Methotrexate enhances the anti-inflammatory effect of CF101 via up-regulation of the A(3 )adenosine receptor expression

Methotrexate (MTX) exerts an anti-inflammatory effect via its metabolite adenosine, which activates adenosine receptors. The A(3 )adenosine receptor (A(3)AR) was found to be highly expressed in inflammatory tissues and peripheral blood mononuclear cells (PBMCs) of rats with adjuvant-induced arthritis (AIA). CF101 (IB-MECA), an A(3)AR agonist, was previously found to inhibit the clinical and pathological manifestations of AIA. The aim of the present study was to examine the effect of MTX on A(3)AR expression level and the efficacy of combined treatment with CF101 and MTX in AIA rats. AIA rats were treated with MTX, CF101, or both agents combined. A(3)AR mRNA, protein expression and exhibition were tested in paw and PBMC extracts from AIA rats utilizing immunohistochemistry staining, RT-PCR and Western blot analysis. A(3)AR level was tested in PBMC extracts from patients chronically treated with MTX and healthy individuals. The effect of CF101, MTX and combined treatment on A(3)AR expression level was also tested in PHA-stimulated PBMCs from healthy individuals and from MTX-treated patients with rheumatoid arthritis (RA). Combined treatment with CF101 and MTX resulted in an additive anti-inflammatory effect in AIA rats. MTX induced A(2A)AR and A(3)AR over-expression in paw cells from treated animals. Moreover, increased A(3)AR expression level was detected in PBMCs from MTX-treated RA patients compared with cells from healthy individuals. MTX also increased the protein expression level of PHA-stimulated PBMCs from healthy individuals. The increase in A(3)AR level was counteracted in vitro by adenosine deaminase and mimicked in vivo by dipyridamole, demonstrating that receptor over-expression was mediated by adenosine. In conclusion, the data presented here indicate that MTX induces increased A(3)AR expression and exhibition, thereby potentiating the inhibitory effect of CF101 and supporting combined use of these drugs to treat RA

Methotrexate enhances the anti-inflammatory effect of CF101 via up-regulation of the A(3 )adenosine receptor expression

Methotrexate (MTX) exerts an anti-inflammatory effect via its metabolite adenosine, which activates adenosine receptors. The A(3 )adenosine receptor (A(3)AR) was found to be highly expressed in inflammatory tissues and peripheral blood mononuclear cells (PBMCs) of rats with adjuvant-induced arthritis (AIA). CF101 (IB-MECA), an A(3)AR agonist, was previously found to inhibit the clinical and pathological manifestations of AIA. The aim of the present study was to examine the effect of MTX on A(3)AR expression level and the efficacy of combined treatment with CF101 and MTX in AIA rats. AIA rats were treated with MTX, CF101, or both agents combined. A(3)AR mRNA, protein expression and exhibition were tested in paw and PBMC extracts from AIA rats utilizing immunohistochemistry staining, RT-PCR and Western blot analysis. A(3)AR level was tested in PBMC extracts from patients chronically treated with MTX and healthy individuals. The effect of CF101, MTX and combined treatment on A(3)AR expression level was also tested in PHA-stimulated PBMCs from healthy individuals and from MTX-treated patients with rheumatoid arthritis (RA). Combined treatment with CF101 and MTX resulted in an additive anti-inflammatory effect in AIA rats. MTX induced A(2A)AR and A(3)AR over-expression in paw cells from treated animals. Moreover, increased A(3)AR expression level was detected in PBMCs from MTX-treated RA patients compared with cells from healthy individuals. MTX also increased the protein expression level of PHA-stimulated PBMCs from healthy individuals. The increase in A(3)AR level was counteracted in vitro by adenosine deaminase and mimicked in vivo by dipyridamole, demonstrating that receptor over-expression was mediated by adenosine. In conclusion, the data presented here indicate that MTX induces increased A(3)AR expression and exhibition, thereby potentiating the inhibitory effect of CF101 and supporting combined use of these drugs to treat RA

On the validity of the centrality hypothesis in cross-sectional between-subject networks of psychopathology

