Maude: specification and programming in rewriting logic

Maude is a high-level language and a high-performance system supporting executable specification and declarative programming in rewriting logic. Since rewriting logic contains equational logic, Maude also supports equational specification and programming in its sublanguage of functional modules and theories. The underlying equational logic chosen for Maude is membership equational logic, that has sorts, subsorts, operator overloading, and partiality definable by membership and equality conditions. Rewriting logic is reflective, in the sense of being able to express its own metalevel at the object level. Reflection is systematically exploited in Maude endowing the language with powerful metaprogramming capabilities, including both user-definable module operations and declarative strategies to guide the deduction process. This paper explains and illustrates with examples the main concepts of Maude's language design, including its underlying logic, functional, system and object-oriented modules, as well as parameterized modules, theories, and views. We also explain how Maude supports reflection, metaprogramming and internal strategies. The paper outlines the principles underlying the Maude system implementation, including its semicompilation techniques. We conclude with some remarks about applications, work on a formal environment for Maude, and a mobile language extension of Maude

Non-specific inhibition of dipeptidyl peptidases 8/9 by dipeptidyl peptidase 4 inhibitors negatively affects mesenchymal stem cell differentiation

DPP4 may play a relevant role in MSC differentiation into osteoblasts or adipocytes. Dipeptidyl peptidase 4 (DPP4) inhibitors (DPP4i), such as sitagliptin and vildagliptin, are used as antidiabetic drugs. However, vildagliptin is not a specific DPP4i and also inhibits DPP8/9, which is involved in energy metabolism and immune regulation. The aim of this study is to evaluate how sitagliptin, vildagliptin or 1G244 (a DPP8/9 specific inhibitor) may influence cell viability, as well as osteogenic and adipogenic differentiation in human mesenchymal stem cells (MSC). Viability, apoptosis, osteoblastogenesis and adipogenesis markers, as well as protein synthesis of β-catenin, were studied in MSC cultures induced to differentiate into osteoblasts or adipocytes in the presence or absence of sitagliptin, vildagliptin or 1G244. The two tested DPP4i did not affect MSC viability, but 1G244 significantly decreased it in MSC and osteoblast-induced cells. Additionally, 1G244 and vildagliptin inhibited osteogenesis and adipogenesis, unlike sitagliptin. Therefore, inhibition of DPP4 did not affect MSC viability and differentiation, whereas inhibition of DPP8/9 negatively affected MSC. To the best of our knowledge, these results show for the first time that DPP8/9 have an important role in the viability and differentiation of human MSC. This data can be considered for human clinical use of drugs affecting DPP8/9 activity

Aplicación de la dinamometría isocinética para establecer perfiles de riesgo de lesión isquiosural en futbolistas profesionales. [The use of isokinetic dynamometry to establish risk profiles of hamstring injury in professional football players].

<p align="justify">Las lesiones en la musculatura isquiosural son frecuentes en el fútbol profesional y han sido relacionadas con el desequilibrio entre la fuerza de los flexores y extensores de rodilla. El objetivo de nuestro estudio fue comprobar si la ratio de fuerza máxima excéntrica de flexores/concéntrica de extensores (ratio Flexexc30/Extcon240) y el ángulo de rodilla donde la musculatura isquiosural alcanza su máximo momento de fuerza, son variables útiles para establecer perfiles de riesgo de lesión isquiosural en futbolistas profesionales. Veinte jugadores de un equipo de la Segunda División de la Liga de Fútbol Profesional realizaron bilateralmente un test isocinético de flexión excéntrica de rodilla a 30º/s y extensión concéntrica de rodilla a 240º/s durante la pretemporada. Tras calcular la ratio Flexexc30/Extcon240 y el ángulo de máximo momento de fuerza, se registraron las lesiones sufridas por los jugadores a lo largo de la temporada. Los resultados mostraron que dos de los cinco jugadores lesionados presentaron ratios Flexexc30/Extcon240 menores de 0.89, valor que ha sido utilizado previamente para determinar el desequilibrio entre la musculatura flexora y extensora de rodilla y el riesgo de lesión (Croisier, Ganteaume, Binet, Genty, y Ferret, 2008). Además, otros dos de los jugadores lesionados obtuvieron ratios entre 0.93 y 1.00. Por otro lado, no se encontraron diferencias en el ángulo de máximo momento de fuerza entre jugadores lesionados y no lesionados. Estos resultados indican que la ratio Flexexc30/Extcon240 puede ser un índice útil para determinar el riesgo de lesión isquiosural en futbolistas profesionales.</p>Abstract<p align="justify">Hamstring injuries are common in professional football and have been related to the imbalance between knee flexor and extensor strength. The aim of our study was to establish whether the flexor eccentric/extensor concentric strength ratio (Flexexc30/Extcon240 ratio) and the knee angle where the peak torque of the hamstring musculature was found, are useful variables to establish risk profiles for hamstring injury in professional football players. Twenty players of a Second Division team of the Liga de Fútbol Profesional bilaterally performed an isokinetic test of eccentric knee flexion at 30º/s and concentric knee extension at 240º/s during the pre-season. The Flexexc30/Extcon240 ratio and the knee angle of peak torque were calculated, and the players’ injuries were registered throughout the season. The results showed that two of the five injured players had Flexexc30/Extcon240 ratios lower than 0.89, value that has been previously used to determine the imbalance between knee flexor and extensor strength and the risk of injury (Croisier, Ganteaume, Binet, Genty, and Ferret, 2008). In addition, another two injured players obtained ratios between 0.93 and 1.00. On the other hand, no differences in the knee angle of peak torque between injured and non-injured players were found. These results indicate that the Flexexc30/Extcon240 ratio may be a useful index to determine the risk of hamstring injury in professional football players.</p>http://dx.doi.org/10.5232/ricyde2013.0340

