On an Intuitionistic Logic for Pragmatics

We reconsider the pragmatic interpretation of intuitionistic logic [21] regarded as a logic of assertions and their justications and its relations with classical logic. We recall an extension of this approach to a logic dealing with assertions and obligations, related by a notion of causal implication [14, 45]. We focus on the extension to co-intuitionistic logic, seen as a logic of hypotheses [8, 9, 13] and on polarized bi-intuitionistic logic as a logic of assertions and conjectures: looking at the S4 modal translation, we give a denition of a system AHL of bi-intuitionistic logic that correctly represents the duality between intuitionistic and co-intuitionistic logic, correcting a mistake in previous work [7, 10]. A computational interpretation of cointuitionism as a distributed calculus of coroutines is then used to give an operational interpretation of subtraction.Work on linear co-intuitionism is then recalled, a linear calculus of co-intuitionistic coroutines is dened and a probabilistic interpretation of linear co-intuitionism is given as in [9]. Also we remark that by extending the language of intuitionistic logic we can express the notion of expectation, an assertion that in all situations the truth of p is possible and that in a logic of expectations the law of double negation holds. Similarly, extending co-intuitionistic logic, we can express the notion of conjecture that p, dened as a hypothesis that in some situation the truth of p is epistemically necessary

Chu's construction: a proof-theoretic approach

The essential interaction between classical and intuitionistic features in the system of linear logic is best described in the language of category theory. Given a symmetric monoidal closed category C with products, the category C x C^op can be given the structure of a *-autonomous category by a special case of the Chu construction. The main result of the paper is to show that the intuitionistic translations induced by Girard trips on a proof net determine the functor from the free *-autonomous category on a set of atoms {P, P',...} to C x C^op, where C is the free monoidal closed category with products and coproducts on the set of atoms {P_O, P_I, P'_O, P'_I, ...} (a pair P_O, P_I in C for each atom P of A)

Two paradigms of logical computation in affine logic?

We propose a notion of symmetric reduction for a system of proof nets for multiplicative Affine Logic with Mix. We prove that such a reduction has the strong normalization and Church-Rosser properties. A notion of irrelevance in a proof net is defined and the possibility of cancelling the irrelevant parts without erasing the entire net is taken as one of the correctness conditions. Therefore purely local cut-reductions are given, minimizing cancellation and suggesting a paradigm of "computation without garbage collection". Reconsidering Ketonen and Weyhrauch's decision procedure for affine logic, the use od the mix rule is related to the non-determinism of classical proof theory. The question arises whether these features of classical cut-elimination are really irreducible to the familiar paradigm of cut-elimination in intuitionistic and linea logic

A Kripke-style Semantics for the Intuitionistic Logic of Pragmatics ILP

We give a Kripke style semantics for an intuitionistic logic for pragmatics ILP, with consists of the Horn fragment of relevant logic to express causal relations between (elementary formulas for) assertions and obligations in the framework of propositional intuitionistic logic as a logic of assertions. In order to prove the completeness theorem we give a decision procedure that given an ILP sequent S either returns a cut-free derivation of S or constructs a finite counter-model, if S is not provable. As a corollary we have the finite model property for ILP and also a new proof that the cut rule is eliminable in ILP

Proof nets for bi-intuitionistic linear logic

Bi-Intuitionistic Linear Logic (BILL) is an extension of Intuitionistic Linear Logic with a par, dual to the tensor, and subtraction, dual to linear implication. It is the logic of categories with a monoidal closed and a monoidal co-closed structure that are related by linear distributivity, a strength of the tensor over the par. It conservatively extends Full Intuitionistic Linear Logic (FILL), which includes only the par. We give proof nets for the multiplicative, unit-free fragment MBILL-. Correctness is by local rewriting in the style of Danos contractibility, which yields sequentialization into a relational sequent calculus extending the existing one for FILL. We give a second, geometric correctness condition combining Danos-Regnier switching and Lamarche\u27s Essential Net criterion, and demonstrate composition both inductively and as a one-off global operation

Inhibition of heparanase protects against chronic kidney dysfunction following ischemia/reperfusion injury

