Genetic Inhibition of Phosphorylation of the Translation Initiation Factor eIF2alpha Does Not Block Abeta-Dependent Elevation of BACE1 and APP Levels or Reduce Amyloid Pathology in a Mouse Model of Alzheimer's Disease

beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) initiates the production of beta-amyloid (Abeta), the major constituent of amyloid plaques in Alzheimer's disease (AD). BACE1 is elevated approximately 2-3 fold in AD brain and is concentrated in dystrophic neurites near plaques, suggesting BACE1 elevation is Abeta-dependent. Previously, we showed that phosphorylation of the translation initiation factor eIF2alpha de-represses translation of BACE1 mRNA following stress such as energy deprivation. We hypothesized that stress induced by Abeta might increase BACE1 levels by the same translational mechanism involving eIF2alpha phosphorylation. To test this hypothesis, we used three different genetic strategies to determine the effects of reducing eIF2alpha phosphorylation on Abeta-dependent BACE1 elevation in vitro and in vivo: 1) a two-vector adeno-associated virus (AAV) system to express constitutively active GADD34, the regulatory subunit of PP1c eIF2alpha phosphatase; 2) a non-phosphorylatable eIF2alpha S51A knockin mutation; 3) a BACE1-YFP transgene lacking the BACE1 mRNA 5' untranslated region (UTR) required for eIF2alpha translational regulation. The first two strategies were used in primary neurons and 5XFAD transgenic mice, while the third strategy was employed only in 5XFAD mice. Despite very effective reduction of eIF2alpha phosphorylation in both primary neurons and 5XFAD brains, or elimination of eIF2alpha-mediated regulation of BACE1-YFP mRNA translation in 5XFAD brains, Abeta-dependent BACE1 elevation was not decreased. Additionally, robust inhibition of eIF2alpha phosphorylation did not block Abeta-dependent APP elevation in primary neurons, nor did it reduce amyloid pathology in 5XFAD mice. We conclude that amyloid-associated BACE1 elevation is not caused by translational de-repression via eIF2alpha phosphorylation, but instead appears to involve a post-translational mechanism. These definitive genetic results exclude a role for eIF2alpha phosphorylation in Abeta-dependent BACE1 and APP elevation. We suggest a vicious pathogenic cycle wherein Abeta42 toxicity induces peri-plaque BACE1 and APP accumulation in dystrophic neurites leading to exacerbated Abeta production and plaque progression

Proximity Effects and Nonequilibrium Superconductivity in Transition-Edge Sensors

We have recently shown that normal-metal/superconductor (N/S) bilayer TESs (superconducting Transition-Edge Sensors) exhibit weak-link behavior.1 Here we extend our understanding to include TESs with added noise-mitigating normal-metal structures (N structures). We find TESs with added Au structures also exhibit weak-link behavior as evidenced by exponential temperature dependence of the critical current and Josephson-like oscillations of the critical current with applied magnetic field. We explain our results in terms of an effect converse to the longitudinal proximity effect (LoPE)1, the lateral inverse proximity effect (LaiPE), for which the order parameter in the N/S bilayer is reduced due to the neighboring N structures. Resistance and critical current measurements are presented as a function of temperature and magnetic field taken on square Mo/Au bilayer TESs with lengths ranging from 8 to 130 {\mu}m with and without added N structures. We observe the inverse proximity effect on the bilayer over in-plane distances many tens of microns and find the transition shifts to lower temperatures scale approximately as the inverse square of the in- plane N-structure separation distance, without appreciable broadening of the transition width. We also present evidence for nonequilbrium superconductivity and estimate a quasiparticle lifetime of 1.8 \times 10-10 s for the bilayer. The LoPE model is also used to explain the increased conductivity at temperatures above the bilayer's steep resistive transition.Comment: 10 pages, 8 figure

A systematic review and meta-analysis of 271 PCDH19-variant individuals identifies psychiatric comorbidities, and association of seizure onset and disease severity

