Muscle Proteomic Profile before and after Enzyme Replacement Therapy in Late-Onset Pompe Disease

Mutations in the acidic alpha-glucosidase (GAA) coding gene cause Pompe disease. Late-onset Pompe disease (LOPD) is characterized by progressive proximal and axial muscle weakness and atrophy, causing respiratory failure. Enzyme replacement therapy (ERT), based on recombinant human GAA infusions, is the only available treatment; however, the efficacy of ERT is variable. Here we address the question whether proteins at variance in LOPD muscle of patients before and after 1 year of ERT, compared withhealthy age-matched subjects (CTR), reveal a specific signature. Proteins extracted from skeletal muscle of LOPD patients and CTR were analyzed by combining gel based (two-dimensional difference gel electrophoresis) and label-free (liquid chromatography-mass spectrometry) proteomic approaches, and ingenuity pathway analysis. Upstream regulators targeting autophagy and lysosomal tethering were assessed by immunoblotting. 178 proteins were changed in abundance in LOPD patients, 47 of them recovered normal level after ERT. Defects in oxidative metabolism, muscle contractile protein regulation, cytoskeletal rearrangement, and membrane reorganization persisted. Metabolic changes, ER stress and UPR (unfolded protein response) contribute to muscle proteostasis dysregulation with active membrane remodeling (high levels of LC3BII/LC3BI) and accumulation of p62, suggesting imbalance in the autophagic process. Active lysosome biogenesis characterizes both LOPD PRE and POST, unparalleled by molecules involved in lysosome tethering (VAMP8, SNAP29, STX17, and GORASP2) and BNIP3. In conclusion this study reveals a specific signature that suggests ERT prolongation and molecular targets to ameliorate patient’s outcome.     

Expanding Phenotype of Schimke Immuno-Osseous Dysplasia: Congenital Anomalies of the Kidneys and of the Urinary Tract and Alteration of NK Cells

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in SMARCAL1. A phenotype–genotype correlation has been attempted and variable expressivity of biallelic SMARCAL1 variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the SMARCAL1 gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD—both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7Rα expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with SMARCAL1 mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.     

Human migration networks and policy interventions: bringing population distributions in line with system optimization

In this paper, we demonstrate that, through policy interventions, in the form of subsidies, a system‐optimum for a multiclass human migration network can be achieved, despite the migrants, who can be refugees, behaving in a user‐optimized manner. The formulation and analysis are conducted using variational inequality theory. The policy intervention allows governmental decision‐makers to moderate the flow of migrants while enhancing societal welfare. An algorithm is proposed and applied to compute the solutions to a series of numerical examples, with changes in initial populations and utility functions, inspired by a pandemic, followed by a natural disaster.     

Effects of context on the immediate interpretation of unambiguous nouns.

Effects of prior sentential context on the interpretation of unambiguous nouns were investigated in 2 cross-modal priming experiments. Exp 1 showed that a prior priming context affects word interpretation during lexical access by facilitating the recovery of contextually relevant aspects of meaning and inhibiting the recovery of irrelevant aspects. Exp 2 showed that lexical decision on a visual word related to an aspect of meaning of an unambiguous noun is facilitated only by a sentential context containing the noun and priming that aspect. Such facilitation occurs neither when the unambiguous noun is replaced by a substitute noun in the same sentential context, nor when the unambiguous noun occurs in a sentence priming an aspect of its meaning unrelated to the visual word. Furthermore, neither of these 2 conditions produced effects on lexical decision reliably different either from each other or from a sentential context completely unrelated to the visual word. Findings argue against the context-independent model of lexical access and support the hypothesis that lexical access may be affected by prior sentential context. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reasoning by model: The case of multiple quantification.

A theory of deductive reasoning is presented for a major class of inferences that has not been investigated by psychologists: inferences that depend on multiply-quantified premises (e.g., "None of the Princeton letters is in the same place as any of the Dublin letters"). It is argued that reasoners construct mental models based on their knowledge of the meanings of quantifiers (and other terms, including relational expressions). Three experiments corroborate the model theory's prediction that inferences that require the construction of only 1 model will be easier than those that require more than 1 model. The model theory assumes that the logical properties of quantifiers emerge from their meanings and are not mentally represented in rules of inference. How such a semantic process can occur compositionally (i.e., guided by the syntactic analysis of sentences) is described. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Genome renewal: A new phenomenon revealed from a genetic study of 43 strains of Saccharomyces cerevisiae derived from natural fermentation of grape musts

We have analyzed by genetic means 43 strains of Saccharomyces that had been isolated from fermenting grape musts in Italy. Twenty eight of these strains were isolated from 28 cellars in the Region of Emilia Romagna. The other 15 strains came from 5 fermentations at four cellars near the city of Arpino, which is located south and east of Rome. We found that 20 of the 28 strains from Emilia Romagna were heterozygous at from one to seven loci. The balance were, within the limits of our detection, completely homozygous. All these strains appeared to be diploid and most were homozygous for the homothallism gene (HO/HO). Spore viability varied greatly between the different strains and showed an inverse relation with the degree of heterozygosity. Several of the strains, and in particular those from Arpino, yielded asci that came from genetically different cells. These different cells could be interpreted to have arisen from a heterozygote that had sporulated and, because of the HO gene, yielded homozygous diploid spore clones. We propose that natural wine yeast strains can undergo such changes and thereby change a multiple heterozygote into completely homozygous diploids, some of which may replace the original heterozygous diploid. We call this process ‘genome renewal’.     

Biotechnological H2S gas treatment with Thiobacillus ferrooxidans

In this paper a novel process for biotechnological abatement of hydrogen sulphide is presented which details the fundamentals of chemical and biological phenomena involved. The process is based on the combination of two steps to form a closed cycle which has special enviornmental advantages. The chemical step corresponds to the abatement reaction itself with absorption of the gas in a ferric solution. The biological step is related to the regeneration of the absorbing solution by means of specific bacterial strains. Particular interest is devoted to the biological kinetics of the regeneration stage, where several inhibition phenomena appear, and are also related to parameters such as temperature and pH. Results of experimental runs of gas absorption in a laboratory scale plant are also described.