Valosin Containing Protein (VCP): A Multistep Regulator of Autophagy

Valosin containing protein (VCP) has emerged as a central protein in the regulation of the protein quality control (PQC) system. VCP mutations are causative of multisystem proteinopathies, which include neurodegenerative diseases (NDs), and share various signs of altered proteostasis, mainly associated with autophagy malfunctioning. Autophagy is a complex multistep degradative system essential for the maintenance of cell viability, especially in post-mitotic cells as neurons and differentiated skeletal muscle cells. Interestingly, many studies concerning NDs have focused on autophagy impairment as a pathological mechanism or autophagy activity boosting to rescue the pathological phenotype. The role of VCP in autophagy has been widely debated, but recent findings have defined new mechanisms associated with VCP activity in the regulation of autophagy, showing that VCP is involved in different steps of this pathway. Here we will discuss the multiple activity of VCP in the autophagic pathway underlying its leading role either in physiological or pathological conditions. A better understanding of VCP complexes and mechanisms in regulating autophagy could define the altered mechanisms by which VCP directly or indirectly causes or modulates different human diseases and revealing possible new therapeutic approaches for NDs.     

Automatic normalization of short texts by combining statistical and rule-based techniques

Short texts are typically composed of small number of words, most of which are abbreviations, typos and other kinds of noise. This makes the noise to signal ratio relatively high for this specific category of text. A high proportion of noise in the data is undesirable for analysis procedures as well as machine learning applications. Text normalization techniques are used to reduce the noise and improve the quality of text for processing and analysis purposes. In this work, we propose a combination of statistical and rule-based techniques to normalize short texts. More specifically, we focus our attention on SMS messages. We base our normalization approach on a statistical machine translation system which translates from noisy data to clean data. This system is trained on a small manually annotated set. Then, we study several automatic methods to extract more general rules from the normalizations generated with the statistical machine translation system. We illustrate the proposed methodology by conducting some experiments with a SMS Haitian-Créole data collection. In order to evaluate the performance of our methodology we use several Haitian-Créole dictionaries, the well-known perplexity criteria and the achieved reduction of vocabulary.     

Step semantics of boolean nets

Boolean nets are a family of Petri net models with very simple markings which are sets of places. We investigate several classes of boolean nets distinguished by different kinds of individual connections between places and transitions, as well as different ways in which these connections are combined in order to specify the effect of executing steps of transitions. The latter aspect can be captured by connection monoids. A key advantage of using connection monoids is that by describing the step semantics of a class of Petri nets in terms of a connection monoid, one can apply results developed within a general theory of Petri net synthesis. In this paper, we provide an extensive classification of boolean nets which can be described by connection monoids. This classification is based on the realisation that the different ways of interpreting combinations of connections can be made explicit using a higher level monoid. Moreover, we demonstrate that connection monoids can capture other behavioural properties of boolean nets, such as structural conflicts between transitions.     

Sexual Dimorphism in Brown Adipose Tissue Activation and White Adipose Tissue Browning

The present narrative review gathers the studies reported so far, addressing sex differences in the effects of cold exposure, feeding pattern and age on brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. In rodents, when exposed to decreasing temperatures, females activate thermogenesis earlier. Results obtained in humans go in the same line, although they do not provide results as solid as those obtained in rodents. Regarding the effects of overfeeding, interesting sex differences on BAT thermogenic capacity have been reported, and the greater or lower sensitivity of each sex to this dietary situation seems to be dependent on the type of feeding. In the case of energy restriction, females are more sensitive than males. In addition, sex differences have also been observed in thermogenesis changes induced by phenolic compound administration. During sexual development, an increase in BAT mass and BAT activity takes place. This phenomenon is greater in boys than in girls, probably due to its relation to muscle-mass growth. The opposite situation takes place during ageing, a lifespan period where thermogenic capacity declines, this being more acute in men than in women. Finally, the vast majority of the studies have reported a higher susceptibility to developing WAT browning amongst females. The scarcity of results highlights the need for further studies devoted to analysing this issue, in order to provide valuable information for a more personalised approach.     

MTCProv: a practical provenance query framework for many-task scientific computing

Scientific research is increasingly assisted by computer-based experiments. Such experiments are often composed of a vast number of loosely-coupled computational tasks that are specified and automated as scientific workflows. This large scale is also characteristic of the data that flows within such “many-task” computations (MTC). Provenance information can record the behavior of such computational experiments via the lineage of process and data artifacts. However, work to date has focused on lineage data models, leaving unsolved issues of recording and querying other aspects, such as domain-specific information about the experiments, MTC behavior given by resource consumption and failure information, or the impact of environment on performance and accuracy. In this work we contribute with MTCProv, a provenance query framework for many-task scientific computing that captures the runtime execution details of MTC workflow tasks on parallel and distributed systems, in addition to standard prospective and data derivation provenance. To help users query provenance data we provide a high level interface that hides relational query complexities. We evaluate MTCProv using an application in protein science, and describe how important query patterns such as correlations between provenance, runtime data, and scientific parameters are simplified and expressed.     

ARAXA: Storing and managing Active XML documents

Active XML (AXML) documents combine extensional XML data with intentional data defined through Web service calls. The dynamic properties of these documents pose challenges to both storage and data materialization techniques. In this paper, we present ARAXA, a non-intrusive approach to store and manage AXML documents. We also define a methodology to materialize AXML documents at query time. The storage approach of ARAXA is based on plain relational tables and user-defined functions of Object-Relational DBMS to trigger the service calls. By using a DBMS we benefit from efficient storage tools and query optimization. Approaches without DBMS support have to process XML in main memory or provide for virtual memory solutions. One of the main advantages of ARAXA is that AXML documents do not need to be loaded into main memory at query processing time. This is crucial when dealing with large documents. The experimental results with ARAXA prototype show that our approach is scalable and capable of dealing with large AXML documents.     

The Significance of Cell Surface N-Glycosylation for Internalization and Potency of Cytotoxic Conjugates Targeting Receptor Tyrosine Kinases

Precise anticancer therapies employing cytotoxic conjugates constitute a side-effect-limited, highly attractive alternative to commonly used cancer treatment modalities, such as conventional chemotherapy, radiotherapy or surgical interventions. Receptor tyrosine kinases are a large family of N-glycoproteins intensively studied as molecular targets for cytotoxic conjugates in various cancers. At the cell surface, these receptors are embedded in a dense carbohydrate layer formed by numerous plasma membrane glycoproteins. The complexity of the cell surface architecture is further increased by galectins, secreted lectins capable of recognizing and clustering glycoconjugates, affecting their motility and activity. Cell surface N-glycosylation is intensively remodeled by cancer cells; however, the contribution of this phenomenon to the efficiency of treatment with cytotoxic conjugates is largely unknown. Here, we evaluated the significance of N-glycosylation for the internalization and toxicity of conjugates targeting two model receptor tyrosine kinases strongly implicated in cancer: HER2 and FGFR1. We employed three conjugates of distinct molecular architecture and specificity: Affibody_HER2-vcMMAE (targeting HER2), vcMMAE-KCK-FGF1.E and T-Fc-vcMMAE (recognizing different epitopes within FGFR1). We demonstrated that inhibition of N-glycosylation reduced the cellular uptake of all conjugates tested and provided evidence for a role of the galectin network in conjugate internalization. In vitro binding studies revealed that the reduced uptake of conjugates is not due to impaired HER2 and FGFR1 binding. Importantly, we demonstrated that alteration of N-glycosylation can affect the cytotoxic potential of conjugates. Our data implicate a key role for cell surface N-glycosylation in the delivery of cytotoxic conjugates into cancer cells.     

Unravelling the Inflammatory Processes in the Early Stages of Diabetic Nephropathy and the Potential Effect of (Ss)-DS-ONJ

Inflammatory processes play a central role in the pathogenesis of diabetic nephropathy (DN) in the early stages of the disease. The authors demonstrate that the glycolipid mimetic (S_s)-DS-ONJ is able to abolish inflammation via the induction of autophagy flux and provokes the inhibition of inflammasome complex in ex vivo and in vitro models, using adult kidney explants from BB rats. The contribution of (S_s)-DS-ONJ to reducing inflammatory events is mediated by the inhibition of classical stress kinase pathways and the blocking of inflammasome complex activation. The (S_s)-DS-ONJ treatment is able to inhibit the epithelial-to-mesenchymal transition (EMT) progression, but only when the IL18 levels are reduced by the treatment. These findings suggest that (S_s)-DS-ONJ could be a novel, and multifactorial treatment for DN.     

Valproate Targets Mammalian Gastrulation Impairing Neural Tissue Differentiation and Development of the Placental Source In Vitro

The teratogenic activity of valproate (VPA), an antiepileptic and an inhibitor of histone deacetylase (HDACi), is dose-dependent in humans. Previous results showed that VPA impairs in vitro development and neural differentiation of the gastrulating embryo proper. We aimed to investigate the impact of a lower VPA dose in vitro and whether this effect is retained in transplants in vivo. Rat embryos proper (E9.5) and ectoplacental cones were separately cultivated at the air-liquid interface with or without 1 mM VPA. Embryos were additionally cultivated with HDACi Trichostatin A (TSA), while some cultures were syngeneically transplanted under the kidney capsule for 14 days. Embryos were subjected to routine histology, immunohistochemistry, Western blotting and pyrosequencing. The overall growth of VPA-treated embryos in vitro was significantly impaired. However, no differences in the apoptosis or proliferation index were found. Incidence of the neural tissue was lower in VPA-treated embryos than in controls. TSA also impaired growth and neural differentiation in vitro. VPA-treated embryos and their subsequent transplants expressed a marker of undifferentiated neural cells compared to controls where neural differentiation markers were expressed. VPA increased the acetylation of histones. Our results point to gastrulation as a sensitive period for neurodevelopmental impairment caused by VPA.