System dependence graphs in sequential Erlang

The system dependence graph (SDG) is a data structure used in the imperative paradigm for different static analysis, and particularly, for program slicing. Program slicing allows us to determine the part of a program (called slice) that influences a given variable of interest. Thanks to the SDG, we can produce precise slices for interprocedural programs. Unfortunately, the SDG cannot be used in the functional paradigm due to important features that are not considered in this formalism (e.g., pattern matching, higher-order, composite expressions, etc.). In this work we propose the first adaptation of the SDG to a functional language facing these problems. We take Erlang as the host language and we adapt the algorithms used to slice the SDG to produce precise slices of Erlang interprocedural programs. As a proof-of-concept, we have implemented a program slicer for Erlang based on our SDGs.This work has been partially supported by the Spanish Ministerio de Ciencia e Innovaci´on under grant TIN2008-06622-C03-02 and by the Generalitat Valenciana under grant PROMETEO/2011/052. Salvador Tamarit was partially supported by the Spanish MICINN under FPI grant BES-2009-015019Silva Galiana, JF.; Tamarit Muñoz, S.; Tomás Franco, C. (2012). System dependence graphs in sequential Erlang. En Fundamental Approaches to Software Engineering. Springer Verlag (Germany). 486-500. https://doi.org/10.1007/978-3-642-28872-2_33S486500Agrawal, H., Horgan, J.R.: Dynamic program slicing. In: Programming Language Design and Implementation (PLDI), pp. 246–256 (1990)Brown, C.: Tool Support for Refactoring Haskell Programs. PhD thesis, School of Computing, University of Kent, Canterbury, Kent, UK (2008)Cheda, D., Silva, J., Vidal, G.: Static slicing of rewrite systems. Electron. Notes Theor. Comput. Sci. 177, 123–136 (2007)Ferrante, J., Ottenstein, K.J., Warren, J.D.: The Program Dependence Graph and Its Use in Optimization. ACM Transactions on Programming Languages and Systems 9(3), 319–349 (1987)Field, J., Ramalingam, G., Tip, F.: Parametric program slicing. In: Proceedings of the 22nd ACM SIGPLAN-SIGACT Symposium on Principles of Programming Languages, POPL 1995, pp. 379–392. ACM, New York (1995)Horwitz, S., Reps, T., Binkley, D.: Interprocedural slicing using dependence graphs. ACM Transactions Programming Languages and Systems 12(1), 26–60 (1990)Korel, B., Laski, J.: Dynamic Program Slicing. Information Processing Letters 29(3), 155–163 (1988)Larsen, L., Harrold, M.J.: Slicing object-oriented software. In: Proceedings of the 18th International Conference on Software Engineering, ICSE 1996, pp. 495–505. IEEE Computer Society, Washington, DC (1996)Liang, D., Harrold, M.J.: Slicing objects using system dependence graphs. In: Proceedings of the International Conference on Software Maintenance, ICSM 1998, pp. 358–367. IEEE Computer Society, Washington, DC (1998)Lindahl, T., Sagonas, K.F.: Typer: a type annotator of erlang code. In: Sagonas, K.F., Armstrong, J. (eds.) Erlang Workshop, pp. 17–25. ACM (2005)Lindahl, T., Sagonas, K.F.: Practical type inference based on success typings. In: Bossi, A., Maher, M.J. (eds.) PPDP, pp. 167–178. ACM (2006)Ochoa, C., Silva, J., Vidal, G.: Dynamic slicing based on redex trails. In: Proceedings of the 2004 ACM SIGPLAN Symposium on Partial Evaluation and Semantics-Based Program Manipulation, PEPM 2004, pp. 123–134. ACM, New York (2004)Reps, T., Turnidge, T.: Program Specialization via Program Slicing. In: Danvy, O., Thiemann, P., Glück, R. (eds.) Dagstuhl Seminar 1996. LNCS, vol. 1110, pp. 409–429. Springer, Heidelberg (1996)Rodrigues, N.F., Barbosa, L.S.: Component identification through program slicing. In: Proc. of Formal Aspects of Component Software (FACS 2005). Elsevier ENTCS, pp. 291–304. Elsevier (2005)Tip, F.: A survey of program slicing techniques. Journal of Programming Languages 3(3), 121–189 (1995)Tóth, M., Bozó, I., Horváth, Z., Lövei, L., Tejfel, M., Kozsik, T.: Impact Analysis of Erlang Programs Using Behaviour Dependency Graphs. In: Horváth, Z., Plasmeijer, R., Zsók, V. (eds.) CEFP 2009. LNCS, vol. 6299, pp. 372–390. Springer, Heidelberg (2010)Walkinshaw, N., Roper, M., Wood, M., Roper, N.W.M.: The java system dependence graph. In: Third IEEE International Workshop on Source Code Analysis and Manipulation, p. 5 (2003)Weiser, M.: Program Slicing. In: Proceedings of the 5th International Conference on Software Engineering, pp. 439–449. IEEE Press (1981)Widera, M.: Flow graphs for testing sequential erlang programs. In: Proceedings of the 2004 ACM SIGPLAN Workshop on Erlang, ERLANG 2004, pp. 48–53. ACM, New York (2004)Widera, M., Informatik, F.: Concurrent erlang flow graphs. In: Proceedings of the Erlang/OTP User Conference (2005)Zhao, J.: Slicing aspect-oriented software. In: Proceedings of the 10th International Workshop on Program Comprehension, IWPC 2002, pp. 251–260. IEEE Computer Society, Washington, DC (2002

