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

O Mapa das Cortes: perspectivas cartográficas

O presente trabalho realiza uma análise exaustiva do Mapa das Cortes, aplicando critérios da cartografia, em particular da cartografia matemática. Assim, analisam-se: autor, escala, projeção, meridiano de origem, cores, convenções, simbologia e outros. Após uma análise morfológica qualitativa, passa-se a um exame quantitativo, comparando esse mapa com um atual, bastante preciso: com o auxílio de um programa de cartografia digital e uma planilha eletrônica foram comparadas as coordenadas geográficas (latitude e longitude) de mais de 430 pontos. A quantificação sistemática e detalhada dos erros em diferentes regiões, da costa atlântica à região amazônica, mostrou aspectos surpreendentes de como o Mapa das Cortes (MC) foi habilmente construído. Essa análise permitiu quantificar de maneira mais precisa as distorções, identificando em que locais foram introduzidas e seu caráter indubitavelmente proposital.In this paper, we present a thorough analysis of the Map of the Courts based on criteria used in cartography, particularly mathematical cartography. As such, it takes into account the following elements: author, scale, projection, the prime meridian, colors, conventions, symbology, and other. After a qualitative morphological analysis, we move on to a quantitative examination by comparing the said map with a quite accurate present-day chart, using a digital cartography software application and spreadsheet to match the geographic coordinates (latitude and longitude) of over 430 points. The systematic and detailed quantification of errors in various areas, from the Atlantic coast to the Amazon region, revealed surprising aspects as to how skillfully the Map of the Courts was constructed. This analysis enabled us to quantify the distortions more accurately and thus identify the locations where they were introduced as well their unquestionable intentional character

A New Linear Logic for Deadlock-Free Session-Typed Processes

The π -calculus, viewed as a core concurrent programming language, has been used as the target of much research on type systems for concurrency. In this paper we propose a new type system for deadlock-free session-typed π -calculus processes, by integrating two separate lines of work. The first is the propositions-as-types approach by Caires and Pfenning, which provides a linear logic foundation for session types and guarantees deadlock-freedom by forbidding cyclic process connections. The second is Kobayashi’s approach in which types are annotated with priorities so that the type system can check whether or not processes contain genuine cyclic dependencies between communication operations. We combine these two techniques for the first time, and define a new and more expressive variant of classical linear logic with a proof assignment that gives a session type system with Kobayashi-style priorities. This can be seen in three ways: (i) as a new linear logic in which cyclic structures can be derived and a CYCLE -elimination theorem generalises CUT -elimination; (ii) as a logically-based session type system, which is more expressive than Caires and Pfenning’s; (iii) as a logical foundation for Kobayashi’s system, bringing it into the sphere of the propositions-as-types paradigm

Superconductivity of bulk CaC6

We have obtained bulk samples of the graphite intercalation compound, CaC6, by a novel method of synthesis from highly oriented pyrolytic graphite. The crystal structure has been completely determined showing that it is the only member of the MC6, metal-graphite compounds, which has rhombohedral symmetry. We have clearly shown the occurrence of superconductivity in the bulk sample at 11.5K, using magnetization measurements.Comment: 8 pages of text + 4 figures = 12 page

Untyping Typed Algebras and Colouring Cyclic Linear Logic

We prove "untyping" theorems: in some typed theories (semirings, Kleene algebras, residuated lattices, involutive residuated lattices), typed equations can be derived from the underlying untyped equations. As a consequence, the corresponding untyped decision procedures can be extended for free to the typed settings. Some of these theorems are obtained via a detour through fragments of cyclic linear logic, and give rise to a substantial optimisation of standard proof search algorithms.Comment: 21

Analysis of skeletal muscle function in the C57BL6/SV129 syncoilin knockout mouse

Syncoilin is a 64-kDa intermediate filament protein expressed in skeletal muscle and enriched at the perinucleus, sarcolemma, and myotendinous and neuromuscular junctions. Due to its pattern of cellular localization and binding partners, syncoilin is an ideal candidate to be both an important structural component of myocytes and a potential mediator of inherited myopathies. Here we present a report of a knockout mouse model for syncoilin and the results of an investigation into the effect of a syncoilin null state on striated muscle function in 6–8-week-old mice. An analysis of proteins known to associate with syncoilin showed that ablation of syncoilin had no effect on absolute expression or spatial localization of desmin or alpha dystrobrevin. Our syncoilin-null animal exhibited no differences in cardiotoxin-induced muscle regeneration, voluntary wheel running, or enforced treadmill exercise capacity, relative to wild-type controls. Finally, a mechanical investigation of isolated soleus and extensor digitorum longus indicated a potential differential reduction in muscle strength and resilience. We are the first to present data identifying an increased susceptibility to muscle damage in response to an extended forced exercise regime in syncoilin-deficient muscle. This study establishes a second viable syncoilin knockout model and highlights the importance of further investigations to determine the role of syncoilin in skeletal muscle

Imaging in the time of NFD/NSF: do we have to change our routines concerning renal insufficiency?

To date there are potential chronology-based but not conclusive reasons to believe that at least some of the gadolinium complexes play a causative role in the pathophysiology of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). Still, the exact pathogenesis and the risk for patients is unclear beside the obvious connection to moderate to severe renal insufficiency. So far, MR imaging with Gd-enhancement was regarded as the safest imaging modality in these patients—the recent development creates tremendous uncertainty in the MR-community. Nevertheless, one should remember that, despite the over 200 cases of NSF and about 100 with proven involvement of Gd3+, the vast majority of over 200 million patients exposed to gadolinium since the 1980s have tolerated these agents well. Importantly, NSF is a rare disease and does not appear to occur in patients without renal impairment. Many patients and researchers have undergone MR investigations with Gd exposure in the past. For those, it is essential to know about the safety of the agents at normal renal function. We can hope that pharmacoepidemiological and preclinical studies will allow us to better understand the pathophysiology and role of the various MR contrast agents in the near future

Islet Oxygen Consumption Rate (OCR) Dose Predicts Insulin Independence in Clinical Islet Autotransplantation

Background: Reliable in vitro islet quality assessment assays that can be performed routinely, prospectively, and are able to predict clinical transplant outcomes are needed. In this paper we present data on the utility of an assay based on cellular oxygen consumption rate (OCR) in predicting clinical islet autotransplant (IAT) insulin independence (II). IAT is an attractive model for evaluating characterization assays regarding their utility in predicting II due to an absence of confounding factors such as immune rejection and immunosuppressant toxicity. Methods: Membrane integrity staining (FDA/PI), OCR normalized to DNA (OCR/DNA), islet equivalent (IE) and OCR (viable IE) normalized to recipient body weight (IE dose and OCR dose), and OCR/DNA normalized to islet size index (ISI) were used to characterize autoislet preparations (n = 35). Correlation between pre-IAT islet product characteristics and II was determined using receiver operating characteristic analysis. Results: Preparations that resulted in II had significantly higher OCR dose and IE dose (p<0.001). These islet characterization methods were highly correlated with II at 6–12 months post-IAT (area-under-the-curve (AUC) = 0.94 for IE dose and 0.96 for OCR dose). FDA/PI (AUC = 0.49) and OCR/DNA (AUC = 0.58) did not correlate with II. OCR/DNA/ISI may have some utility in predicting outcome (AUC = 0.72). Conclusions: Commonly used assays to determine whether a clinical islet preparation is of high quality prior to transplantation are greatly lacking in sensitivity and specificity. While IE dose is highly predictive, it does not take into account islet cell quality. OCR dose, which takes into consideration both islet cell quality and quantity, may enable a more accurate and prospective evaluation of clinical islet preparations