, FtsY, as an apo protein and in two different complexes with a non-hydrolysable GTP analog (GMPPNP). These structures reveal intermediate conformations of FtsY containing GMPPNP and explain how the conserved active site residues position the nucleotide into a non-catalytic conformation. The basis for the lower specificity of binding of nucleotide in FtsY prior to heterodimerization with the SRP conjugate Ffh is also shown. We propose that these structural changes represent discrete conformational states assumed by FtsY during targeting complex formation and dissociation

Assessing the reliability of retrospective reports of adverse childhood experiences among adolescents with documented childhood maltreatment

The literature suggests that childhood maltreatment is related to a higher probability of developing psychopathology and disease in adulthood. However, some authors have questioned the reliability of self-reports of maltreatment, suggesting that psychopathology at the time of evaluation affects self-reports. We evaluated the reliability of the self-reports of 79 young adults who were identified in childhood by Child Protective Services by comparing two moments of evaluation. Psychological and physical symptoms were tested to evaluate their interference with the reports. We found good to excellent agreement, with no significant correlation between the changes in self-reported experiences and the changes in physical and psychological symptoms, suggesting that the reliability of reports is not related to the health state at the time of the report

Nanoscale structure of amyloid-β plaques in Alzheimer’s disease

Abstract Soluble amyloid-β (Aβ) is considered to be a critical component in the pathogenesis of Alzheimer’s disease (AD). Evidence suggests that these non-fibrillar Aβ assemblies are implicated in synaptic dysfunction, neurodegeneration and cell death. However, characterization of these species comes mainly from studies in cellular or animal models, and there is little data in intact human samples due to the lack of adequate optical microscopic resolution to study these small structures. Here, to achieve super-resolution in all three dimensions, we applied Array Tomography (AT) and Stimulated Emission Depletion microscopy (STED), to characterize in postmortem human brain tissue non-fibrillar Aβ structures in amyloid plaques of cases with autosomal dominant and sporadic AD. Ultrathin sections scanned with super-resolution STED microscopy allowed the detection of small Aβ structures of the order of 100 nm. We reconstructed a whole human amyloid plaque and established that plaques are formed by a dense core of higher order Aβ species (~0.022 µm3) and a peripheral halo of smaller Aβ structures (~0.003 µm3). This work highlights the potential of AT-STED for human neuropathological studies

Regulation of Mycobacterium tuberculosis-Dependent HIV-1 Transcription Reveals a New Role for NFAT5 in the Toll-Like Receptor Pathway

Tuberculosis (TB) disease in HIV co-infected patients contributes to increased mortality by activating innate and adaptive immune signaling cascades that stimulate HIV-1 replication, leading to an increase in viral load. Here, we demonstrate that silencing of the expression of the transcription factor nuclear factor of activated T cells 5 (NFAT5) by RNA interference (RNAi) inhibits Mycobacterium tuberculosis (MTb)-stimulated HIV-1 replication in co-infected macrophages. We show that NFAT5 gene and protein expression are strongly induced by MTb, which is a Toll-like receptor (TLR) ligand, and that an intact NFAT5 binding site in the viral promoter of R5-tropic HIV-1 subtype B and subtype C molecular clones is required for efficent induction of HIV-1 replication by MTb. Furthermore, silencing by RNAi of key components of the TLR pathway in human monocytes, including the downstream signaling molecules MyD88, IRAK1, and TRAF6, significantly inhibits MTb-induced NFAT5 gene expression. Thus, the innate immune response to MTb infection induces NFAT5 gene and protein expression, and NFAT5 plays a crucial role in MTb regulation of HIV-1 replication via a direct interaction with the viral promoter. These findings also demonstrate a general role for NFAT5 in TLR- and MTb-mediated control of gene expression

Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline

Exclusion of NFAT5 from Mitotic Chromatin Resets Its Nucleo-Cytoplasmic Distribution in Interphase

The transcription factor NFAT5 is a major inducer of osmoprotective genes and is required to maintain the proliferative capacity of cells exposed to hypertonic stress. In response to hypertonicity, NFAT5 translocates to the nucleus, binds to regulatory regions of osmoprotective genes and activates their transcription. Besides stimulus-specific regulatory mechanisms, the activity of transcription factors in cycling cells is also regulated by the passage through mitosis, when most transcriptional processes are downregulated. It was not known whether mitosis could be a point of control for NFAT5.Using confocal microscopy we observed that NFAT5 was excluded from chromatin during mitosis in both isotonic and hypertonic conditions. Analysis of NFAT5 deletions showed that exclusion was mediated by the carboxy-terminal domain (CTD). NFAT5 mutants lacking this domain showed constitutive binding to mitotic chromatin independent of tonicity, which caused them to localize in the nucleus and remain bound to chromatin in the subsequent interphase without hypertonic stimulation. We analyzed the contribution of the CTD, DNA binding, and nuclear import and export signals to the subcellular localization of this factor. Our results indicated that cytoplasmic localization of NFAT5 in isotonic conditions required both the exclusion from mitotic DNA and active nuclear export in interphase. Finally, we identified several regions within the CTD of NFAT5, some of them overlapping with transactivation domains, which were separately capable of causing its exclusion from mitotic chromatin.Our results reveal a multipart mechanism regulating the subcellular localization of NFAT5. The transactivating module of NFAT5 switches its function from an stimulus-specific activator of transcription in interphase to an stimulus-independent repressor of binding to DNA in mitosis. This mechanism, together with export signals acting in interphase, resets the cytoplasmic localization of NFAT5 and prevents its nuclear accumulation and association with DNA in the absence of hypertonic stress