Homeodomain Interacting Protein Kinase 2: A Target for Alzheimer's Beta Amyloid Leading to Misfolded p53 and Inappropriate Cell Survival

BACKGROUND: Homeodomain interacting protein kinase 2 (HIPK2) is an evolutionary conserved serine/threonine kinase whose activity is fundamental in maintaining wild-type p53 function, thereby controlling the destiny of cells when exposed to DNA damaging agents. We recently reported an altered conformational state of p53 in tissues from patients with Alzheimer's Disease (AD) that led to an impaired and dysfunctional response to stressors. METHODOLOGY/PRINCIPAL FINDINGS: Here we examined the molecular mechanisms underlying the impairment of p53 activity in two cellular models, HEK-293 cells overexpressing the amyloid precursor protein and fibroblasts from AD patients, starting from recent findings showing that p53 conformation may be regulated by HIPK2. We demonstrated that beta-amyloid 1-40 induces HIPK2 degradation and alters HIPK2 binding activity to DNA, in turn regulating the p53 conformational state and vulnerability to a noxious stimulus. Expression of HIPK2 was analysed by western blot experiments, whereas HIPK2 DNA binding was examined by chromatin immunoprecipitation analysis. In particular, we evaluated the recruitment of HIPK2 onto some target promoters, including hypoxia inducible factor-1alpha and metallothionein 2A. CONCLUSIONS/SIGNIFICANCE: These results support the existence of a novel amyloid-based pathogenetic mechanism in AD potentially leading to the survival of injured dysfunctional cells

Northern JHK Standard Stars for Array Detectors

We report J, H and K photometry of 86 stars in 40 fields in the northern hemisphere. The fields are smaller than or comparable to a 4x4 arcmin field-of-view, and are roughly uniformly distributed over the sky, making them suitable for a homogeneous broadband calibration network for near-infrared panoramic detectors. K magnitudes range from 8.5 to 14, and J-K colors from -0.1 to 1.2. The photometry is derived from a total of 3899 reduced images; each star has been measured, on average, 26.0 times per filter on 5.5 nights. Typical errors on the photometry are about 0.012.Comment: 10 pages including 3 figures, one separate figure on four pages. The finding chart of the AS-30 field and a few coordinates have been corrected. GIF finding charts can also be found at http://www.arcetri.astro.it/~hunt/std.htm

Morphology of the 12-micron Seyfert Galaxies: II. Optical and Near-Infrared Image Atlas

We present 263 optical and near-infrared (NIR) images for 42 Seyfert 1s and 48 Seyfert 2s, selected from the Extended 12-micron Galaxy Sample. Elliptically-averaged profiles are derived from the images, and isophotal radii and magnitudes are calculated from these. We also report virtual aperture photometry, that judging from comparison with previous work, is accurate to roughly 0.05mag in the optical, and 0.07mag in the NIR. Our B-band isophotal magnitude and radii, obtained from ellipse fitting, are in good agreement with those of RC3. When compared with the B band, V, I, J, and K isophotal diameters show that the colors in the outer regions of Seyferts are consistent with the colors of normal spirals. Differences in the integrated isophotal colors and comparison with a simple model show that the active nucleus+bulge is stronger and redder in the NIR than in the optical. Finally, roughly estimated Seyfert disk surface brightnesses are significantly brighter in B and K than those in normal spirals of similar morphological type.Comment: 17 pgs including figures; Table 2 is a separate file. Complete Figure 1 is available by contacting the authors. Accepted for publication in ApJ

Testing the performance of a blind burst statistic

In this work we estimate the performance of a method for the detection of burst events in the data produced by interferometric gravitational wave detectors. We compute the receiver operating characteristics in the specific case of a simulated noise having the spectral density expected for Virgo, using test signals taken from a library of possible waveforms emitted during the collapse of the core of Type II Supernovae.Comment: 8 pages, 6 figures, Talk given at the GWDAW2002 worksho

Inertial control of the mirror suspensions of the VIRGO interferometer for gravitational wave detection

In order to achieve full detection sensitivity at low frequencies, the mirrors of interferometric gravitational wave detectors must be isolated from seismic noise. The VIRGO vibration isolator, called 'superattenuator', is fully effective at frequencies above 4 Hz. Nevertheless, the residual motion of the mirror at the mechanical resonant frequencies of the system are too large for the interferometer locking system and must be damped. A multidimensional feedback system, using inertial sensors and digital processing, has been designed for this purpose. An experimental procedure for determining the feedback control of the system has been defined. In this paper a full description of the system is given and experimental results are presented.Comment: 17 pages, 11 figures, accepted for publication on Review of Scientific Instrument

