The development of high-throughput DNA sequencing technologies has enabled large-scale characterization of functional antibody repertoires, a new method of understanding protective and pathogenic ...immune responses. Important parameters to consider when sequencing antibody repertoires include the methodology, the B-cell population and clinical characteristics of the individuals analysed, and the bioinformatic analysis. Although focused sequencing of immunoglobulin heavy chains or complement determining regions can be utilized to monitor particular immune responses and B-cell malignancies, high-fidelity analysis of the full-length paired heavy and light chains expressed by individual B cells is critical for characterizing functional antibody repertoires. Bioinformatic identification of clonal antibody families and recombinant expression of representative members produces recombinant antibodies that can be used to identify the antigen targets of functional immune responses and to investigate the mechanisms of their protective or pathogenic functions. Integrated analysis of coexpressed functional genes provides the potential to further pinpoint the most important antibodies and clonal families generated during an immune response. Sequencing antibody repertoires is transforming our understanding of immune responses to autoimmunity, vaccination, infection and cancer. We anticipate that antibody repertoire sequencing will provide next-generation biomarkers, diagnostic tools and therapeutic antibodies for a spectrum of diseases, including rheumatic diseases.
Rheumatoid arthritis (RA) is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability. Though prior studies have demonstrated ...the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear. To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA. To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1-12 years prior to disease onset. We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines. We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing). We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes. At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA. Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-α, IL-6, IL-12p70, and IFN-γ. Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread. Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This ambitious volume chronicles and analyzes from a critical globalization perspective the social, economic, and political changes sweeping across Latin America from the 1970s through the present ...day. Sociologist William I. Robinson summarizes his theory of globalization and discusses how Latin America’s political economy has changed as the states integrate into the new global production and financial system, focusing specifically on the rise of nontraditional agricultural exports, the explosion of maquiladoras, transnational tourism, and the export of labor and the import of remittances. He follows with an overview of the clash among global capitalist forces, neoliberalism, and the new left in Latin America, looking closely at the challenges and dilemmas resistance movements face and their prospects for success.
Through three case studies—the struggles of the region's indigenous peoples, the immigrants rights movement in the United States, and the Bolivarian Revolution in Venezuela—Robinson documents and explains the causes of regional socio-political tensions, provides a theoretical framework for understanding the present turbulence, and suggests possible outcomes to the conflicts.
Based on years of fieldwork and empirical research, this study elucidates the tensions that globalization has created and shows why Latin America is a battleground for those seeking to shape the twenty-first century’s world order.
•Novel stored-value card fraud detection system.•Novel use of hidden Markov model for modeling merchant transactions.•Findings on data from a large stored-value card transaction processor.•Findings ...on experiments evaluating the model quality under various conditions.
Stored-value cards, or prepaid cards, are increasingly popular. Like credit cards, their use is vulnerable to fraud, costing merchants and card processors millions of dollars. Prior techniques to automate fraud detection rely on a priori rules or specialized learned models associated with the customer. Mostly, these techniques do not consider fraud sequences or changing behavior, which can lead to false alarms. This study demonstrates how a transaction model can be dynamically created and updated, and fraud can be automatically detected for prepaid cards. A card processing company creates models of the store terminals rather than the customers, in part, because of the anonymous nature of prepaid cards. The technique automatically creates, updates, and compares hidden Markov models (HMM) of merchant terminals. We present fraud detection and experiments on real transactional data, showing the efficiency and effectiveness of the approach. In the fraud test cases, derived from known fraud cases, the technique has a good F-score. The technique can detect fraud in real-time for merchants, as card transactions are processed by a modern transaction processing system.