Renal ischemia/reperfusion (I/R) injury occurs in patients undergoing renal transplantation and with acute kidney injury and is responsible for the development of chronic allograft dysfunction as characterized by parenchymal alteration and fibrosis. Heparanase (HPSE), an endoglycosidase that regulates EMT and macrophage polarization, is an active player in the biological response triggered by ischemia/reperfusion (I/R) injury. I/R was induced in vivo by clamping left renal artery for 30 min in wt C57BL/6J mice. Animals were daily treated and untreated with Roneparstat (an inhibitor of HPSE) and sacrificed after 8 weeks. HPSE, fibrosis, EMT-markers, inflammation and oxidative stress were evaluated by biomolecular and histological methodologies together with the evaluation of renal histology and measurement of renal function parameters. 8 weeks after I/R HPSE was upregulated both in renal parenchyma and plasma and tissue specimens showed clear evidence of renal injury and fibrosis. The inhibition of HPSE with Roneparstat-restored histology and fibrosis level comparable with that of control. I/R-injured mice showed a significant increase of EMT, inflammation and oxidative stress markers but they were significantly reduced by treatment with Roneparstat. Finally, the inhibition of HPSE in vivo almost restored renal function as measured by BUN, plasma creatinine and albuminuria. The present study points out that HPSE is actively involved in the mechanisms that regulate the development of renal fibrosis arising in the transplanted organ as a consequence of ischemia/reperfusion damage. HPSE inhibition would therefore constitute a new pharmacological strategy to reduce acute kidney injury and to prevent the chronic pro-fibrotic damage induced by I/R

Transcriptomics: A Step behind the Comprehension of the Polygenic Influence on Oxidative Stress, Immune Deregulation, and Mitochondrial Dysfunction in Chronic Kidney Disease.

Chronic kidney disease (CKD) is an increasing and global health problem with a great economic burden for healthcare system. Therefore to slow down the progression of this condition is a main objective in nephrology. It has been extensively reported that microinflammation, immune system deregulation, and oxidative stress contribute to CKD progression. Additionally, dialysis worsens this clinical condition because of the contact of blood with bioincompatible dialytic devices. Numerous studies have shown the close link between immune system impairment and CKD but most have been performed using classical biomolecular strategies. These methodologies are limited in their ability to discover new elements and enable measuring the simultaneous influence of multiple factors. The "omics" techniques could overcome these gaps. For example, transcriptomics has revealed that mitochondria and inflammasome have a role in pathogenesis of CKD and are pivotal elements in the cellular alterations leading to systemic complications. We believe that a larger employment of this technique, together with other "omics" methodologies, could help clinicians to obtain new pathogenetic insights, novel diagnostic biomarkers, and therapeutic targets. Finally, transcriptomics could allow clinicians to personalize therapeutic strategies according to individual genetic background (nutrigenomic and pharmacogenomic). In this review, we analyzed the available transcriptomic studies involving CKD patients

Involvement of heparanase in the pathogenesis of acute kidney injury: Nephroprotective effect of PG545

Despite the high prevalence of acute kidney injury (AKI) and its association with increased morbidity and mortality, therapeutic approaches for AKI are disappointing. This is largely attributed to poor understanding of the pathogenesis of AKI. Heparanase, an endoglycosidase that cleaves heparan sulfate, is involved in extracellular matrix turnover, inflammation, kidney dysfunction, diabetes, fibrosis, angiogenesis and cancer progression. The current study examined the involvement of heparanase in the pathogenesis of ischemic reperfusion (I/R) AKI in a mouse model and the protective effect of PG545, a potent heparanase inhibitor. I/R induced tubular damage and elevation in serum creatinine and blood urea nitrogen to a higher extent in heparanase over-expressing transgenic mice vs. wild type mice. Moreover, TGF-\u3b2, vimentin, fibronectin and \u3b1-smooth muscle actin, biomarkers of fibrosis, and TNF\u3b1, IL6 and endothelin-1, biomarkers of inflammation, were upregulated in I/R induced AKI, primarily in heparanase transgenic mice, suggesting an adverse role of heparanase in the pathogenesis of AKI. Remarkably, pretreatment of mice with PG545 abolished kidney dysfunction and the up-regulation of heparanase, pro-inflammatory (i.e., IL-6) and pro-fibrotic (i.e., TGF-\u3b2) genes induced by I/R. The present study provides new insights into the involvement of heparanase in the pathogenesis of ischemic AKI.Our results demonstrate that heparanase plays a deleterious role in the development of renal injury and kidney dysfunction,attesting heparanase inhibition as a promising therapeutic approach for AKI

