Genetic and Epigenomic Modifiers of Diabetic Neuropathy

Diabetic neuropathy (DN), the most common chronic and progressive complication of diabetes mellitus (DM), strongly affects patients’ quality of life. DN could be present as peripheral, autonomous or, clinically also relevant, uremic neuropathy. The etiopathogenesis of DN is multifactorial, and genetic components play a role both in its occurrence and clinical course. A number of gene polymorphisms in candidate genes have been assessed as susceptibility factors for DN, and most of them are linked to mechanisms such as reactive oxygen species production, neurovascular impairments and modified protein glycosylation, as well as immunomodulation and inflammation. Different epigenomic mechanisms such as DNA methylation, histone modifications and non-coding RNA action have been studied in DN, which also underline the importance of “metabolic memory” in DN appearance and progression. In this review, we summarize most of the relevant data in the field of genetics and epigenomics of DN, hoping they will become significant for diagnosis, therapy and prevention of DN.     

The Age-Sensitive Efficacy of Calorie Restriction on Mitochondrial Biogenesis and mtDNA Damage in Rat Liver

Calorie restriction (CR) is the most efficacious treatment to delay the onset of age-related changes such as mitochondrial dysfunction. However, the sensitivity of mitochondrial markers to CR and the age-related boundaries of CR efficacy are not fully elucidated. We used liver samples from ad libitum-fed (AL) rats divided in: 18-month-old (AL-18), 28-month-old (AL-28), and 32-month-old (AL-32) groups, and from CR-treated (CR) 28-month-old (CR-28) and 32-month-old (CR-32) counterparts to assay the effect of CR on several mitochondrial markers. The age-related decreases in citrate synthase activity, in TFAM, MFN2, and DRP1 protein amounts and in the mtDNA content in the AL-28 group were prevented in CR-28 counterparts. Accordingly, CR reduced oxidative mtDNA damage assessed through the incidence of oxidized purines at specific mtDNA regions in CR-28 animals. These findings support the anti-aging effect of CR up to 28 months. Conversely, the protein amounts of LonP1, Cyt c, OGG1, and APE1 and the 4.8 Kb mtDNA deletion content were not affected in CR-28 rats. The absence of significant differences between the AL-32 values and the CR-32 counterparts suggests an age-related boundary of CR efficacy at this age. However, this only partially curtails the CR benefits in counteracting the generalized aging decline and the related mitochondrial involvement.     

Performance-Analyse und -Optimierung in der Softwareentwicklung

Nicht-funktionale Anforderungen an ein Softwaresystem beschreiben Aspekte, die nicht direkt die Funktionalit?t, wie sie der Benutzer sieht, betreffen.     

Agens Faber: Toward a Theory of Artefacts for MAS

Human intelligence has evolved along with the use of more and more sophisticated tools, allowing Homo Faber (from Homo Habilis to Homo Sapiens Sapiens) to cope with environment changes, as well as to adapt the environment to his needs. Analogously, in this seminal paper we introduce the notion of Agens Faber, conveying the idea that agent intelligence should not be considered as separated by the agent ability to perceive and affect the environment—and so, that agent intelligence is strictly related to the artefacts that enable, mediate and govern any agent (intelligent) activity.

Along this line, we first discuss the notion of artefact for MAS in general, then we try to devise out the admissible / required / desirable features of an artefact for MAS. We elaborate on the many sorts of possible relations between agents and artefacts, focusing in particular on the issue of the rational exploitation of artefacts, and also rough out a possible taxonomy of artefacts for MAS.     

Influence of HIV-related immunodeficiency on the histopathology of chronic hepatitis C