Osteoarthritis (OA) has long been viewed as a degenerative disease of cartilage, but accumulating evidence indicates that inflammation has a critical role in its pathogenesis. Furthermore, we now ...appreciate that OA pathogenesis involves not only breakdown of cartilage, but also remodelling of the underlying bone, formation of ectopic bone, hypertrophy of the joint capsule, and inflammation of the synovial lining. That is, OA is a disorder of the joint as a whole, with inflammation driving many pathologic changes. The inflammation in OA is distinct from that in rheumatoid arthritis and other autoimmune diseases: it is chronic, comparatively low-grade, and mediated primarily by the innate immune system. Current treatments for OA only control the symptoms, and none has been FDA-approved for the prevention or slowing of disease progression. However, increasing insight into the inflammatory underpinnings of OA holds promise for the development of new, disease-modifying therapies. Indeed, several anti-inflammatory therapies have shown promise in animal models of OA. Further work is needed to identify effective inhibitors of the low-grade inflammation in OA, and to determine whether therapies that target this inflammation can prevent or slow the development and progression of the disease.
Individuals at high risk of developing seropositive rheumatoid arthritis (RA) can be identified for translational research and disease prevention studies through the presence of highly informative ...and predictive patterns of RA-related autoantibodies, especially anti-citrullinated protein antibodies (ACPAs), in the serum. In serologically positive individuals without arthritis, designated ACPA positive at risk, the presence of mucosal inflammatory processes associated with the presence of local ACPA production has been demonstrated. In other at-risk populations, local RA-related autoantibody production is present even in the absence of serum autoantibodies. Additionally, a proportion of at-risk individuals exhibit local mucosal ACPA production in the lung, as well as radiographic small-airway disease, sputum hypercellularity and increased neutrophil extracellular trap formation. Other mucosal sites in at-risk individuals also exhibit autoantibody production, inflammation and/or evidence of dysbiosis. As the proportion of individuals who exhibit such localized inflammation-associated ACPA production is substantially higher than the likelihood of an individual developing future RA, this finding raises the hypothesis that mucosal ACPAs have biologically relevant protective roles. Identifying the mechanisms that drive both the generation and loss of externally focused mucosal ACPA production and promote systemic autoantibody expression and ultimately arthritis development should provide insights into new therapeutic approaches to prevent RA.
It is commonplace for observers to see the increasingly prominent role of the BRICS in international economic and political affairs as a Southern challenge to global capitalism and the power of the ...core Trilateral nation-states. Extant accounts remain mired in a tenacious realist debate over the extent to which the BRICS are challenging the prevailing international order. I suggest that we shift the paradigmatic focus in discussion of the BRICS phenomenon towards a global capitalism perspective that breaks with such a nation-state/inter-state framework. Global integration and transnational capitalist class formation has advanced significantly in the BRICS. BRICS protagonism is aimed less at challenging the prevailing international order than at opening up space in the global system for more extensive integration and a less asymmetric global capitalism. The article examines agricultural subsidies, US-China relations and international trade agreements as empirical reference points in arguing that the concept of the transnational state provides a more satisfying explanatory framework for understanding the BRICS phenomenon than the variety of realist approaches. By misreading the BRICS critical scholars and the global left run the risk of becoming cheerleaders for repressive states and transnational capitalists in the South. We would be better off by a denouement of the BRICS states and siding with 'BRICS from below' struggles of popular and working class forces.
The standard method for the storage and preservation of RNA has been at ultra-low temperatures. However, reliance on liquid nitrogen and freezers for storage of RNA has multiple downsides. Recently ...new techniques have been developed for storing RNA at room temperature utilizing desiccation and are reported to be an effective alternative for preserving RNA integrity. In this study we compared frozen RNA samples stored for up to one year to those which had been desiccated using RNAstable (Biomatrica, Inc., San Diego, CA) and stored at room temperature. RNA samples were placed in aliquots and stored after desiccation or frozen (at -80°C), and were analyzed for RNA Integrity Number (RIN), and by qPCR, and RNA sequencing. Our study shows that RNAstable is able to preserve desiccated RNA samples at room temperature for up to one year, and that RNA preserved by desiccation is comparable to cryopreserved RNA for downstream analyses including real-time-PCR and RNA sequencing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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