A thermophysical study of the melting process in alkyl chain metal n-alkanoates: The thallium (I) series

The peculiar thermal behavior of the thallium(I) n-alkanoates series (consisting in several transitions between polymorphic and mesomorphic phases) in comparison with other metallic n-alkanoates series is stated. The allowance of highly accurate adiabatic heat capacity data permits a study of the CH2CH2 contributions to the lattice heat capacity curve at low temperature. Moreover, in this series an anomalous gradual enhancement of the lattice heat capacity has been interpreted from vibrational spectroscopy results as a noncooperative effect due to the internal hindered rotation of the alkyl chain (formation of gauche defects, even in the solid state). The thermodynamics of the “stepwise melting process” from the totally ordered solid at low temperature to the isotropic liquid is based on a revised lattice heat-capacity curve. This was used to evaluate the energy and entropy not only of the clear first order transitions present in the series but also of the described noncooperative effect. The CH2CH2 enthalpy and entropy contribution for this series is estimated and a comparison with the published values for other series is carried out. Moreover, the texture of the mesophases is revealed by polarized light microscopy. © 1999 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69602/2/JCPSA6-111-8-3590-1.pd

Mitochondrial angiotensin receptors in dopaminergic neurons. Role in cell protection and aging-related vulnerability to neurodegeneration

The renin-angiotensin system (RAS) was initially considered as a circulating humoral system controlling blood pressure, being kidney the key control organ. In addition to the \u27classical\u27 humoral RAS, a second level in RAS, local or tissular RAS, has been identified in a variety of tissues, in which local RAS play a key role in degenerative and aging-related diseases. The local brain RAS plays a major role in brain function and neurodegeneration. It is normally assumed that the effects are mediated by the cell-surface-specific G-protein-coupled angiotensin type 1 and 2 receptors (AT1 and AT2). A combination of in vivo (rats, wild-type mice and knockout mice) and in vitro (primary mesencephalic cultures, dopaminergic neuron cell line cultures) experimental approaches (confocal microscopy, electron microscopy, laser capture microdissection, transfection of fluorescent-tagged receptors, treatments with fluorescent angiotensin, western blot, polymerase chain reaction, HPLC, mitochondrial respirometry and other functional assays) were used in the present study. We report the discovery of AT1 and AT2 receptors in brain mitochondria, particularly mitochondria of dopaminergic neurons. Activation of AT1 receptors in mitochondria regulates superoxide production, via Nox4, and increases respiration. Mitochondrial AT2 receptors are much more abundant and increase after treatment of cells with oxidative stress inducers, and produce, via nitric oxide, a decrease in mitochondrial respiration. Mitochondria from the nigral region of aged rats displayed altered expression of AT1 and AT2 receptors. AT2-mediated regulation of mitochondrial respiration represents an unrecognized primary line of defence against oxidative stress, which may be particularly important in neurons with increased levels of oxidative stress such as dopaminergic neurons. Altered expression of AT1 and AT2 receptors with aging may induce mitochondrial dysfunction, the main risk factor for neurodegeneratio

Neurodevelopment Genes in Lampreys Reveal Trends for Forebrain Evolution in Craniates

The forebrain is the brain region which has undergone the most dramatic changes through vertebrate evolution. Analyses conducted in lampreys are essential to gain insight into the broad ancestral characteristics of the forebrain at the dawn of vertebrates, and to understand the molecular basis for the diversifications that have taken place in cyclostomes and gnathostomes following their splitting. Here, we report the embryonic expression patterns of 43 lamprey genes, coding for transcription factors or signaling molecules known to be involved in cell proliferation, stemcellness, neurogenesis, patterning and regionalization in the developing forebrain. Systematic expression patterns comparisons with model organisms highlight conservations likely to reflect shared features present in the vertebrate ancestors. They also point to changes in signaling systems –pathways which control the growth and patterning of the neuroepithelium-, which may have been crucial in the evolution of forebrain anatomy at the origin of vertebrates

Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>Several recent studies have shown that angiotensin type 1 receptor (AT1) antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ). PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions.</p> <p>Methods</p> <p>We have investigated whether oral treatment with telmisartan (the most potent PPAR-γ activator among AT1 blockers) provides neuroprotection against dopaminergic cell death and neuroinflammation, and the possible role of PPAR-γ activation in any such neuroprotection. We used a mouse model of parkinsonism induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and co-administration of the PPAR-γ antagonist GW9662 to study the role of PPAR-γ activation. In addition, we used AT1a-null mice lesioned with MPTP to study whether deletion of AT1 in the absence of any pharmacological effect of AT1 blockers provides neuroprotection, and investigated whether PPAR-γ activation may also be involved in any such effect of AT1 deletion by co-administration of the PPAR-γ antagonist GW9662.</p> <p>Results</p> <p>We observed that telmisartan protects mouse dopaminergic neurons and inhibits the microglial response induced by administration of MPTP. The protective effects of telmisartan on dopaminergic cell death and microglial activation were inhibited by co-administration of GW9662. Dopaminergic cell death and microglial activation were significantly lower in AT1a-null mice treated with MPTP than in mice not subjected to AT1a deletion. Interestingly, the protective effects of AT1 deletion were also inhibited by co-administration of GW9662.</p> <p>Conclusion</p> <p>The results suggest that telmisartan provides effective neuroprotection against dopaminergic cell death and that the neuroprotective effect is mediated by PPAR-γ activation. However, the results in AT1-deficient mice show that blockage of AT1, unrelated to the pharmacological properties of AT1 blockers, also protects against dopaminergic cell death and neuroinflammation. Furthermore, the results show that PPAR-γ activation is involved in the anti-inflammatory and neuroprotective effects of AT1 deletion.</p

Gi/o-protein coupled receptors in the aging brain

Cells translate extracellular signals to regulate processes such as differentiation, metabolism and proliferation, via transmembranar receptors. G protein-coupled receptors (GPCRs) belong to the largest family of transmembrane receptors, with over 800 members in the human species. Given the variety of key physiological functions regulated by GPCRs, these are main targets of existing drugs. During normal aging, alterations in the expression and activity of GPCRs have been observed. The central nervous system (CNS) is particularly affected by these alterations, which results in decreased brain functions, impaired neuroregeneration, and increased vulnerability to neuropathologies, such as Alzheimer's and Parkinson diseases. GPCRs signal via heterotrimeric G proteins, such as Go, the most abundant heterotrimeric G protein in CNS. We here review age-induced effects of GPCR signaling via the Gi/o subfamily at the CNS. During the aging process, a reduction in protein density is observed for almost half of the Gi/o-coupled GPCRs, particularly in age-vulnerable regions such as the frontal cortex, hippocampus, substantia nigra and striatum. Gi/o levels also tend to decrease with aging, particularly in regions such as the frontal cortex. Alterations in the expression and activity of GPCRs and coupled G proteins result from altered proteostasis, peroxidation of membranar lipids and age-associated neuronal degeneration and death, and have impact on aging hallmarks and age-related neuropathologies. Further, due to oligomerization of GPCRs at the membrane and their cooperative signaling, down-regulation of a specific Gi/o-coupled GPCR may affect signaling and drug targeting of other types/subtypes of GPCRs with which it dimerizes. Gi/o-coupled GPCRs receptorsomes are thus the focus of more effective therapeutic drugs aiming to prevent or revert the decline in brain functions and increased risk of neuropathologies at advanced ages.This work was supported by Fundação para a Ciência e Tecnologia, Centro 2020 and Portugal 2020, the COMPETE program, QREN, and the European Union (FEDER program) via the GoBack project (PTDC/CVT-CVT/32261/2017), the pAGE program (Centro-01-0145-FEDER-000003), and Institute for Biomedicine iBiMED (UID/BIM/04501/2013; UID/BIM/04501/2019).publishe

Stimulatory effects of single low-level irradiations with X-rays on functions of murine peritoneal macrophages

A number of epidemiological and experimental data indicate that exposures to low doses of low-LET ionising radiation may trigger the activity of natural anti-tumour immune mechanisms and inhibit tumour growth. In the present study, we assessed the cytotoxic activity and production of nitric oxide, superoxide anions, and tumour necrosis factor-alfa in peritoneal macrophages collected from BALB/c mice exposed to single whole-body irradiations with 0.1, 0.2, or 1.0 Gy X-rays. The results indicate that all the tested parameters were significantly up-regulated in macrophages obtained from mice exposed to 0.1 or 0.2 Gy X-rays but not in those collected from the sham-irradiated and 1.0 Gy-exposed animals