OBJECTIVE: There is substantial evidence demonstrating the aggravating effect of human immunodeficiency virus (HIV) infection on the progression of chronic hepatitis C virus (HCV) infection. There is however, little data on the affect of certain factors which could affect liver pathology findings in patients with concomitant HIV infection such as the duration of HIV infection or T-cell subpopulation counts. We examined pathology findings in patients with concomitant HIV and HCV infections to determine the impact of immunodepression. PATIENTS AND METHODS: We reviewed liver pathology data collected in patients with concomitant HIV and HCV infections grouping patients according to severity of the liver pathology: group 1 = cirrhosis or active hepatitis; group 2 = minimally active hepatitis or histologically normal liver. Transparietal liver biopsies were obtained for the work-up of viral hepatitis or because of long-term unexplained fever or suspected lymphoma. Epidemiological and biological data were obtained from medical files. The duration of the liver disease was estimated from the date of exposure to risk of immunodepression as determined by the peripheral CD4+ and CD8+ counts. All pathology specimens were read by two pathologists who established the Knodell score for each patient. RESULTS: Fifty patients were included: 23 were classed in group 1 and 28 in group 2. The Knodell score was significantly different between the two groups, 11 +/- 4 and 4 +/- 3 respectively (p < 0.0001). Disease duration was similar for the two groups: mean 8 years. Mean CD4+ count was significantly higher in group 1: 312/mm3 versus 110/mm3 for group 2 (p = 0.0057); as was the mean CD8+ count (758/mm3 versus 360/mm3, p = 0.0013). For the entire study population, there was a significantly negative correlation (p < 0.05) between the Knodell score and the CD4+ count (r = 0.31) and for the CD8+ count (r = 0.41). CONCLUSION: HCV-related liver pathology in patients co-infected with HIV depends on the level of immunodepression. CD8+ counts are better correlated with pathology findings than with CD4+ counts.     

Qualitative analysis of motion properties of semistate models of large-scale systems

This paper studies the behavior of motions of large-scale (LS) semistate systems (SSS) governed byP _i (t)x _i =M _i (t,x _i )x _i +f _i (t)+h _i (t, x), i=1,2,...,s, =(x ₁ ^T x ₂ ^T x _s ^T )^T, where matricesP _i (t) are singular. Using Lyapunov's approach and the tools for LS system analysis, a variant of attractivity and ultimate boundedness of appropriate time-variable sets are investigated. The results are based on a specific choice of the aggregate functions. It is assumed that the reduction of equations to a normal form of lower order is inconvenient. The aggregation-decomposition approach used in this paper reduces the dimensionality of an aggregate matrix of the system to the number of its systems. Motion properties of LS systems are deduced from the properties of its isolated subsystems, the character of interconnections, and the conditions imposed on the system aggregate matrix. Sufficient algebraic conditions for the above-mentioned motion properties are developed.     

Bone Marrow-Mesenchymal Stromal Cell Secretome as Conditioned Medium Relieves Experimental Skeletal Muscle Damage Induced by Ex Vivo Eccentric Contraction

Bone marrow-mesenchymal stem/stromal cells (MSCs) may offer promise for skeletal muscle repair/regeneration. Growing evidence suggests that the mechanisms underpinning the beneficial effects of such cells in muscle tissue reside in their ability to secrete bioactive molecules (secretome) with multiple actions. Hence, we examined the effects of MSC secretome as conditioned medium (MSC-CM) on ex vivo murine extensor digitorum longus muscle injured by forced eccentric contraction (EC). By combining morphological (light and confocal laser scanning microscopies) and electrophysiological analyses we demonstrated the capability of MSC-CM to attenuate EC-induced tissue structural damages and sarcolemnic functional properties’ modifications. MSC-CM was effective in protecting myofibers from apoptosis, as suggested by a reduced expression of pro-apoptotic markers, cytochrome c and activated caspase-3, along with an increase in the expression of pro-survival AKT factor. Notably, MSC-CM also reduced the EC-induced tissue redistribution and extension of telocytes/CD34⁺ stromal cells, distinctive cells proposed to play a “nursing” role for the muscle resident myogenic satellite cells (SCs), regarded as the main players of regeneration. Moreover, it affected SC functionality likely contributing to replenishment of the SC reservoir. This study provides the necessary groundwork for further investigation of the effects of MSC secretome in the setting of skeletal muscle injury and regenerative medicine.     

meSAT: multiple encodings of CSP to SAT

One approach for solving Constraint Satisfaction Problems (CSP) (and related Constraint Optimization Problems (COP)) involving integer and Boolean variables is reduction to propositional satisfiability problem (SAT). A number of encodings (e.g., direct, log, support, order) for this purpose exist as well as specific encodings for some constraints that are often encountered (e.g., cardinality constraints, global constraints). However, there is no single encoding that performs well on all classes of problems and there is a need for a system that supports multiple encodings. We present a system that translates specifications of finite linear CSP problems into SAT instances using several well-known encodings, and their combinations. We also present a methodology for selecting a suitable encoding based on simple syntactic features of the input CSP instance. Thorough evaluation has been performed on large publicly available corpora and our encoding selection method improves upon the efficiency of existing encodings and state-of-the-art tools used in comparison.