The inhibitor of differentiation-2 promotes synovial fibroblast-dependent osteoclastogenesis in rheumatoid arthritis

Objectives: Despite indirect evidence suggesting that low oxygen levels might occur in the rheumatoid arthritis (RA) synovium, direct proof of the presence of hypoxia in the arthritic synovium as well as the relevance of low oxygen levels for joint destruction is lacking. The aim of this study was to analyse the distribution of hypoxia in arthritic joints and to evaluate the molecular effects of the hypoxic environment on the phenotype of RA synovial fibroblasts (SF).<p></p> Methods: The hypoxia marker EF-5 was applied in mice with the collagen-induced arthritis (CIA). Expression profile analysis with hypoxic and normoxic SF was performed using subtractive hybridization and microarray. The expression of the inhibitor of differentiation-2 (Id-2), CD68 (macrophage marker) and prolyl hydroxylase (fibroblast marker) was evaluated by immunohistochemistry on synovial tissues from RA, osteoarthritis patients and CIA mice. To evaluate the function of Id-2 in SF, cells were transfected with the pcDNA3.1 containing cDNA for Id-2 or Id-2-specific siRNA or mock controls. The expression of Id-2 and genes regulated by Id-2 in transfected SF was evaluated by SYBR Green real-time PCR and western blot. SF stably transfected with Id-2 were cocultured with bone marrow cells in a transwell system. The expression of the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin were measured by real-time PCR. The development of osteoclasts was evaluated by visualization of the activity of tartrate-resistant acid phosphatase.<p></p> Results: Using the hypoxia marker EF-5 we found that in mice with CIA, synovial cells invading bone and cartilage are exposed to reduced oxygen levels. Expression profile studies identified Id-2 as being upregulated under low oxygen conditions. In addition, IL-1beta stimulation increased the expression of Id-2 in these cells. Histological studies of RA synovium and CIA synovium showed strong expression of Id-2 in SF at sites of synovial invasion into bone. Overproduction of Id-2 in SF by stable transfection triggered the expression of several genes promoting osteoclastogenesis, including BMP-2, PTHrP, Wnt5a and vascular endothelial growth factor. Conversely, the suppression of endogenous Id-2 led to the downregulation of the expression of these molecules. Consistent with these findings coculture of Id-2 transfected SF with bone marrow cells increased the expression of the osteoclast differentiation factor RANKL, and decreased the expression of the osteoclast inhibitory factor osteoprotegerin in bone marrow stromal cells, which was followed by an increase in the number of osteoclasts.<p></p> Conclusion: Taken together, our data provide evidence that hypoxia is present at sites of synovial invasion in RA and that Id-2 induced by hypoxia contributes at these sites to joint destruction by promoting SF-dependent osteoclastogenesis

Economic and environmental strategic water management in the shale gas industry: Application of cooperative game theory

In this work, a mixed‐integer linear programming (MILP) model is developed to address optimal shale gas‐water management strategies among shale gas companies that operate relatively close. The objective is to compute a distribution of water‐related costs and profit among shale companies to achieve a stable agreement on cooperation among them that allows increasing total benefits and reducing total costs and environmental impacts. We apply different solution methods based on cooperative game theory: The Core, the Dual Core, the Shapley value, and the minmax Core. We solved different case studies including a large problem involving four companies and 207 wells. In this example, individual cost distribution (storage cost, freshwater withdrawal cost, transportation cost, and treatment cost) assigned to each player is included. The results show that companies that adopt cooperation strategies improve their profits and enhance the sustainability of their operations through the increase in recycled water.The authors gratefully acknowledge the financial support by the Ministry of Economy, Industry, and Competitiveness from Spain, under the projects CTQ2016-77968-C3-1-P and CTQ2016-77968-C3-2-P (AEI/FEDER, UE)

Bilateral synchronous occurrence of three different histological types of renal tumor: a case report

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Crossings, Motzkin paths and Moments

Kasraoui, Stanton and Zeng, and Kim, Stanton and Zeng introduced certain $q$-analogues of Laguerre and Charlier polynomials. The moments of these orthogonal polynomials have combinatorial models in terms of crossings in permutations and set partitions. The aim of this article is to prove simple formulas for the moments of the $q$-Laguerre and the $q$-Charlier polynomials, in the style of the Touchard-Riordan formula (which gives the moments of some $q$-Hermite polynomials, and also the distribution of crossings in matchings). Our method mainly consists in the enumeration of weighted Motzkin paths, which are naturally associated with the moments. Some steps are bijective, in particular we describe a decomposition of paths which generalises a previous construction of Penaud for the case of the Touchard-Riordan formula. There are also some non-bijective steps using basic hypergeometric series, and continued fractions or, alternatively, functional equations.Comment: 21 page