Epilepsy and Mental Retardation Limited to Females (EFMR) is an infantile onset disorder characterized by clusters of seizures. EFMR is due to mutations in the X-chromosome gene PCDH19, and is underpinned by cellular mosaicism due to X-chromosome inactivation in females or somatic mutation in males. This review characterizes the neuropsychiatric profile of this disorder and examines the association of clinical and molecular factors with neuropsychiatric outcomes. Data were extracted from 38 peer-reviewed original articles including 271 individual cases. We found that seizure onset ≤12 months was significantly associated (p = 4.127 × 10⁻⁷) with more severe intellectual disability, compared with onset >12 months. We identified two recurrent variants p.Asn340Ser and p.Tyr366Leufs*10 occurring in 25 (20 unrelated) and 30 (11 unrelated) cases, respectively. PCDH19 mutations were associated with psychiatric comorbidities in approximately 60% of females, 80% of affected mosaic males, and reported in nine hemizygous males. Hyperactive, autistic, and obsessive-compulsive features were most frequently reported. There were no genotype-phenotype associations in the individuals with recurrent variants or the group overall. Age at seizure onset can be used to provide more informative prognostic counseling.Kristy L Kolc, Lynette G Sadleir, Ingrid E Scheffer, Atma Ivancevic, Rachel Roberts, Duyen H Pham, Jozef Gec

Superconducting Effects in Optimization of Magnetic Penetration Thermometers for X-ray Microcalorimeters

Like MMCs, MPTs enable high energy microcalorimeters with zero bias power dissipation and potential resolution < 1 eV. MPTs can provide d(phi)/dT as large as 1000 (Phi)(sub 0)/K, with no excess noise, thereby reducing the importance of SQUID noise. Long coherence length in a Type-I superconducting MoAu film offers multiple advantages for efficient flux expulsion in MPT. Region of steepest d(phi)/dT is the Meissner effect in the small device; flux is expelled/penetrates to minimize free energy. Steepness of transition can be engineered with choice of film thickness and coil pitch relative to lambda(sub eff)(0), ratio of T/T(sub c), and bias circuit inductance

Thermal Fluctuation Noise in Mo/Au Superconducting Transition-Edge Sensor Microcalorimeters

In many superconducting transition-edge sensor (TES) microcalorimeters, the measured electrical noise exceeds theoretical estimates based on a thermal model of a single body thermally connected to a heat bath. Here, we report on noise and complex impedance measurements of a range of designs of TESs made with a Mo/Au bilayer. We have fitted the measured data using a two-body model, where the x-ray absorber and the TES are connected by an internal thermal conductance Gae. We find that the so-called excess noise measured in these devices is consistent with the noise generated from the internal thermal fluctuations between the x-ray absorber and the TES. Our fitted parameters are consistent with the origin of Gae being from the finite thermal conductance of the TES itself. These results suggest that even in these relatively low resistance Mo/Au TESs, the internal thermal conductance of the TES may add significant additional noise and could account for all the measured excess noise. Furthermore, we find that around regions of the superconducting transition with rapidly changing derivative of resistance with respect to temperature, an additional noise mechanism may dominate. These observations may lead to a greater understanding of TES devices and allow the design of TES microcalorimeters with improved performance

Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy

Peer reviewe

Development of Kilo-Pixel Arrays of Transition-Edge Sensors for X-Ray Spectroscopy

We are developing kilo-pixel arrays of transition-edge sensor (TES) microcalorimeters for future X-ray astronomy observatories or for use in laboratory astrophysics applications. For example, Athena/XMS (currently under study by the european space agency) would require a close-packed 32x32 pixel array on a 250-micron pitch with < 3.0 eV full-width-half-maximum energy resolution at 6 keV and at count-rates of up to 50 counts/pixel/second. We present characterization of 32x32 arrays. These detectors will be readout using state of the art SQUID based time-domain multiplexing (TDM). We will also present the latest results in integrating these detectors and the TDM readout technology into a 16 row x N column field-able instrument

Science Objectives for an X-Ray Microcalorimeter Observing the Sun

We present the science case for a broadband X-ray imager with high-resolution spectroscopy, including simulations of X-ray spectral diagnostics of both active regions and solar flares. This is part of a trilogy of white papers discussing science, instrument (Bandler et al. 2010), and missions (Bookbinder et al. 2010) to exploit major advances recently made in transition-edge sensor (TES) detector technology that enable resolution better than 2 eV in an array that can handle high count rates. Combined with a modest X-ray mirror, this instrument would combine arcsecondscale imaging with high-resolution spectra over a field of view sufficiently large for the study of active regions and flares, enabling a wide range of studies such as the detection of microheating in active regions, ion-resolved velocity flows, and the presence of non-thermal electrons in hot plasmas. It would also enable more direct comparisons between solar and stellar soft X-ray spectra, a waveband in which (unusually) we currently have much better stellar data than we do of the Sun