Background In the network approach to psychopathology, psychiatric disorders are considered networks of causally active symptoms (nodes), with node centrality hypothesized to reflect symptoms’ causal influence within a network. Accordingly, centrality measures have been used in numerous network-based cross-sectional studies to identify specific treatment targets, based on the assumption that deactivating highly central nodes would proliferate to other nodes in the network, thereby collapsing the network structure and alleviating the overall psychopathology (i.e., the centrality hypothesis). Methods Here, we summarize three types of evidence pertaining to the centrality hypothesis in psychopathology. First, we discuss the validity of the theoretical assumptions underlying the centrality hypothesis in psychopathology. We then summarize the methodological aspects of extant studies using centrality measures as predictors of symptom change following treatment, while delineating their main findings and several of their limitations. Finally, using a specific dataset of 710 treatment-seeking patients with posttraumatic stress disorder (PTSD) as an example, we empirically examine node centrality as a predictor of therapeutic change, replicating the approach taken by previous studies, while addressing some of their limitations. Specifically, we investigated whether three pre-treatment centrality indices (strength, predictability, and expected influence) were significantly correlated with the strength of the association between a symptom’s change and the change in the severity of all other symptoms in the network from pre- to post-treatment (Δnode-Δnetwork association). Using similar analyses, we also examine the predictive validity of two simple non-causal node properties (mean symptom severity and infrequency of symptom endorsement). Results Of the three centrality measures, only expected influence successfully predicted how strongly changes in nodes/symptoms were associated with change in the remainder of the nodes/symptoms. Importantly, when excluding the amnesia node, a well-documented outlier in the phenomenology of PTSD, none of the tested centrality measures predicted symptom change. Conversely, both mean symptom severity and infrequency of symptom endorsement, two standard non-network-derived indices, were found to be more predictive than expected influence and remained significantly predictive also after excluding amnesia from the network analyses. Conclusions The centrality hypothesis in its current form is ill-defined, showing no consistent supporting evidence in the context of cross-sectional, between-subject networks

Modular ‘Click-in-Emulsion’ Bone-Targeted Nanogels

A new class of nanogel demonstrates modular biodistribution and affinity for bone. Nanogels, ~70 nm in diameter and synthesized via an astoichiometric click-chemistry in-emulsion method, controllably display residual, free clickable functional groups. Functionalization with a bisphosphonate ligand results in significant binding to bone on the inner walls of marrow cavities, liver avoidance, and anti-osteoporotic effects.National Institutes of Health (U.S.) (RO1 DE016516)National Institutes of Health (U.S.) (R01 EB000244)Damon Runyon Cancer Research Foundation (DFS-#2050-10

Noncoding deletions reveal a gene that is critical for intestinal function.

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes

Globalization and the "Cooperative Difference"

Opposing logics support the global capital market and cooperatives. The first, in its pursuit of maximum gain, tends to detach itself from non-economic considerations. The latter, in their pursuit of maximum member and community servicing, have to subordinate the economic to social and other meta-economic considerations if they want to preserve their difference and raison d' etre. For the purpose of this paper and drawing on Polanyi, the separateness of the economic from other institutions of society will be denoted as disembeddedness and its contrary as embeddedness. The disembeddedness/embeddedness phenomenon can be observed at the micro and macro level and is viewed here as strongly related to the "cooperative difference". It is argued that: I) the greater the degree of disembeddedness in a cooperative, the less it is likely to differ from non-cooperative organizations, mainly investor owned firms (IOFs); 2) the greater the degree of embeddedness in a cooperative, the more it is likely to differ from other organizations; 3) the greater the degree of global disembeddedness, the greater the capacity of mainstream economics to weaken the cooperatives; 4) the greater the degree of global embeddedness, the greater the cooperatives' capacity for asserting and defending their difference. These propositions are put to the test of empirical experiences

Beyond Traditional Models: Multi-Stakeholder Cooperatives and their Differential Roles

The multi-stakeholder cooperative emerges as an innovative organization departing from the traditional single-stakeholder consumer and producer models. The multi-stakeholding approach aims at broadening the scope of those who have a strong stake in the cooperative's success. This, however, is not necessarily related to the notion of membership. This article develops this point drawing upon two distinct cases: on the one -hand the "hybrid" cooperative, characterized by the figure of the external investor and, on the other hand, the newly emerging multi-stakeholder cooperatives characterized by a strong community and social alternative orientation. It is argued that the two organizational types widely differ as to their short-term objectives and broader implications. Further to a theoretical introduction, practical examples illustrate the differential roles of both types at a time of growing market competition

Kibbutz, Cooperation and the Issue of Embeddedness

The contemporary kibbutz is the best exemplification of the fifth and last stage of cooperative development envisaged by the Rochdale Pioneers when they opened their consumer store in 1844. This closeness to the modern cooperative movement at its birth, however, didn't contribute to a feeling of belonging to a "cooperative family". Throughout the years, despite its formal cooperative incorporation, the kibbutz considered itself as a meta-cooperative phenomenon. The idea that, being situated at the apex of a pyramid of levels of cooperative integration, might confer on the kibbutz the task of extending self-management - as a social resource - to other segments of society, never became part of its political-ideological agenda. On the other hand, the Israeli society seems to badly need alternatives to such prevailing patterns as over-consumption, selfinterest and profit-seeking. When properly understood and implemented, the cooperative model can offer a valid alternative by subordinating the economic component to the social one. The first is embedded in the latter, in a system which - by definition - remunerates participation rather than capital. It is argued that failure to see the kibbutz as part of a macro network of horizontal solidary links, prevented it from acting as an outward-oriented "change agent" of cooperation and possibly contributed to weaken its inner structure as a comprehensive all-village cooperative. Both levels - the micro local and the macro national - seem to be at a loss