Soluble tau species, not neurofibrillary aggregates, disrupt neural system integration in a tau transgenic model

Neurofibrillary tangles are a feature of Alzheimer disease and other tauopathies, and while they are generally believed to be markers of neuronal pathology, there is little evidence evaluating whether tangles directly impact neuronal function. To investigate the response of cells in hippocampal circuits to complex behavioral stimuli, we used an environmental enrichment paradigm to induce expression of an immediate-early gene, Arc, in the rTg4510 mouse model of tauopathy. These mice reversibly overexpress P301L tau and exhibit substantial neurofibrillary tangle deposition, neuronal loss, and memory deficits. Employing fluorescent in situ hybridization to detect Arc mRNA, we found that rTg4510 mice have impaired hippocampal Arc expression both without stimulation and in response to environmental enrichment; this likely reflects the combination of functional impairments of existing neurons and loss of neurons. However, tangle-bearing cells were at least as likely as non-tangle-bearing neurons to exhibit Arc expression in response to enrichment. Transgene suppression with doxycycline for 6 weeks resulted in increased percentages of Arc-positive cells in rTg4510 brains compared to untreated transgenics, restoring enrichment-induced Arc mRNA levels to that of wild-type controls despite the continued presence of neurofibrillary pathology. We interpret these data to indicate that soluble tau contributes to impairment of hippocampal function, while tangles do not preclude neurons from responding in a functional circuit

Promoter Binding by the Adr1 Transcriptional Activator May Be Regulated by Phosphorylation in the DNA-Binding Region

Background: Post-translational modification regulates promoter-binding by Adr1, a Zn-finger transcriptional activator of glucose-regulated genes. Support for this model includes the activation of an Adr1-dependent gene in the absence of Adr1 protein synthesis, and a requirement for the kinase Snf1 for Adr1 DNA-binding. A fusion protein with the Adr1 DNA-binding domain and a heterologous activation domain is glucose-regulated, suggesting that the DNA binding region is the target of regulation. Methodology/Principal Findings: Peptide mapping identified serine 98 adjacent to the Zn-fingers as a phosphorylation site. An antibody specific for phosphorylated serine 98 on Adr1 showed that the level of phosphorylated Adr1 relative to the level of total Adr1 decreased with glucose derepression, in a Snf1-dependent manner. Relative phosphorylation decreased in a PHO85 mutant, and this mutant constitutively expressed an Adr1-dependent reporter. Pho85 did not phosphorylate Adr1 in vitro, suggesting that it affects Adr1 indirectly. Mutation of serine 98 to the phosphomimetic amino acid aspartate reduced in vitro DNA-binding of the recombinant Adr1 DNA-binding domain. Mutation to aspartate or alanine affected activation of a reporter by full-length Adr1, and in vivo promoter binding. Conclusions/Significance: Mutation of Adr1 serine 98 affects in vitro and in vivo DNA binding, and phosphorylation of serine 98 in vivo correlates with glucose availability, suggesting that Adr1 promoter-binding is regulated in part by serine 98 phosphorylation

Uptake of hepatitis C specialist services and treatment following diagnosis by dried blood spot in Scotland

Background: Dried blood spot (DBS) testing for hepatitis C (HCV) was introduced to Scotland in 2009. This minimally invasive specimen provides an alternative to venipuncture and can overcome barriers to testing in people who inject drugs (PWID). Objectives: The objective of this study was to determine rates and predictors of: exposure to HCV, attendance at specialist clinics and anti-viral treatment initiation among the DBS tested population in Scotland. Study design: DBS testing records were deterministically linked to the Scottish HCV Clinical database prior to logistic regression analysis. Results: In the first two years of usage in Scotland, 1322 individuals were tested by DBS of which 476 were found to have an active HCV infection. Linkage analysis showed that 32% had attended a specialist clinic within 12 months of their specimen collection date and 18% had begun anti-viral therapy within 18 months of their specimen collection date. A significantly reduced likelihood of attendance at a specialist clinic was evident amongst younger individuals (<35 years), those of unknown ethnic origin and those not reporting injecting drug use as a risk factor. Conclusion: We conclude that DBS testing in non-clinical settings has the potential to increase diagnosis and, with sufficient support, treatment of HCV infection among PWID

Jackknifing in Non-Linear Regression

1 online resource (PDF, 18 pages

Draft Nuclear Genome Sequence of the Liquid Hydrocarbon-Accumulating Green Microalga Botryococcus braunii Race B (Showa).

