Bioinformatics Approaches for Predicting Kinase–Substrate Relationships

Protein phosphorylation, catalyzed by protein kinases, is the main posttranslational modification in eukaryotes, regulating essential aspects of cellular function. Using mass spectrometry techniques, a profound knowledge has been achieved in the localization of phosphorylated residues at proteomic scale. Although it is still largely unknown, the protein kinases are responsible for such modifications. To fill this gap, many computational algorithms have been developed, which are capable to predict kinase–substrate relationships. The greatest difficulty for these approaches is to model the complex nature that determines kinase–substrate specificity. The vast majority of predictors is based on the linear primary sequence pattern that surrounds phosphorylation sites. However, in the intracellular environment the protein kinase specificity is influenced by contextual factors, such as protein–protein interactions, substrates co-expression patterns, and subcellular localization. Only recently, the development of phosphorylation predictors has begun to incorporate these variables, significantly improving specificity of these methods. An accurate modeling of kinase–substrate relationships could be the greatest contribution of bioinformatics to understand physiological cell signaling and its pathological impairment

The Amyloid Precursor Protein Intracellular Domain-Fe65 Multiprotein Complexes: A Challenge to the Amyloid Hypothesis for Alzheimer's Disease?

Since its proposal in 1994, the amyloid cascade hypothesis has prevailed as the mainstream research subject on the molecular mechanisms leading to the Alzheimer's disease (AD). Most of the field had been historically based on the role of the different forms of aggregation of β-amyloid peptide (Aβ). However, a soluble intracellular fragment termed amyloid precursor protein (APP) intracellular domain (AICD) is produced in conjunction with Aβ fragments. This peptide had been shown to be highly toxic in both culture neurons and transgenic mice models. With the advent of this new toxic fragment, the centerpiece for the ethiology of the disease may be changed. This paper discusses the potential role of multiprotein complexes between the AICD and its adapter protein Fe65 and how this could be a potentially important new agent in the neurodegeneration observed in the AD

A geometrical calibration method for the PIXSCAN micro-CT scanner

Reconstruction in Cone-Beam Tomography can suffer from artifacts due to geometrical misalignments of the source-detector system. They can be avoided by a complete and precise description of the system. We present a high precision method for the geometric calibration for the PIXSCAN, a small animal X-ray CT scanner demonstrator based on hybrid pixel detectors (XPAD2). The specificities of the XPAD2 detectors (dead pixels, tilts and gaps between modules...) made the calibration of the PIXSCAN quite difficult. The method uses a calibration object consisting of a hollow cylinder of polycarbonate on which we positioned four metallic balls. It requires 360 X-ray images (1° increments). An analytic expression of the 3 image ellipses has been derived. It is used for a least square regression of the 13 alignment parameters after a correction of the internal XPAD2 geometry. Our method is fast and completely automated, achieving a precision of about 30 μm

Mitochondria and Calcium Regulation as Basis of Neurodegeneration Associated With Aging

Age is the main risk factor for the onset of neurodegenerative diseases. A decline of mitochondrial function has been observed in several age-dependent neurodegenerative diseases and may be a major contributing factor in their progression. Recent findings have shown that mitochondrial fitness is tightly regulated by Ca2+ signals, which are altered long before the onset of measurable histopathology hallmarks or cognitive deficits in several neurodegenerative diseases including Alzheimer’s disease (AD), the most frequent cause of dementia. The transfer of Ca2+ from the endoplasmic reticulum (ER) to the mitochondria, facilitated by the presence of mitochondria-associated membranes (MAMs), is essential for several physiological mitochondrial functions such as respiration. Ca2+ transfer to mitochondria must be finely regulated because excess Ca2+ will disturb oxidative phosphorylation (OXPHOS), thereby increasing the generation of reactive oxygen species (ROS) that leads to cellular damage observed in both aging and neurodegenerative diseases. In addition, excess Ca2+ and ROS trigger the opening of the mitochondrial transition pore mPTP, leading to loss of mitochondrial function and cell death. mPTP opening probably increases with age and its activity has been associated with several neurodegenerative diseases. As Ca2+ seems to be the initiator of the mitochondrial failure that contributes to the synaptic deficit observed during aging and neurodegeneration, in this review, we aim to look at current evidence for mitochondrial dysfunction caused by Ca2+ miscommunication in neuronal models of neurodegenerative disorders related to aging, with special emphasis on AD

Recent advances in the application of stable isotope ratio analysis in forensic chemistry

