The “elitist approach” to democratization contends that “democratic regimes that last have seldom, if ever, been instituted by mass popular actors” (Huntington 1984:212). This article subjects this ...observation to empirical scrutiny using statistical analyses of new democracies over the past half-century and a case study. Contrary to the elitist approach, I argue that new democracies growing out of mass mobilization are more likely to survive than are new democracies that were born amid quiescence. Survival analysis of 112 young democracies in 80 different countries based on original data shows that the longer the mobilization, the more likely the ensuing democracy is to survive. I use a case study of South Africa to investigate the mechanisms. I argue that sustained unarmed uprisings have generated the longest-lasting new democracies—largely because they are forced to develop an organizational structure, which provides a leadership cadre for the new regime, forges links between the government and society, and strengthens checks on the power of the post-transition government.
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BFBNIB, INZLJ, NMLJ, NUK, OILJ, PNG, SAZU, UKNU, UL, UM, UPUK, ZRSKP
What accounts for the formation and disintegration of social movement alliances? The dominant approach in social movement studies stresses the role of political opportunities and threats in ...facilitating or undermining alliances between oppositional groups. This article argues, by contrast, that the convergence and divergence of contenders' perceptions mediate between political opportunities and shifting alliances. Whereas previous studies conceptualize perceptions as global assessments of actors' environments, I disaggregate three dimensions of the concept: optimism about state elites, optimism about state institutions, and optimism about contentious collective action. The Iranian Reform Movement of 1997 to 2005 offers a nearly ideal case for the study of perceptions and alliances, because it encompasses a variety of opposition groups whose alliances formed and disintegrated over the course of the movement's rise and decline. This article examines shifting perceptions of opportunity among these groups and documents how these perceptions affected alliances, independent of state repression and groups' ultimate goals.
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BFBNIB, INZLJ, NMLJ, NUK, OILJ, PNG, SAZU, UKNU, UL, UM, UPUK, ZRSKP
Novel single-cell-based technologies hold the promise of matching T cell receptor (TCR) sequences with their cognate peptide-MHC recognition motif in a high-throughput manner. Parallel capture of TCR ...transcripts and peptide-MHC is enabled through the use of reagents labeled with DNA barcodes. However, analysis and annotation of such single-cell sequencing (SCseq) data are challenged by dropout, random noise, and other technical artifacts that must be carefully handled in the downstream processing steps. We here propose a rational, data-driven method termed ITRAP (improved T cell Receptor Antigen Paring) to deal with these challenges, filtering away likely artifacts, and enable the generation of large sets of TCR-pMHC sequence data with a high degree of specificity and sensitivity, thus outputting the most likely pMHC target per T cell. We have validated this approach across 10 different virus-specific T cell responses in 16 healthy donors. Across these samples, we have identified up to 1494 high-confident TCR-pMHC pairs derived from 4135 single cells.
The scholarship on the consequences of social revolutions contends that social revolutions boost state capacity and strengthen the state’s developmental projects. Social justice and addressing the ...needs of ordinary citizens were central themes in the discourse of the Iranian Revolution and the Islamic Republic that emerged as the post-revolutionary regime with the fall of the monarchy in Iran. In this essay, I assess the performance of the post-revolutionary state in Iran according to various development indicators, comparing the post-revolutionary regime with the pre-revolutionary regime. My examination of indicators relating to health, education, poverty, income inequality, and housing presents more of a mixed result than the overall improvement that scholarship has anticipated and that the post-revolutionary regime promised. Furthermore, there is evidence of declines in some important areas of development and welfare provision. Based on this analysis, I propose directions for future research on the developmental outcome of revolutions.
Abstract
Over the last several decades, dozens of dictatorships have become democracies. Yet while each has held free and fair elections, they have varied in the extent to which their citizens ...realize the ideal of self-rule. Why do some democracies distribute power to citizens while other democracies withhold it? Existing research is suggestive, but its implications are ambiguous. Cross-national studies have focused on democracy’s formal dimensions, while work on substantive democracy is case-based. We find that one of the most consistent and powerful explanations of substantive democratization is the length of unarmed pro-democratic mobilization prior to a transition. Through a case study of Brazil, we illustrate that these movements matter in three ways: first, because practices of self-organizing model and enable democratic reforms; second, because movement veterans use state office to deepen democracy; and third, because long movements yield civil societies with the capacity to demand the continuous deepening of democracy.