Botryococcus braunii has long been known as a prodigious producer of liquid hydrocarbon oils that can be converted into combustion engine fuels. This draft genome for the B race of B. braunii will allow researchers to unravel important hydrocarbon biosynthetic pathways and identify possible regulatory networks controlling this unusual metabolism

Tunable Correlated Chern Insulator and Ferromagnetism in Trilayer Graphene/Boron Nitride Moir\'e Superlattice

Studies on two-dimensional electron systems in a strong magnetic field first revealed the quantum Hall (QH) effect, a topological state of matter featuring a finite Chern number (C) and chiral edge states. Haldane later theorized that Chern insulators with integer QH effects could appear in lattice models with complex hopping parameters even at zero magnetic field. The ABC-trilayer graphene/hexagonal boron nitride (TLG/hBN) moir\'e superlattice provides an attractive platform to explore Chern insulators because it features nearly flat moir\'e minibands with a valley-dependent electrically tunable Chern number. Here we report the experimental observation of a correlated Chern insulator in a TLG/hBN moir\'e superlattice. We show that reversing the direction of the applied vertical electric field switches TLG/hBN's moir\'e minibands between zero and finite Chern numbers, as revealed by dramatic changes in magneto-transport behavior. For topological hole minibands tuned to have a finite Chern number, we focus on 1/4 filling, corresponding to one hole per moir\'e unit cell. The Hall resistance is well quantized at h/2e2, i.e. C = 2, for |B| > 0.4 T. The correlated Chern insulator is ferromagnetic, exhibiting significant magnetic hysteresis and a large anomalous Hall signal at zero magnetic field. Our discovery of a C = 2 Chern insulator at zero magnetic field should open up exciting opportunities for discovering novel correlated topological states, possibly with novel topological excitations, in nearly flat and topologically nontrivial moir\'e minibands.Comment: 16 pages, 4 figures, and 2 extended figure

Retinotopic organization of human visual cortex mapped with positron-emission tomography

The retinotopic organization of primary visual cortex was mapped in normal human volunteers. Positron-emission tomographic measurements of regional cerebral blood flow were employed to detect focal functional brain activation. Oxygen-15-labeled water, delivered by intravenous bolus, was used as the blood flow tracer to allow multiple stimulated- state (n = 5) and control-state (n = 3) measurements to be acquired for each of 7 subjects. Responses were identified by applying a maximum- detection algorithm to subtraction-format images of the stimulus- induced change in cerebral blood flow. Response locales were described using a standardized system of stereotactic coordinates. Changes in stimulus location (macular, perimacular, peripheral, upper-field, lower- field) caused systematic, highly significant changes in response locale within visual cortex. Discrete extrastriate visual responses were also observed

On two problems in graph Ramsey theory

We study two classical problems in graph Ramsey theory, that of determining the Ramsey number of bounded-degree graphs and that of estimating the induced Ramsey number for a graph with a given number of vertices. The Ramsey number r(H) of a graph H is the least positive integer N such that every two-coloring of the edges of the complete graph $K_N$ contains a monochromatic copy of H. A famous result of Chv\'atal, R\"{o}dl, Szemer\'edi and Trotter states that there exists a constant c(\Delta) such that r(H) \leq c(\Delta) n for every graph H with n vertices and maximum degree \Delta. The important open question is to determine the constant c(\Delta). The best results, both due to Graham, R\"{o}dl and Ruci\'nski, state that there are constants c and c' such that 2^{c' \Delta} \leq c(\Delta) \leq 2^{c \Delta \log^2 \Delta}. We improve this upper bound, showing that there is a constant c for which c(\Delta) \leq 2^{c \Delta \log \Delta}. The induced Ramsey number r_{ind}(H) of a graph H is the least positive integer N for which there exists a graph G on N vertices such that every two-coloring of the edges of G contains an induced monochromatic copy of H. Erd\H{o}s conjectured the existence of a constant c such that, for any graph H on n vertices, r_{ind}(H) \leq 2^{c n}. We move a step closer to proving this conjecture, showing that r_{ind} (H) \leq 2^{c n \log n}. This improves upon an earlier result of Kohayakawa, Pr\"{o}mel and R\"{o}dl by a factor of \log n in the exponent.Comment: 18 page