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 In addition, we present some of our own previously unpublished data on the effects of exogenous Aβ on primary brain cultures that contain both neurons and glial cells.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

Activation of Extracellular-signal Regulated Kinase (ERK1/2) by Fluid Shear is Ca\u3csup\u3e2+\u3c/sup\u3e- and ATP-dependent in MC3T3-E1 Osteoblasts

To determine the role of Ca2+ signaling in activation of the Mitogen-Activated Protein Kinase (MAPK) pathway, we subjected MC3T3-E1 pre-osteoblastic cells to inhibitors of Ca2+ signaling during application of fluid shear stress (FSS). FSS only activated ERK1/2, rapidly inducing phosphorylation within 5 min of the onset of shear. Phosphorylation of ERK1/2 (pERK1/2) was significantly reduced when Cai2+ was chelated with BAPTA or when Ca2+ was removed from the flow media. Inhibition of both the L-type voltage-sensitive Ca2+ channel and the mechanosensitive cation-selective channel blocked FSS-induced pERK1/2. Inhibition of phospholipase C with U73122 significantly reduced pERK1/2. This inhibition did not result from blockage of intracellular Ca2+ release, but a loss of PKC activation. Recent data suggests a role of ATP release and purinergic receptor activation in mechanotransduction. Apyrase-mediated hydrolysis of extracellular ATP completely blocked FSS-induced phosphorylation of ERK1/2, while the addition of exogenous ATP to static cells mimicked the effects of FSS on pERK1/2. Two P2 receptors, P2Y2 and P2X7, have been associated with the anabolic responses of bone to mechanical loading. Using both iRNA techniques and primary osteoblasts isolated from P2X7 knockout mice, we found that the P2X7, but not the P2Y2, purinergic receptor was involved in ERK1/2 activation under FSS. These data suggest that FSS-induced ERK1/2 phosphorylation requires Ca2+-dependent ATP release, however both increased Cai2+ and PKC activation are needed for complete activation. Further, this ATP-dependent ERK1/2 phosphorylation is mediated through P2X7, but not P2Y2, purinergic receptors

Measurement of environmental gamma exposure by thermoluminescence dosimetry

Energy dependence, angular dependence, and linearity of response to exposure levels were studied for the thermoluminescent dosimeter used in an environmental monitoring network. The dosimeter consisted of a manganese activated calcium fluoride phosphor (Ca F₂: Mn) bonded to a helical heating element and encapsulated in a gas filled glass tube. Energy dependence was studied using a K-alpha, K-beta x-ray fluorescence system which produced energies from 6.47 keV to 100.96 keV. The response to ¹³⁷ Cs and ⁶⁰ Co gamma was also tested. The curve generated by the data may be useful to correct dosimeter readings when the energy of the radiation is known. Angular dependence at 662 keV produced a 20 percent drop in response for radiation parallel to the dosimeter axis compared to the most sensitive incident angle of 90° . For exposures between 10 mR and 1 R the response of the dosimeter was linear within ± 5 percent, however for exposures greater than 1 R, there was an over-response which increased with exposure. When the reader was adjusted to read correctly at 100 mR, the response to 3000 R, the highest exposure given, was 32 percent high. For the conditions usually encountered in environmental monitoring, the dosimeter can be used with no more than a simple calibration correction. If, on the other hand, low energy radiation, very directional beams, or high exposures are encountered, further corrections may be necessary

The Mesozoic palaeorelief of the northern Tian Shan (China)

International audienceThe Tian Shan range offers a natural laboratory to study orogenic processes. Most of the previous studies focused on either the Palaeozoic evolution of the range or its Cenozoic intracontinental evolution linked with the India-Asia collision. In this study, it is shown that detailed field investigations on the relationship between sedimentary cover and basement constrain the Mesozoic evolution of the northern Tian Shan. Sedimentological observations argue for a limited transport distance for Lower and Uppermost Jurassic deposits. Geological sections presented in this paper show that, in preserved locations, Triassic to Jurassic sedimentary series present a continuous onlap type sedimentary unconformity on the top of the basement. At different scales, observations clearly evidence the existence of major palaeorelief during the Mesozoic. According to the present study, the topography of the current Tian Shan range and the associated movements along its northern front structures cannot be considered as the consequence of Cenozoic reactivation alone

Three-color femtosecond source for simultaneous excitation of three fluorescent proteins in two-photon fluorescence microscopy

We demonstrate a fiber-based, three-color femtosecond source for simultaneous imaging of three fluorescent proteins (FPs) using two-photon fluorescence microscopy (2PM). The three excitation wavelengths at 775 nm, 864 nm and 950 nm, are obtained through second harmonic generation (SHG) of the 1550-nm pump laser and the 1728-nm and 1900-nm solitons generated through soliton self-frequency shift (SSFS) in a large-mode-area (LMA) fiber. These energetic pulses are well matched to the two-photon excitation peaks of red, cyan and yellow fluorescent proteins (TagRFPs, TagCFPs, and TagYFPs) for efficient excitation. We demonstrate simultaneous 2PM of human melanoma cells expressing a “rainbow” combination of these three fluorescent proteins

The Wide Integral Field Infrared Spectrograph: Commissioning Results and On-sky Performance

We have recently commissioned a novel infrared ($0.9-1.7$ $\mu$m) integral field spectrograph (IFS) called the Wide Integral Field Infrared Spectrograph (WIFIS). WIFIS is a unique instrument that offers a very large field-of-view (50$^{\prime\prime}$ x 20$^{\prime\prime}$) on the 2.3-meter Bok telescope at Kitt Peak, USA for seeing-limited observations at moderate spectral resolving power. The measured spatial sampling scale is $\sim1\times1^{\prime\prime}$ and its spectral resolving power is $R\sim2,500$ and $3,000$ in the $zJ$ ($0.9-1.35$ $\mu$m) and $H_{short}$ ($1.5-1.7$ $\mu$m) modes, respectively. WIFIS's corresponding etendue is larger than existing near-infrared (NIR) IFSes, which are mostly designed to work with adaptive optics systems and therefore have very narrow fields. For this reason, this instrument is specifically suited for studying very extended objects in the near-infrared such as supernovae remnants, galactic star forming regions, and nearby galaxies, which are not easily accessible by other NIR IFSes. This enables scientific programs that were not originally possible, such as detailed surveys of a large number of nearby galaxies or a full accounting of nucleosynthetic yields of Milky Way supernova remnants. WIFIS is also designed to be easily adaptable to be used with larger telescopes. In this paper, we report on the overall performance characteristics of the instrument, which were measured during our commissioning runs in the second half of 2017. We present measurements of spectral resolving power, image quality, instrumental background, and overall efficiency and sensitivity of WIFIS and compare them with our design expectations. Finally, we present a few example observations that demonstrate WIFIS's full capability to carry out infrared imaging spectroscopy of extended objects, which is enabled by our custom data reduction pipeline.Comment: Published in the Proceedings of SPIE Astronomical Telescopes and Instrumentation 2018. 17 pages, 13 figure

Sputtered NiO_x Films for Stabilization of p^+n-lnP Photoanodes for Solar-Driven Water Oxidation

A photoanode protection strategy using a multifunctional NiO_x coating is presented. The ransparency/antireflectivity, low electrochromism, conduction of holes, corrosion protection, and active electrocatalysis for water-oxidation half-reaction are described