Regulation of human mTOR complexes by DEPTOR

The vertebrate-specific DEP domain-containing mTOR interacting protein (DEPTOR), an oncoprotein or tumor suppressor, has important roles in metabolism, immunity, and cancer. It is the only protein that binds and regulates both complexes of mammalian target of rapamycin (mTOR), a central regulator of cell growth. Biochemical analysis and cryo-EM reconstructions of DEPTOR bound to human mTOR complex 1 (mTORC1) and mTORC2 reveal that both structured regions of DEPTOR, the PDZ domain and the DEP domain tandem (DEPt), are involved in mTOR interaction. The PDZ domain binds tightly with mildly activating effect, but then acts as an anchor for DEPt association that allosterically suppresses mTOR activation. The binding interfaces of the PDZ domain and DEPt also support further regulation by other signaling pathways. A separate, substrate-like mode of interaction for DEPTOR phosphorylation by mTOR complexes rationalizes inhibition of non-stimulated mTOR activity at higher DEPTOR concentrations. The multifaceted interplay between DEPTOR and mTOR provides a basis for understanding the divergent roles of DEPTOR in physiology and opens new routes for targeting the mTOR-DEPTOR interaction in disease

The OPERA experiment Target Tracker

The main task of the Target Tracker detector of the long baseline neutrino oscillation OPERA experiment is to locate in which of the target elementary constituents, the lead/emulsion bricks, the neutrino interactions have occurred and also to give calorimetric information about each event. The technology used consists in walls of two planes of plastic scintillator strips, one per transverse direction. Wavelength shifting fibres collect the light signal emitted by the scintillator strips and guide it to both ends where it is read by multi-anode photomultiplier tubes. All the elements used in the construction of this detector and its main characteristics are described.Comment: 25 pages, submitted to Nuclear Instrument and Method

Phylogenetic Distribution of Intron Positions in Alpha-Amylase Genes of Bilateria Suggests Numerous Gains and Losses

Most eukaryotes have at least some genes interrupted by introns. While it is well accepted that introns were already present at moderate density in the last eukaryote common ancestor, the conspicuous diversity of intron density among genomes suggests a complex evolutionary history, with marked differences between phyla. The question of the rates of intron gains and loss in the course of evolution and factors influencing them remains controversial. We have investigated a single gene family, alpha-amylase, in 55 species covering a variety of animal phyla. Comparison of intron positions across phyla suggests a complex history, with a likely ancestral intronless gene undergoing frequent intron loss and gain, leading to extant intron/exon structures that are highly variable, even among species from the same phylum. Because introns are known to play no regulatory role in this gene and there is no alternative splicing, the structural differences may be interpreted more easily: intron positions, sizes, losses or gains may be more likely related to factors linked to splicing mechanisms and requirements, and to recognition of introns and exons, or to more extrinsic factors, such as life cycle and population size. We have shown that intron losses outnumbered gains in recent periods, but that “resets” of intron positions occurred at the origin of several phyla, including vertebrates. Rates of gain and loss appear to be positively correlated. No phase preference was found. We also found evidence for parallel gains and for intron sliding. Presence of introns at given positions was correlated to a strong protosplice consensus sequence AG/G, which was much weaker in the absence of intron. In contrast, recent intron insertions were not associated with a specific sequence. In animal Amy genes, population size and generation time seem to have played only minor roles in shaping gene structures

