Evolution of the arginase fold and functional diversity

Novel structural superfamilies can be identified among the large number of protein structures deposited in the Protein Data Bank based on conservation of fold in addition to conservation of amino acid sequence. Since sequence diverges more rapidly than fold in protein Evolution, proteins with little or no significant sequence identity are occasionally observed to adopt similar folds, thereby reflecting unanticipated evolutionary relationships. Here, we review the unique alpha/beta fold first observed in the manganese metalloenzyme rat liver arginase, consisting of a parallel eight-stranded beta-sheet surrounded by several helices, and its evolutionary relationship with the zinc-requiring and/or iron-requiring histone deacetylases and acetylpolyamine amidohydrolases. Structural comparisons reveal key features of the core alpha/beta fold that contribute to the divergent metal ion specificity and stoichiometry required for the chemical and biological functions of these enzymes.     

Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome

Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.     

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10?12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10?11) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10??) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10?11) and a tag SNP for NAT2 acetylation status (P = 4 × 10?11), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.     

The insulin-degrading enzyme is an allosteric modulator of the 20S proteasome and a potential competitor of the 19S

The interaction of insulin-degrading enzyme (IDE) with the main intracellular proteasome assemblies (i.e, 30S, 26S and 20S) was analyzed by enzymatic activity, mass spectrometry and native gel electrophoresis. IDE was mainly detected in association with assemblies with at least one free 20S end and biochemical investigations suggest that IDE competes with the 19S in vitro. IDE directly binds the 20S and affects its proteolytic activities in a bimodal fashion, very similar in human and yeast 20S, inhibiting at (IDE)?≤?30 nM and activating at (IDE)?≥?30 nM. Only an activating effect is observed in a yeast mutant locked in the “open” conformation (i.e., the α-3ΔN 20S), envisaging a possible role of IDE as modulator of the 20S “open”–”closed” allosteric equilibrium. Protein–protein docking in silico proposes that the interaction between IDE and the 20S could involve the C-term helix of the 20S α-3 subunit which regulates the gate opening of the 20S.     

Mechanisms of protein homeostasis (proteostasis) maintain stem cell identity in mammalian pluripotent stem cells

Protein homeostasis, or proteostasis, is essential for cell function, development, and organismal viability. The composition of the proteome is adjusted to the specific requirements of a particular cell type and status. Moreover, multiple metabolic and environmental conditions challenge the integrity of the proteome. To maintain the quality of the proteome, the proteostasis network monitors proteins from their synthesis through their degradation. Whereas somatic stem cells lose their ability to maintain proteostasis with age, immortal pluripotent stem cells exhibit a stringent proteostasis network associated with their biological function and intrinsic characteristics. Moreover, growing evidence indicates that enhanced proteostasis mechanisms play a central role in immortality and cell fate decisions of pluripotent stem cells. Here, we will review new insights into the melding fields of proteostasis and pluripotency and their implications for the understanding of organismal development and survival.     

Three classical Cepheid variable stars in the nuclear bulge of the Milky Way

The nuclear bulge is a region with a radius of about 200 parsecs around the centre of the Milky Way. It contains stars with ages ranging from a few million years to over a billion years, yet its star-formation history and the triggering process for star formation remain to be resolved. Recently, episodic star formation, powered by changes in the gas content, has been suggested. Classical Cepheid variable stars have pulsation periods that decrease with increasing age, so it is possible to probe the star-formation history on the basis of the distribution of their periods. Here we report the presence of three classical Cepheids in the nuclear bulge with pulsation periods of approximately 20?days, within 40 parsecs (projected distance) of the central black hole. No Cepheids with longer or shorter periods were found. We infer that there was a period about 25 million years ago, and possibly lasting until recently, in which star formation increased relative to the period of 30-70 million years ago.     

Symmetries and Symmetry-Breakings: The Fabric of Physical Interactions and the Flow of Time

This short note develops some ideas along the lines of the stimulating paper by Heylighen (Found Sci 15 4(3):345–356, 2010a). It summarizes a theme in several writings with Francis Bailly, downloadable from this author’s web page. The “geometrization” of time and causality is the common ground of the analysis hinted here and in Heylighen’s paper. Heylighen adds a logical notion, consistency, in order to understand a possible origin of the selective process that may have originated this organization of natural phenomena. We will join our perspectives by hinting to some gnoseological complexes, common to mathematics and physics, which may shed light on the issues raised by Heylighen.     

Tentative business confidence indicators for the Italian economy

This paper concerns the cyclical evolution of the Italian economy and, in particular, the role of confidence indicators. In the first part of the paper various confidence indicators, computed according to the European Commission (EC) methodology, are investigated. In particular, the analysis concentrates on the dynamics of some business climate indicators referred to the supply side of the economy (i.e. manufacturing, retail and construction industries). In the second part of the analysis, new confidence indicators exploring the wide informative set characterizing the ISAE business surveys are computed. The ability of these indicators in predicting the short‐term evolution of GDP, here considered as a reference series, is compared with that of the previous EC confidence indicators. Finally, in the third part, some estimates of the relationship between the chosen business confidence indicator and some driving variables are presented. Copyright © 2003 John Wiley & Sons, Ltd.