Vagus nerve stimulation for depression: efficacy and safety in a European study

Background Vagus nerve stimulation (VNS) therapy is associated with a decrease in seizure frequency in partial-onset seizure patients. Initial trials suggest that it may be an effective treatment, with few side-effects, for intractable depression. Method An open, uncontrolled European multi-centre study (D03) of VNS therapy was conducted, in addition to stable pharmacotherapy, in 74 patients with treatment-resistant depression (TRD). Treatment remained unchanged for the first 3 months; in the subsequent 9 months, medications and VNS dosing parameters were altered as indicated clinically. Results The baseline 28-item Hamilton Depression Rating Scale (HAMD-28) score averaged 34. After 3 months of VNS, response rates (50% reduction in baseline scores) reached 37% and remission rates (HAMD-28 score <10) 17%. Response rates increased to 53% after 1 year of VNS, and remission rates reached 33%. Response was defined as sustained if no relapse occurred during the first year of VNS after response onset; 44% of patients met these criteria. Median time to response was 9 months. Most frequent side-effects were voice alteration (63% at 3 months of stimulation) and coughing (23%). Conclusions VNS therapy was effective in reducing severity of depression; efficacy increased over time. Efficacy ratings were in the same range as those previously reported from a USA study using a similar protocol; at 12 months, reduction of symptom severity was significantly higher in the European sample. This might be explained by a small but significant difference in the baseline HAMD-28 score and the lower number of treatments in the current episode in the European stud

Micrometeoroid Events in LISA Pathfinder

The zodiacal dust complex, a population of dust and small particles that pervades the Solar System, provides important insight into the formation and dynamics of planets, comets, asteroids, and other bodies. Here we present a new set of data obtained using a novel technique: direct measurements of momentum transfer to a spacecraft from individual particle impacts. This technique is made possible by the extreme precision of the instruments flown on the LISA Pathfinder spacecraft, a technology demonstrator for a future space-based gravitational wave observatory that operated near the first Sun-Earth Lagrange point from early 2016 through Summer of 2017. Using a simple model of the impacts and knowledge of the control system, we show that it is possible to detect impacts and measure properties such as the transferred momentum (related to the particle's mass and velocity), direction of travel, and location of impact on the spacecraft. In this paper, we present the results of a systematic search for impacts during 4348 hours of Pathfinder data. We report a total of 54 candidates with momenta ranging from 0.2$\,\mu\textrm{Ns}$ to 230$\,\mu\textrm{Ns}$. We furthermore make a comparison of these candidates with models of micrometeoroid populations in the inner solar system including those resulting from Jupiter-family comets, Oort-cloud comets, Hailey-type comets, and Asteroids. We find that our measured population is consistent with a population dominated by Jupiter-family comets with some evidence for a smaller contribution from Hailey-type comets. This is in agreement with consensus models of the zodiacal dust complex in the momentum range sampled by LISA Pathfinder.Comment: 22 pages, 14 figures, accepted in Ap

Sub-femto-g free fall for space-based gravitational wave observatories: LISA pathfinder results

We report the first results of the LISA Pathfinder in-flight experiment. The results demonstrate that two free-falling reference test masses, such as those needed for a space-based gravitational wave observatory like LISA, can be put in free fall with a relative acceleration noise with a square root of the power spectral density of 5.2 ± 0.1 fm s−2/√Hz or (0.54 ± 0.01) × 10−15 g/√Hz, with g the standard gravity, for frequencies between 0.7 and 20 mHz. This value is lower than the LISA Pathfinder requirement by more than a factor 5 and within a factor 1.25 of the requirement for the LISA mission, and is compatible with Brownian noise from viscous damping due to the residual gas surrounding the test masses. Above 60 mHz the acceleration noise is dominated by interferometer displacement readout noise at a level of (34.8 ± 0.3) fm/√Hz, about 2 orders of magnitude better than requirements. At f ≤ 0.5 mHz we observe a low-frequency tail that stays below 12 fm s−2/√Hz down to 0.1 mHz. This performance would allow for a space-based gravitational wave observatory with a sensitivity close to what was originally foreseen for LISA

LISA Pathfinder closed-loop analysis: a model breakdown of the in-loop observables

This paper describes a methodology to analyze, in the frequency domain, the steady-state control performances of the LISA Pathfinder mission. In particular, it provides a technical framework to give a comprehensive understanding of the spectra of all the degrees of freedom by breaking them down into their various physical origins, hence bringing out the major contributions of the control residuals. A reconstruction of the measured in-loop output, extracted from a model of the closed-loop system, is shown as an instance to illustrate the potential of such a model breakdown of the data