A Spectroscopic study of colchicine in the solid state and in solution by multinuclear magnetic resonance and vibrational circular dichroism

Although almost 200-years-old, several unknown aspects remain to be explored of colchicine, the unique available drug for acute flares of gout. In this article, we report density-functional theory (DFT) studies of geometry, energy, and NMR; 1H-, 13C-, and 15N-NMR chemical shifts and some spin-spin coupling constants, including the complete analysis of the saturated part (ring B); the assignment of both enantiomers by NMR using a chiral solvating agent; solid-state NMR experiments of the different forms of natural and racemic colchicine, and IR and vibrational circular dichroism (VCD) studies of these same forms. Copyright © 2014 Verlag Helvetica Chimica Acta AG, Zürich.Peer Reviewe

Flavonoid Phloretin Inhibits Adipogenesis and Increases OPG Expression in Adipocytes Derived from Human Bone-Marrow Mesenchymal Stromal-Cells

Phloretin (a flavonoid abundant in apple), has antioxidant, anti-inflammatory, and glucose-transporter inhibitory properties. Thus, it has interesting pharmacological and nutraceutical potential. Bone-marrow mesenchymal stem cells (MSC) have high differentiation capacity, being essential for maintaining homeostasis and regenerative capacity in the organism. Yet, they preferentially differentiate into adipocytes instead of osteoblasts with aging. This has a negative impact on bone turnover, remodeling, and formation. We have evaluated the effects of phloretin on human adipogenesis, analyzing MSC induced to differentiate into adipocytes. Expression of adipogenic genes, as well as genes encoding OPG and RANKL (involved in osteoclastogenesis), protein synthesis, lipid-droplets formation, and apoptosis, were studied. Results showed that 10 and 20 µM phloretin inhibited adipogenesis. This effect was mediated by increasing beta-catenin, as well as increasing apoptosis in adipocytes, at late stages of differentiation. In addition, this chemical increased OPG gene expression and OPG/RANKL ratio in adipocytes. These results suggest that this flavonoid (including phloretin-rich foods) has interesting potential for clinical and regenerative-medicine applications. Thus, such chemicals could be used to counteract obesity and prevent bone-marrow adiposity. That is particularly useful to protect bone mass and treat diseases like osteoporosis, which is an epidemic worldwide

Biochemical Characterization of a Trypanosomatid Isolated from the Plant Amaranthus retroflexus

A protozoan flagelate has recently been isolated from Amaranthus retroflexus. This plant grows near economically important crops in southeastern Spain, which are known to be parasitized by Phytomonas spp. The present study focuses on the characterization of the energy metabolism of this new isolate. These flagellates utilize glucose efficiently as their primary energy source, although they are unable to completely degrade it. They excrete ethanol, acetate, glycine, and succinate in lower amount, as well as ammonium. The presence of glycosomes was indicated by the early enzymes of the glycolytic pathway, one enzyme of the glycerol pathway (glycerol kinase), and malate dehydrogenase. No evidence of a fully functional citric-acid cycle was found. In the absence of catalase activity, these flagellates showed significant superoxide dismutase activity located in the glycosomal and cytosolic fractions. These trypanosomes, despite being morphologically and metabolically similar to other Phytomonas isolated from the same area, showed significant differences, suggesting that they are phylogenetically different species

Maresin 1 activates brown adipose tissue and promotes browning of white adipose tissue in mice