In vitro effects of interleukin (IL)-1 beta inhibition on the epithelial-to-mesenchymal transition (EMT) of renal tubular and hepatic stellate cells

BACKGROUND: The epithelial to mesenchymal transition (EMT) is a multi-factorial biological mechanism involved in renal and hepatic fibrosis and the IL-1 beta has been assumed as a mediator of this process although data are not exhaustive. Therefore, the aim of our study was to evaluate the role of this cytokine in the EMT of renal proximal tubular epithelial cells (HK-2) and stellate cells (LX-2) and the protective/anti-fibrotic effect of its inhibition by Canakinumab (a specific human monoclonal antibody targeted against IL-1beta). METHODS: Both cell types were treated with IL-1 beta (10 ng/ml) for 6 and 24 h with and without Canakinumab (5 \u3bcg/ml). As control we used TGF-beta (10 ng/ml). Expression of EMT markers (vimentin, alpha-SMA, fibronectin) were evaluated through western blotting and immunofluorescence. Genes expression for matrix metalloproteinases (MMP)-2 was measured by Real-Time PCR and enzymatic activity by zymography. Cellular motility was assessed by scratch assay. RESULTS: IL-1 beta induced a significant up-regulation of EMT markers in both cell types and increased the MMP-2 protein expression and enzymatic activity, similarly to TGF-beta. Moreover, IL-1 beta induced a higher rate of motility in HK-2. Canakinumab prevented all these modifications in both cell types. CONCLUSIONS: Our results clearly demonstrate the role of IL-1 beta in the EMT of renal/stellate cells and it underlines, for the first time, the therapeutic potential of its specific inhibition on the prevention/minimization of organ fibrosis

Epithelial to mesenchymal transition in the liver field: the double face of Everolimus in vitro.

Everolimus (EVE), a mammalian target of rapamycin inhibitor, has been proposed as liver transplant immunosuppressive drug, gaining wide interest also for the treatment of cancer. Although an appropriate tolerance, it may induce several adverse effects, such as fibro-interstitial pneumonitis due to the acquisition of activated myofibroblasts. The exact molecular mechanism associated with epithelial to mesenchymal transition (EMT) may be crucial also in the liver context. This work examines the role and the molecular mediators of EMT in hepatic stellate cell (HSC) and human liver cancer cells (HepG2) and the potential role of EVE to maintain the epithelial phenotype rather than to act as a potential initiators of EMT.Real time-PCR and western blot have been used to assess the capability of EVE at low-therapeutic (10 nM) and high (100 nM) dose to induce an in vitro EMT in HSC and HepG2.Biomolecular experiments demonstrated that low concentration of EVE (10 nM) did not modify the gene expression of alpha-smooth muscle actin (α-SMA), Vimentin (VIM), Fibronectin (FN) in both HSC and HepG2 cells, whereas EVE at 100 nM induced a significant over-expression of all the three above-mentioned genes and an increment of α-SMA and FN protein levels. Additionally, 100 nM of EVE induced a significant phosphorylation of AKT and an up-regulation of TGF-β expression in HSC and HepG2 cells.Our data, although obtained in an in vitro model, revealed, for the first time, that high concentration of EVE may induce EMT in liver cells confirming previous published evidences obtained in renal cells. Additionally, they suggested that mTOR-I should be administered at the lowest dose able to maximize their important and specific therapeutic properties minimizing or avoiding fibrosis-related adverse effects.In summary, if confirmed by additional studies, our results could be useful for researchers to standardize new therapeutic immunosuppressive and anticancer drugs protocols