Phytochemicals Analysis and Medicinal Potentials of Hydroalcoholic Extract from Curtisia dentata (Burm.f) C.A. Sm Stem Bark

Curtisia dentata (CD) is a vulnerable medicinal plant used for the treatment of stomach ailments in South Africa. However, there is a lack of sufficient data on its phytochemical components and medicinal properties. The phytochemical analysis of the extract was estimated using standard assay methods while its antibacterial activity was determined by the agar dilution method against selected bacteria. The antioxidant activity of the extract was done using ferric reducing power, 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic-acid (ABTS), nitric oxide (NO), hydrogen peroxide (H2O2) and lipid peroxidation (LPO). The cytotoxicity assay of the extract was assessed using the brine shrimp lethality test with LC50 value of 0.302 mg/mL. The antibacterial activity of the extract demonstrated an appreciable broad spectrum activity against the tested bacteria with minimum inhibitory concentration (MIC) ranges between 5000 and 0.5 mg/L. Both phenol and flavonoid concentrations were 14.86 mg tannic acid equivalent/g and 13.64 mg quercetin equivalent/g, respectively. The percentage composition of saponins (13.26) was highest, followed by steroids (1.42), while alkaloids and tannins had the same value of 0.51. Similarly, IC50 values of the extract against DPPH, ABTS, H2O2, LPO and NO were 0.017, 0.018, 0.159, 0.06 and 0.052 mg/mL, respectively. The reducing power of the extract was found to be concentration dependent. Our data suggest that the 70% ethanol extract from the CD extract has antibacterial and antioxidant properties due to the presence of bio-active compounds and thus support its folkloric use in the treatment of diseases

Predicting Impaired Extinction of Traumatic Memory and Elevated Startle

Emotionally traumatic experiences can lead to debilitating anxiety disorders, such as phobias and Post-Traumatic Stress Disorder (PTSD). Exposure to such experiences, however, is not sufficient to induce pathology, as only up to one quarter of people exposed to such events develop PTSD. These statistics, combined with findings that smaller hippocampal size prior to the trauma is associated with higher risk of developing PTSD, suggest that there are pre-disposing factors for such pathology. Because prospective studies in humans are limited and costly, investigating such pre-dispositions, and thus advancing understanding of the genesis of such pathologies, requires the use of animal models where predispositions are identified before the emotional trauma. Most existing animal models are retrospective: they classify subjects as those with or without a PTSD-like phenotype long after experiencing a traumatic event. Attempts to create prospective animal models have been largely unsuccessful.Here we report that individual predispositions to a PTSD-like phenotype, consisting of impaired rate and magnitude of extinction of an emotionally traumatic event coupled with long-lasting elevation of acoustic startle responses, can be revealed following exposure to a mild stressor, but before experiencing emotional trauma. We compare, in rats, the utility of several classification criteria and report that a combination of criteria based on acoustic startle responses and behavior in an anxiogenic environment is a reliable predictor of a PTSD-like phenotype.There are individual predispositions to developing impaired extinction and elevated acoustic startle that can be identified after exposure to a mildly stressful event, which by itself does not induce such a behavioral phenotype. The model presented here is a valuable tool for studying the etiology and pathophysiology of anxiety disorders and provides a platform for testing behavioral and pharmacological interventions that can reduce the probability of developing pathologic behaviors associated with such disorders

Borcherds Algebras and N=4 Topological Amplitudes

The perturbative spectrum of BPS-states in the E_8 x E_8 heterotic string theory compactified on T^2 is analysed. We show that the space of BPS-states forms a representation of a certain Borcherds algebra G which we construct explicitly using an auxiliary conformal field theory. The denominator formula of an extension G_{ext} \supset G of this algebra is then found to appear in a certain heterotic one-loop N=4 topological string amplitude. Our construction thus gives an N=4 realisation of the idea envisioned by Harvey and Moore, namely that the `algebra of BPS-states' controls the threshold corrections in the heterotic string.Comment: 39 page