Cultured cell and transgenic mouse models for tau pathology linked to β-amyloid

AbstractThe two histopathological signatures of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles, prompting speculation that a causal relationship exists between the respective building blocks of these abnormal brain structures: the β-amyloid peptides (Aβ) and the neuron-enriched microtubule-associated protein called tau. Transgenic mouse models have provided in vivo evidence for such connections, and cultured cell models have allowed tightly controlled, systematic manipulation of conditions that influence links between Aβ and tau. The emerging evidence supports the view that amyloid pathology lies upstream of tau pathology in a pathway whose details remain largely mysterious. In this communication, we review and discuss published work about the Aβ–tau connection. In addition, we present some of our own previously unpublished data on the effects of exogenous Aβ on primary brain cultures that contain both neurons and glial cells. We report here that continuous exposure to 5 μM non-fibrillar Aβ40 or Aβ42 kills primary brain cells by apoptosis within 2–3 weeks, Aβ42 is more toxic and selective for neurons than Aβ40, and Aβ42, but not Aβ40, induces a transient increase in neurons that are positive for the AD-like PHF1 epitope. These findings demonstrate the greater potency of Aβ42 than Aβ40 at inducing tau pathology and programmed cell death, and corroborate and extend reports that tau-containing cells are more sensitive to Aβ peptides than cells that lack or express low levels of tau

Exploring the Optical Transient Sky with the Palomar Transient Factory

The Palomar Transient Factory (PTF) is a wide-field experiment designed to investigate the optical transient and variable sky on time scales from minutes to years. PTF uses the CFH12k mosaic camera, with a field of view of 7.9 deg^2 and a plate scale of 1 asec/pixel, mounted on the the Palomar Observatory 48-inch Samuel Oschin Telescope. The PTF operation strategy is devised to probe the existing gaps in the transient phase space and to search for theoretically predicted, but not yet detected, phenomena, such as fallback supernovae, macronovae, .Ia supernovae and the orphan afterglows of gamma-ray bursts. PTF will also discover many new members of known source classes, from cataclysmic variables in their various avatars to supernovae and active galactic nuclei, and will provide important insights into understanding galactic dynamics (through RR Lyrae stars) and the Solar system (asteroids and near-Earth objects). The lessons that can be learned from PTF will be essential for the preparation of future large synoptic sky surveys like the Large Synoptic Survey Telescope. In this paper we present the scientific motivation for PTF and describe in detail the goals and expectations for this experiment.Comment: 15 pages, 6 figures, submitted to PAS

Tau-dependent microtubule disassembly initiated by prefibrillar β-amyloid

Alzheimer's Disease (AD) is defined histopathologically by extracellular β-amyloid (Aβ) fibrils plus intraneuronal tau filaments. Studies of transgenic mice and cultured cells indicate that AD is caused by a pathological cascade in which Aβ lies upstream of tau, but the steps that connect Aβ to tau have remained undefined. We demonstrate that tau confers acute hypersensitivity of microtubules to prefibrillar, extracellular Aβ in nonneuronal cells that express transfected tau and in cultured neurons that express endogenous tau. Prefibrillar Aβ42 was active at submicromolar concentrations, several-fold below those required for equivalent effects of prefibrillar Aβ40, and microtubules were insensitive to fibrillar Aβ. The active region of tau was localized to an N-terminal domain that does not bind microtubules and is not part of the region of tau that assembles into filaments. These results suggest that a seminal cell biological event in AD pathogenesis is acute, tau-dependent loss of microtubule integrity caused by exposure of neurons to readily diffusible Aβ

High-Redshift Starbursting Dwarf Galaxies Revealed by GRB Afterglows

We present a study of 15 long-duration gamma-ray burst (GRB) host galaxies at z>2. The GRBs are selected with available early-time afterglow spectra in order to compare interstellar medium (ISM) absorption-line properties with stellar properties of the host galaxies. In addition to five previously studied hosts, we consider new detections for the host galaxies of GRB050820 and GRB060206 and place 2-sigma upper limits to the luminosities of the remaining unidentified hosts. We examine the nature of the host galaxy population and find that (1) the UV luminosity distribution of GRB host galaxies is consistent with expectations from a UV luminosity weighted random galaxy population with a median luminosity of =0.1 L*; (2) there exists a moderate correlation between UV luminosity and SiII 1526 absorption width, which together with the observed large line widths of W(1526)>1.5 Ang for a large fraction of the objects suggests a galactic outflow driven velocity field in the host galaxies; (3) there is tentative evidence for a trend of declining ISM metallicity with decreasing galaxy luminosity in the star-forming galaxy population at z=2-4; (4) the interstellar UV radiation field is found ~ 35-350 times higher in GRB hosts than the Galactic mean value; and (5) additional galaxies are found at < 2" from the GRB host in all fields with known presence of strong MgII absorbers, but no additional faint galaxies are found at < 2" in fields without strong MgII absorbers. Our study confirms that the GRB host galaxies (with known optical afterglows) are representative of unobscured star-forming galaxies at z>2, and demonstrates that high spatial resolution images are necessary for an accurate identification of GRB host galaxies in the presence of strong intervening absorbers.Comment: 24 emulateapj pages, 24 figures, ApJ in press; full-resolution version available at http://lambda.uchicago.edu/public/tmp/ghost.pd