This review paper updates the previous literature in relation to the continued and developing use of stable isotope ratio analysis in samples which are relevant to forensic science. Recent advances in the analysis of drug samples, explosive materials, and samples derived from human and animal samples are discussed. The paper also aims to put the use of isotope ratio mass spectrometry into a forensic context and discuss its evidential potential

Distinct secondary ice production processes observed in radar Doppler spectra: insights from a case study

Secondary ice production (SIP) has an essential role in cloud and precipitation microphysics. In recent years, substantial insights were gained into SIP by combining experimental, modeling, and observational approaches. Remote sensing instruments, among them meteorological radars, offer the possibility of studying clouds and precipitation in extended areas over long time periods and are highly valuable to understand the spatiotemporal structure of microphysical processes. Multi-modal Doppler spectra measured by vertically pointing radars reveal the coexistence, within a radar resolution volume, of hydrometeor populations with distinct properties; as such, they can provide decisive insight into precipitation microphysics. This paper leverages polarimetric radar Doppler spectra as a tool to study the microphysical processes that took place during a snowfall event on 27 January 2021 in the Swiss Jura Mountains during the ICE GENESIS campaign. A multi-layered cloud system was present, with ice particles sedimenting through a supercooled liquid water (SLW) layer in a seeder–feeder configuration. Building on a Doppler peak detection algorithm, we implement a peak labeling procedure to identify the particle type(s) that may be present within a radar resolution volume. With this approach, we can visualize spatiotemporal features in the radar time series that point to the occurrence of distinct mechanisms during different stages of the event. By focusing on three 30 min phases of the case study and by using the detailed information contained in the Doppler spectra, together with dual-frequency radar measurements, aircraft in situ images, and simulated profiles of atmospheric variables, we narrow down the possible processes that could be responsible for the observed signatures. Depending on the availability of SLW and the droplet sizes, on the temperature range, and on the interaction between the liquid and ice particles, various SIP processes are identified as plausible, with distinct fingerprints in the radar Doppler spectra. A simple modeling approach suggests that the ice crystal number concentrations likely exceed typical concentrations of ice-nucleating particles by 1 to 4 orders of magnitude. While a robust proof of occurrence of a given SIP mechanism cannot be easily established, the multi-sensor data provide various independent elements each supporting the proposed interpretations.</p

Background Light in Potential Sites for the ANTARES Undersea Neutrino Telescope

The ANTARES collaboration has performed a series of {\em in situ} measurements to study the background light for a planned undersea neutrino telescope. Such background can be caused by $^{40}$K decays or by biological activity. We report on measurements at two sites in the Mediterranean Sea at depths of 2400~m and 2700~m, respectively. Three photomultiplier tubes were used to measure single counting rates and coincidence rates for pairs of tubes at various distances. The background rate is seen to consist of three components: a constant rate due to $^{40}$K decays, a continuum rate that varies on a time scale of several hours simultaneously over distances up to at least 40~m, and random bursts a few seconds long that are only correlated in time over distances of the order of a meter. A trigger requiring coincidences between nearby photomultiplier tubes should reduce the trigger rate for a neutrino telescope to a manageable level with only a small loss in efficiency.Comment: 18 pages, 8 figures, accepted for publication in Astroparticle Physic

MAP1B Regulates Axonal Development by Modulating Rho-GTPase Rac1 Activity

This article shows a novel function for the MAP1B protein, related to the control of actin dynamics through interaction with Tiam1

The ANTARES Optical Beacon System

ANTARES is a neutrino telescope being deployed in the Mediterranean Sea. It consists of a three dimensional array of photomultiplier tubes that can detect the Cherenkov light induced by charged particles produced in the interactions of neutrinos with the surrounding medium. High angular resolution can be achieved, in particular when a muon is produced, provided that the Cherenkov photons are detected with sufficient timing precision. Considerations of the intrinsic time uncertainties stemming from the transit time spread in the photomultiplier tubes and the mechanism of transmission of light in sea water lead to the conclusion that a relative time accuracy of the order of 0.5 ns is desirable. Accordingly, different time calibration systems have been developed for the ANTARES telescope. In this article, a system based on Optical Beacons, a set of external and well-controlled pulsed light sources located throughout the detector, is described. This calibration system takes into account the optical properties of sea water, which is used as the detection volume of the ANTARES telescope. The design, tests, construction and first results of the two types of beacons, LED and laser-based, are presented.Comment: 21 pages, 18 figures, submitted to Nucl. Instr. and Meth. Phys. Res.