Coordination in compounding

The chapter deals with the expression of coordination relations in compounding. Two macro-types of compounds are identified, namely hyperonymic coordinating compounds (co-compounds), where the referent of the compound is in a superordinate relationship to the meaning of the parts (as Mandarin dao-qiang \u2018sword+spear, weapons\u2019), and hyponymic coordinate compounds, where the referent is in a subordinate relationship to the meaning of the parts (as English actor-director). The chapter also argues that the distribution of these two macro-types is not random but, rather, areally skewed: whereas co-compounds are common in the Eastern part of Eurasia, New Guinea and Mesoamerica, they seem to be absent in Standard Average European languages, where hyponymic coordinating compounds are formed quite freely. Moreover, while co-compounds may belong to different word classes, hyponymic coordinating compounds are (probably) never verbs

mTOR substrate phosphorylation in growth control

The target of rapamycin (TOR), discovered 30 years ago, is a highly conserved serine/threonine protein kinase that plays a central role in regulating cell growth and metabolism. It is activated by nutrients, growth factors, and cellular energy. TOR forms two structurally and functionally distinct complexes, TORC1 and TORC2. TOR signaling activates cell growth, defined as an increase in biomass, by stimulating anabolic metabolism while inhibiting catabolic processes. With emphasis on mammalian TOR (mTOR), we comprehensively reviewed the literature and identified all reported direct substrates. In the context of recent structural information, we discuss how mTORC1 and mTORC2, despite having a common catalytic subunit, phosphorylate distinct substrates. We conclude that the two complexes recruit different substrates to phosphorylate a common, minimal motif

Safe and effective use of alitretinoin in children with recalcitrant hand eczema and other dermatoses - a retrospective analysis

BACKGROUND Alitretinoin is a systemic retinoid licensed for use in adult patients suffering from chronic hand eczema recalcitrant to potent topical steroids. Experience with its use in childhood is lacking. OBJECTIVES To report on the efficacy and safety of alitretinoin treatment in a cohort of children and adolescents with chronic hand eczema (CHE) and other inflammatory skin diseases. METHODS We performed a retrospective chart review of all consecutive patients under the age of 18 years treated with alitretinoin at our paediatric skin centre. Physician's Global Assessment (PGA) was used as the primary outcome measure. RESULTS Thirteen children (9 girls and 4 boys) were enrolled in this study. The median age at start of treatment with alitretinoin was 11.5 years (range 5.8-15.8 years). Nine children were diagnosed with CHE, two with severe atopic dermatitis (AD), and two with inherited ichthyosis [netherton syndrome (NS), autosomal recessive congenital ichthyosis (ARCI)]. Moderate to excellent response (PGA decrease of ≥1 point) was observed in 7 (78%) of the nine patients with CHE, one of the two patients with extensive AD and in the one patient with ARCI. In the remaining four subjects, no convincing effect was documented. Tolerability was overall very good. The most common adverse event was headache in 10 patients (77%) during the initiation of treatment, leading to interruption of therapy in one subject. CONCLUSIONS Alitretinoin seems to be highly effective and safe for the treatment of paediatric CHE and should thus be considered in children with refractory disease under topical therapy. Larger studies are required to corroborate these findings

A novel automatic film changer for high-speed analysis of nuclear emulsions

11 pages, 12 figures, to be published in NIM AThis paper describes the recent development of a novel automatic computer-controlled manipulator for emulsion film placement and removal at the microscope object table (also called stage). The manipulator is designed for mass scanning of emulsion films for the OPERA neutrino oscillation experiment and provides emulsion changing time shorter than 30 seconds with an emulsion film positioning accuracy as good as 20 microns RMS

Wireless sensor network anomalies: Diagnosis and detection strategies

Wireless Sensor Networks (WSNs) can experience problems (anomalies) during deployment, due to dynamic environmental factors or node hardware and software failures. These anomalies demand reliable detection strategies for supporting long term and/or large scale WSN deployments. Several strategies have been proposed for detecting specific subsets of WSN anomalies, yet there is still a need for more comprehensive anomaly detection strategies that jointly address network, node, and data level anomalies. This chapter examines WSN anomalies from an intelligent-based system perspective, covering anomalies that arise at the network, node and data levels. It generalizes a simple process for diagnosing anomalies in WSNs for detection, localization, and root cause determination. A survey of existing anomaly detection strategies also reveals their major design choices, including architecture and user support, and yields guidelines for tailoring new anomaly detection strategies to specific WSN application requirements. © Springer-Verlag Berlin Heidelberg 2011