PTF10fqs: A Luminous Red Nova in the Spiral Galaxy Messier 99

The Palomar Transient Factory (PTF) is systematically charting the optical transient and variable sky. A primary science driver of PTF is building a complete inventory of transients in the local Universe (distance less than 200 Mpc). Here, we report the discovery of PTF10fqs, a transient in the luminosity "gap" between novae and supernovae. Located on a spiral arm of Messier 99, PTF 10fqs has a peak luminosity of Mr = -12.3, red color (g-r = 1.0) and is slowly evolving (decayed by 1 mag in 68 days). It has a spectrum dominated by intermediate-width H (930 km/s) and narrow calcium emission lines. The explosion signature (the light curve and spectra) is overall similar to thatof M85OT2006-1, SN2008S, and NGC300OT. The origin of these events is shrouded in mystery and controversy (and in some cases, in dust). PTF10fqs shows some evidence of a broad feature (around 8600A) that may suggest very large velocities (10,000 km/s) in this explosion. Ongoing surveys can be expected to find a few such events per year. Sensitive spectroscopy, infrared monitoring and statistics (e.g. disk versus bulge) will eventually make it possible for astronomers to unravel the nature of these mysterious explosions.Comment: 12 pages, 12 figures, Replaced with published versio

Equidistribution of zeros of holomorphic sections in the non compact setting

We consider N-tensor powers of a positive Hermitian line bundle L over a non-compact complex manifold X. In the compact case, B. Shiffman and S. Zelditch proved that the zeros of random sections become asymptotically uniformly distributed with respect to the natural measure coming from the curvature of L, as N tends to infinity. Under certain boundedness assumptions on the curvature of the canonical line bundle of X and on the Chern form of L we prove a non-compact version of this result. We give various applications, including the limiting distribution of zeros of cusp forms with respect to the principal congruence subgroups of SL2(Z) and to the hyperbolic measure, the higher dimensional case of arithmetic quotients and the case of orthogonal polynomials with weights at infinity. We also give estimates for the speed of convergence of the currents of integration on the zero-divisors.Comment: 25 pages; v.2 is a final update to agree with the published pape

Physician Perspectives on Telemedicine in Radiation Oncology

PURPOSE: Telemedicine enthusiasm and uptake in radiation oncology rapidly increased during the COVID-19 pandemic, but it is unclear if and how telemedicine should be used after the COVID-19 public health emergency ends is unclear. Herein, we report on our institution\u27s provider experience after the mature adoption of telemedicine. METHODS AND MATERIALS: We distributed a survey to all radiation oncology attending physicians at our institution in October 2021 to assess satisfaction, facilitators, and barriers to telemedicine implementation. We performed quantitative and qualitative analyses to characterize satisfaction and identify influencing factors whether telemedicine is employed. We calculated the average proportion of visits that providers expected to be appropriately performed with telemedicine for each disease site and visit type. RESULTS: A total of 60 of the 82 eligible radiation oncologists (73%) responded to the survey, of whom 78% were satisfied with telemedicine in the radiation oncology department and 83% wished to continue offering video visits after the COVID-19 public health emergency ends. Common patient factors influencing whether physicians offer telemedicine include the patient\u27s travel burden, patient preferences, and whether a physical examination is required. Approximately 20% of new consultations and 50% of weekly management visits were estimated to be appropriate for telemedicine. The central nervous system/pediatrics and thoracic faculty considered telemedicine appropriate for the greatest proportion of new consultations, and 93% of respondents felt comfortable determining whether telemedicine was appropriate. CONCLUSIONS: Surveyed radiation oncologists were satisfied with telemedicine in their practice, and wished to continue offering video visits in the future. Our data suggest that payers should continue to support this patient-centered technology

Enhancing cycling durability of Li-ion batteries with hierarchical structured silicon–graphene hybrid anodes

Hybrid anode materials consisting of micro-sized silicon (Si) particles interconnected with few-layer graphene (FLG) nanoplatelets and sodium-neutralized poly(acrylic acid) as a binder were evaluated for Li-ion batteries. The hybrid film has demonstrated a reversible discharge capacity of ∼1800 mA h g−1 with a capacity retention of 97% after 200 cycles. The superior electrochemical properties of the hybrid anodes are attributed to a durable, hierarchical conductive network formed between Si particles and the multi-scale carbon additives, with enhanced cohesion by the functional polymer binder. Furthermore, improved solid electrolyte interphase (SEI) stability is achieved from the electrolyte additives, due to the formation of a kinetically stable film on the surface of the Si

A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease