Automatic Background Knowledge Selection for Matching Biomedical Ontologies

Ontology matching is a growing field of research that is of critical importance for the semantic web initiative. The use of background knowledge for ontology matching is often a key factor for success, particularly in complex and lexically rich domains such as the life sciences. However, in most ontology matching systems, the background knowledge sources are either predefined by the system or have to be provided by the user. In this paper, we present a novel methodology for automatically selecting background knowledge sources for any given ontologies to match. This methodology measures the usefulness of each background knowledge source by assessing the fraction of classes mapped through it over those mapped directly, which we call the mapping gain. We implemented this methodology in the AgreementMakerLight ontology matching framework, and evaluate it using the benchmark biomedical ontology matching tasks from the Ontology Alignment Evaluation Initiative (OAEI) 2013. In each matching problem, our methodology consistently identified the sources of background knowledge that led to the highest improvements over the baseline alignment (i.e., without background knowledge). Furthermore, our proposed mapping gain parameter is strongly correlated with the F-measure of the produced alignments, thus making it a good estimator for ontology matching techniques based on background knowledge.     

Cellular Prion Protein Promotes Regeneration of Adult Muscle Tissue

It is now well established that the conversion of the cellular prion protein, PrP^C, into its anomalous conformer, PrP^Sc, is central to the onset of prion disease. However, both the mechanism of prion-related neurodegeneration and the physiologic role of PrP^C are still unknown. The use of animal and cell models has suggested a number of putative functions for the protein, including cell signaling, adhesion, proliferation, and differentiation. Given that skeletal muscles express significant amounts of PrP^C and have been related to PrP^C pathophysiology, in the present study, we used skeletal muscles to analyze whether the protein plays a role in adult morphogenesis. We employed an in vivo paradigm that allowed us to compare the regeneration of acutely damaged hind-limb tibialis anterior muscles of mice expressing, or not expressing, PrP^C. Using morphometric and biochemical parameters, we provide compelling evidence that the absence of PrP^C significantly slows the regeneration process compared to wild-type muscles by attenuating the stress-activated p38 pathway, and the consequent exit from the cell cycle, of myogenic precursor cells. Demonstrating the specificity of this finding, restoring PrP^C expression completely rescued the muscle phenotype evidenced in the absence of PrP^C.The cellular prion protein (PrP^C) is a glycoprotein, prominently expressed in the mammalian central nervous system (CNS) and lymphoreticular system, that is anchored to the cell external surface through a glycolipidic moiety. The bad reputation acquired by PrP^C originates from the notion that an aberrant conformer of it (PrP^Sc) is the major component of the prion, the unconventional infectious particle that causes fatal neurodegenerative disorders, i.e., transmissible spongiform encephalopathies (TSE) or prion diseases (56). A wealth of evidence has suggested that the function of PrP^C is beneficial to the cell, but currently, our detailed comprehension of its physiology remains poor. In this respect, the availability of knockout (KO) paradigms for PrP^C has provided less crucial information than expected. Subtle phenotypes, e.g., mild neuropathologic, cognitive, and behavioral deficits, have been described in PrP-KO mice (17, 50), but these animals generally live a normal life span without displaying obvious developmental defects (8, 42). Importantly, the same holds true when the expression of PrP^C is postnatally abrogated (40). The extensive search for PrP^C''s raison d''être has ascribed to the protein a plethora of functions (for updated reviews, see references 1 and 35); among these, roles in cell adhesion, migration, and differentiation have been proposed whereby PrP^C could act by modulating different cell-signaling pathways (63). In this framework, a variety of neuronal proteins have been hypothesized to interact with PrP^C (reviewed in references 1 and 11), for example, cell adhesion molecules or extracellular matrix proteins, which could explain the capacity of PrP^C to mediate the neuritogenesis and neuronal differentiation observed in several cell model systems (13, 22, 23, 27, 36, 59, 64).Although neurons are generally regarded as the model of choice for unraveling the function of PrP^C, the expression of the protein in several other organs suggests that PrP^C has a conserved role in different tissues. Thus, important insight into PrP^C function may also be provided by the analysis of extraneural tissues. One such tissue is skeletal muscle, which has been shown to express PrP^C at significant levels (43, 46) and has been found to upregulate PrP^C levels under stress conditions (71). On the other hand, ablation of the PrP gene has been shown to directly affect skeletal muscles, for example, by enhancing oxidative damage (30) or by diminishing tolerance for physical exercise (51). Skeletal muscles have also been associated with prion pathology, as evidenced by the accumulation of PrP^Sc (or PrP^Sc-like forms) in the muscles of TSE-affected humans and animals (2, 3, 6, 21, 53, 67) and by transgenic-mouse models of some inherited TSEs (16). In addition, overexpression of wild-type (WT) PrP^C (25, 68), or expression of TSE-associated mutants of the protein (16, 66), generates myopathic traits in transgenic mice.In light of these notions, and because intact muscle tissues are more amenable to in vivo manipulations than neural tissue, we set out to analyze the potential role of PrP^C in tissue morphogenesis (38, 41, 46) using an in vivo skeletal-muscle paradigm from two congenic mouse lines expressing (WT) or not expressing (PrP-KO) PrP^C. Importantly, to verify that the PrP-KO muscle phenotype was specifically dependent on the absence of PrP^C, we used PrP-KO mice reconstituted with a PrP transgene (PrP-Tg). The applied protocol consisted of first characterizing the degeneration of the hind-limb tibialis anterior (TA) muscle and then evaluating the myogenic process from the response to inflammation to the full recovery of the muscle. By combining acute insult with adult age, this strategy also had the potential to bypass possible compensatory mechanisms that might mask PrP-KO phenotypes during embryogenesis and/or in adulthood under normal conditions (65).In this study, we provide evidence that, compared to animals expressing PrP^C (WT and PrP-Tg), recovery from damage of adult skeletal muscles was significantly slower in PrP-KO mice. Analysis of the different stages of muscle regeneration allowed us to conclude that PrP^C is one of the factors that govern the early phases of this process, in which the proliferation and differentiation of myogenic precursor cells take place.     

Metabolic interplay between intra- and extra-cellular uridine metabolism via an ATP driven uridine–UTP cycle in brain

Uridine, a pyrimidine nucleoside essential for the synthesis of RNA and biomembranes, has several trophic functions in the central nervous system, that involve a physiological regulation of pyrimidine nucleotides and phospholipids content, and a maintenance of brain metabolism under ischemia, or pathological situations. The understanding of uridine production in the brain is therefore of fundamental importance. Brain has a limited capacity to synthesize ex novo the pyrimidine ring, and a reasonable source of brain uridine is UTP. The kinetics of UTP breakdown, as catalysed by post-mitochondrial brain extracts and membrane preparations reported herein suggests that in normoxic conditions uridine is locally generated in brain exclusively in the extracellular space, and that any uptaken uridine is salvaged to UTP. It is now well established that cytosolic UTP can be released to interact with a subset of P2Y receptors, inducing a variety of molecular and cellular effects, leading to neuroprotection, while uridine is uptaken via an equilibrative or a Na⁺-dependent transport system, to exert its trophic effects in the cytosol. An ATP driven uridine–UTP cycle can be envisaged, based on the strictly compartmentalized processes of uridine salvage to UTP and uridine generation from UTP, in which uptaken uridine is anabolised to UTP in the cytosol, and converted back to uridine in extracellular space.     

Phosphorylation of the alpha subunit of translation initiation factor-2 by PKR mediates protein synthesis inhibition in the mouse brain during status epilepticus

In response to different cellular stresses, a family of protein kinases phosphorylates eIF2alpha (alpha subunit of eukaryotic initiation factor-2), contributing to regulation of both general and genespecific translation proposed to alleviate cellular injury or alternatively induce apoptosis. Recently, we reported eIF2alpha(P) (phosphorylated eIF2alpha) in the brain during SE (status epilepticus) induced by pilocarpine in mice, an animal model of TLE (temporal lobe epilepsy) [Carnevalli, Pereira, Longo, Jaqueta, Avedissian, Mello and Castilho (2004) Neurosci. Lett. 357, 191-194]. We show in the present study that one eIF2alpha kinase family member, PKR (double-stranded-RNA-dependent protein kinase), is activated in the cortex and hippocampus at 30 min of SE, reflecting the levels of eIF2alpha(P) in these areas. In PKR-deficient animals subjected to SE, eIF2alpha phosphorylation was clearly evident coincident with activation of a secondary eIF2alpha kinase, PEK/PERK (pancreatic eIF2alpha kinase/RNA-dependent-protein-kinase-like endoplasmic reticulum kinase), denoting a compensatory mechanism between the two kinases. The extent of eIF2alpha phosphorylation correlated with the inhibition of protein synthesis in the brain, as determined from polysome profiles. We also found that C57BL/6 mice, which enter SE upon pilocarpine administration but are more resistant to seizure-induced neuronal degeneration, showed very low levels of eIF2alpha(P) and no inhibition of protein synthesis during SE. These results taken together suggest that PKR-mediated phosphorylation of eIF2alpha contributes to inhibition of protein synthesis in the brain during SE and that sustained high levels of eIF2alpha phosphorylation may facilitate ensuing cell death in the most affected areas of the brain in TLE.     

Cryopreservation of Human Ovarian Tissue

New and often aggressive treatment schemes allow the successful healing of many young patients with cancer, but the price the young women have to pay is high: many of them lose ovarian function and fertility. Due to the improved long-term survival of adolescents and young women with malignancies undergoing gonadotoxic chemotherapy, preservation of future fertility has been the focus of recent ubiquitarian interest. A feasible solution is the cryopreservation of ovarian tissue. Ovarian tissue, after thawing, can be used in three different ways: 1. grafted into its normal site (orthotopic); 2. grafted into a site other than its normal position (heterotopic), necessitating recourse to in vitro fertilization (IVF); 3. grown and in vitro matured in order to obtain metaphase II oocytes for an IVF program. It is believed that protein supplementation, in cryopreservation solution, is essential for improving ovarian tissue cryopreservation. The aim of this study was to evaluate the ultrastructural appearance of human ovarian tissue cryopreserved in 1.5 M 1,2 propanediol (PROH), 0.2 M sucrose using different protein sources: fetal calf serum (FCS), plasmanate or syntetic serum substitute (SSS). Fresh and frozen/thawed ovarian tissues were compared by transmission electron microscope (TEM), to evaluate the appearance of stromal and follicle cells as affected by different protein sources. Our data indicate that FCS is a better protein support for ovarian tissue cryopreservation when compared to SSS or Plasmanate. In addition the follicles are more resistant to the cryopreservation with respect to stroma.     

Retinoic acid, GABA-ergic, and TGF-beta signaling systems are involved in human cleft palate fibroblast phenotype

During embryogenesis, a complex interplay between extracellular matrix (ECM) molecules, regulatory molecules, and growth factors mediates morphogenetic processes involved in palatogenesis. Transforming growth factor-beta (TGF-beta), retinoic acid (RA), and gamma-aminobutyric acid (GABA)ergic signaling systems are also potentially involved. Using [3H]glucosamine and [35S]methionine incorporation, anion exchange chromatography, semiquantitative radioactive RT-PCR, and a TGF-beta binding assay, we aimed to verify the presence of phenotypic differences between primary cultures of secondary palate (SP) fibroblasts from 2-year-old subjects with familial nonsyndromic cleft lip and/or palate (CLP-SP fibroblasts) and age-matched normal SP (N-SP) fibroblasts. The effects of RA--which, at pharmacologic doses, induces cleft palate in newborns of many species--were also studied. We found an altered ECM production in CLP-SP fibroblasts that synthesized and secreted more glycosaminoglycans (GAGs) and fibronectin (FN) compared with N-SP cells. In CLP-SP cells, TGF-beta3 mRNA expression and TGF-beta receptor number were higher and RA receptor-alpha (RARA) gene expression was increased. Moreover, we demonstrated for the first time that GABA receptor (GABRB3) mRNA expression was upregulated in human CLP-SP fibroblasts. In N-SP and CLP-SP fibroblasts, RA decreased GAG and FN secretion and increased TGF-beta3 mRNA expression but reduced the number of TGF-beta receptors. TGF-beta receptor type I mRNA expression was decreased, TGF-beta receptor type II was increased, and TGF-beta receptor type III was not affected. RA treatment increased RARA gene expression in both cell populations but upregulated GABRB3 mRNA expression only in N-SP cells. These results show that CLP-SP fibroblasts compared with N-SP fibroblasts exhibit an abnormal phenotype in vitro and respond differently to RA treatment, and suggest that altered crosstalk between RA, GABAergic, and TGF-beta signaling systems could be involved in human cleft palate fibroblast phenotype.     

Design, synthesis and SAR of a novel series of benzimidazoles as potent NPY Y5 antagonists

A novel class of benzimidazole NPY Y5 receptor antagonists was prepared exploiting a privileged spirocarbamate moiety. The structure-activity relationship of this series and efforts to achieve a profile suitable for further development and an appropriate pharmacokinetic profile in rat are described. Optimisation led to the identification of the brain penetrant, orally bioavailable Y5 antagonist 9b which significantly inhibited the food intake induced by a Y5 selective agonist with a minimal effective dose of 30mg/kg po.     

Expression and regulation of α‐transducin in the pig gastrointestinal tract

Taste signalling molecules are found in the gastrointestinal (GI) tract suggesting that they participate to chemosensing. We tested whether fasting and refeeding affect the expression of the taste signalling molecule, α‐transducin (G_αtran), throughout the pig GI tract and the peptide content of G_αtran cells. The highest density of G_αtran‐immunoreactive (IR) cells was in the pylorus, followed by the cardiac mucosa, duodenum, rectum, descending colon, jejunum, caecum, ascending colon and ileum. Most G_αtran‐IR cells contained chromogranin A. In the stomach, many G_αtran‐IR cells contained ghrelin, whereas in the upper small intestine many were gastrin/cholecystokinin‐IR and a few somatostatin‐IR. G_αtran‐IR and G_αgust‐IR colocalized in some cells. Fasting (24 h) resulted in a significant decrease in G_αtran‐IR cells in the cardiac mucosa (29.3 ± 0.8 versus 64.8 ± 1.3, P < 0.05), pylorus (98.8 ± 1.7 versus 190.8 ± 1.9, P < 0.0 l), caecum (8 ± 0.01 versus 15.5 ± 0.5, P < 0.01), descending colon (17.8 ± 0.3 versus 23 ± 0.6, P < 0.05) and rectum (15.3 ± 0.3 versus 27.5 ± 0.7, P < 0.05). Refeeding restored the control level of G_αtran‐IR cells in the cardiac mucosa. In contrast, in the duodenum and jejunum, G_αtran‐IR cells were significantly reduced after refeeding, whereas G_αtran‐IR cells density in the ileum was not changed by fasting/refeeding. These findings provide further support to the concept that taste receptors contribute to luminal chemosensing in the GI tract and suggest they are involved in modulation of food intake and GI function induced by feeding and fasting.