Objective Maresin 1 (MaR1) is a docosahexaenoic acid-derived proresolving lipid mediator with insulin-sensitizing and anti-steatosis properties. Here, we aim to unravel MaR1 actions on brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning. Methods MaR1 actions were tested in cultured murine brown adipocytes and in human mesenchymal stem cells (hMSC)-derived adipocytes. In vivo effects of MaR1 were tested in diet-induced obese (DIO) mice and lean WT and Il6 knockout (Il6−/−) mice. Results In cultured differentiated murine brown adipocytes, MaR1 reduces the expression of inflammatory genes, while stimulates glucose uptake, fatty acid utilization and oxygen consumption rate, along with the upregulation of mitochondrial mass and genes involved in mitochondrial biogenesis and function and the thermogenic program. In Leucine Rich Repeat Containing G Protein-Coupled Receptor 6 (LGR6)-depleted brown adipocytes using siRNA, the stimulatory effect of MaR1 on thermogenic genes was abrogated. In DIO mice, MaR1 promotes BAT remodeling, characterized by higher expression of genes encoding for master regulators of mitochondrial biogenesis and function and iBAT thermogenic activation, together with increased M2 macrophage markers. In addition, MaR1-treated DIO mice exhibit a better response to cold-induced BAT activation. Moreover, MaR1 induces a beige adipocyte signature in inguinal WAT of DIO mice and in hMSC-derived adipocytes. MaR1 potentiates Il6 expression in brown adipocytes and BAT of cold exposed lean WT mice. Interestingly, the thermogenic properties of MaR1 were abrogated in Il6−/− mice. Conclusions These data reveal MaR1 as a novel agent that promotes BAT activation and WAT browning by regulating thermogenic program in adipocytes and M2 polarization of macrophages. Moreover, our data suggest that LGR6 receptor is mediating MaR1 actions on brown adipocytes, and that IL-6 is required for the thermogenic effects of MaR1

Maresin 1 activates brown adipose tissue and promotes browning of white adipose tissue in mice

[Objective]: Maresin 1 (MaR1) is a docosahexaenoic acid-derived proresolving lipid mediator with insulin-sensitizing and anti-steatosis properties. Here, we aim to unravel MaR1 actions on brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning. [Methods]: MaR1 actions were tested in cultured murine brown adipocytes and in human mesenchymal stem cells (hMSC)-derived adipocytes. In vivo effects of MaR1 were tested in diet-induced obese (DIO) mice and lean WT and Il6 knockout (Il6−/−) mice. [Results]: In cultured differentiated murine brown adipocytes, MaR1 reduces the expression of inflammatory genes, while stimulates glucose uptake, fatty acid utilization and oxygen consumption rate, along with the upregulation of mitochondrial mass and genes involved in mitochondrial biogenesis and function and the thermogenic program. In Leucine Rich Repeat Containing G Protein-Coupled Receptor 6 (LGR6)-depleted brown adipocytes using siRNA, the stimulatory effect of MaR1 on thermogenic genes was abrogated. In DIO mice, MaR1 promotes BAT remodeling, characterized by higher expression of genes encoding for master regulators of mitochondrial biogenesis and function and iBAT thermogenic activation, together with increased M2 macrophage markers. In addition, MaR1-treated DIO mice exhibit a better response to cold-induced BAT activation. Moreover, MaR1 induces a beige adipocyte signature in inguinal WAT of DIO mice and in hMSC-derived adipocytes. MaR1 potentiates Il6 expression in brown adipocytes and BAT of cold exposed lean WT mice. Interestingly, the thermogenic properties of MaR1 were abrogated in Il6−/− mice. [Conclusions]: These data reveal MaR1 as a novel agent that promotes BAT activation and WAT browning by regulating thermogenic program in adipocytes and M2 polarization of macrophages. Moreover, our data suggest that LGR6 receptor is mediating MaR1 actions on brown adipocytes, and that IL-6 is required for the thermogenic effects of MaR1.The authors received support for the current study from Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación, Spain, MCIN/AEI/10.13039/501100011033 (grants BFU2012-36089 to MJM-A; BFU2015-65937-R to MJM-A, SL-C; PID2019-106982RB-I00 to MJM-A; SAF2017-83813-C3-1-R to LH and PID2021-122766OB-I00 to AMV), cofinanced by the European Regional Development Fund (ERDF); Dept. of Health, Navarra Government (67–2015) to MJM-A; Merck Health Foundation to LH; CIBEROBN (CB12/03/30002; CB06/03/0001; CB06/03/0025) and CIBERDEM (CB07/08/0033) from ISCIII (Spain). “Juan de la Cierva” Grant to MF-G (IJCI-2016-30025) funded by MCIN/AEI/10.13039/501100011033. Predoctoral grant to LML (Asociación de Amigos, Universidad de Navarra/“la Caixa” Banking Foundation) and to LM-F (FPI, BES-2013-064970). S.Q.-V. is supported by a fellowship from the Vicente Lopez Program (Eurecat).Peer reviewe