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BFBNIB, DOBA, INZLJ, IZUM, KILJ, NMLJ, NUK, ODKLJ, PILJ, PNG, PRFLJ, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, ZRSKP
Alkaline sphingomyelinase (NPP7) is expressed by intestinal epithelial cells and is crucial for the digestion of dietary sphingomyelin. NPP7 also inactivates proinflammatory mediators including ...platelet-activating factor and lysophosphatidylcholine. The aim of this study was to examine a potential role for NPP7 in the homeostasis of the intestinal immune system.
We quantified the numbers of B-lymphocytes, plasma cells, T-lymphocytes including regulatory T-lymphocytes (T
), natural killer cells, dendritic cells, macrophages, and neutrophils, in the small and large intestines, the mesenteric lymph nodes and the spleens of heterozygous and homozygous NPP7 knockout (KO) and wildtype (WT) mice. Tissues were examined by immunohistochemistry and stainings quantified using computerized image analysis.
The numbers of both small and large intestinal CD3ε
, CD4
, and CD8α
T-lymphocytes were significantly higher in NPP7 KO compared to WT mice (with a dose-response relationship in the large intestine), whereas T
numbers were unchanged, and dendritic cell numbers reduced. In contrast, the numbers of CD3ε
and CD4
T-lymphocytes in mesenteric lymph nodes were significantly reduced in NPP7 KO mice, while no differences were observed in spleens. The numbers of B-lymphocytes, plasma cells, natural killer cells, macrophages, and neutrophils were similar between genotypes.
NPP7 contributes to the regulation of dendritic cell and T-lymphocyte numbers in mesenteric lymph nodes and both the small and large intestines, thus playing a role in the homeostasis of gut immunity. Although it is likely that the downstream effects of NPP7 activity involve the sphingomyelin metabolites ceramide and spingosine-1-phosphate, the exact mechanisms behind this regulatory function of NPP7 need to be addressed in future studies.
Background
Standard care for patients with high-risk myelodysplastic syndrome (MDS) is hypomethylating agents such as azacitidine (AZA), which can induce expression of methylated tumor-associated ...antigens and therefore potentiate immunotherapeutic targeting.
Method
In this phase 1 trial, we combined AZA with a therapeutic peptide vaccine targeting antigens encoded from
NY-ESO-1, MAGE-A3, PRAME,
and
WT-1
, which have previously been demonstrated to be upregulated by AZA treatment.
Result
Five patients who had responded to AZA monotherapy were included in the study and treated with the vaccine. The combination therapy showed only few adverse events during the study period, whereof none classified as serious. However, no specific immune responses could be detected using intracellular cytokine staining or ELISpot assays. Minor changes in the phenotypic composition of immune cells and their expression of stimulatory and inhibitory markers were detected. All patients progressed to AML with a mean time to progression from inclusion (TTP) of 5.2 months (range 2.8 to 7.6). Mean survival was 18.1 months (range 10.9 to 30.6) from MDS diagnosis and 11.3 months (range 4.3 to 22.2) from inclusion. Sequencing of bone marrow showed clonal expansion of malignant cells, as well as appearance of novel mutations.
Conclusion
The patients progressed to AML with an average time of only five months after initiating the combination therapy. This may be unrelated to the experimental treatment, but the trial was terminated early as there was no sign of clinical benefit or immunological response.
Why the manuscript is especially interesting
This study is the first to exploit the potential synergistic effects of combining a multi-peptide cancer vaccine with epigenetic therapy in MDS. Although our results are negative, they emphasize challenges to induce immune reactivity in patients with high-risk MDS.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The majority of neoantigens arise from unique mutations that are not shared between individual patients, making neoantigen-directed immunotherapy a fully personalized treatment approach. Novel ...technical advances in next-generation sequencing of tumor samples and artificial intelligence (AI) allow fast and systematic prediction of tumor neoantigens. This study investigates feasibility, safety, immunity, and anti-tumor potential of the personalized peptide-based neoantigen vaccine, EVX-01, including the novel CD8
+
T-cell inducing adjuvant, CAF®09b, in patients with metastatic melanoma (NTC03715985). The AI platform PIONEER
TM
was used for identification of tumor-derived neoantigens to be included in a peptide-based personalized therapeutic cancer vaccine. EVX-01 immunotherapy consisted of 6 administrations with 5-10 PIONEER
TM
-predicted neoantigens as synthetic peptides combined with the novel liposome-based Cationic Adjuvant Formulation 09b (CAF®09b) to strengthen T-cell responses. EVX-01 was combined with immune checkpoint inhibitors to augment the activity of EVX-01-induced immune responses. The primary endpoint was safety, exploratory endpoints included feasibility, immunologic and objective responses. This interim analysis reports the results from the first dose-level cohort of five patients. We documented a short vaccine manufacturing time of 48-55 days which enabled the initiation of EVX-01 treatment within 60 days from baseline biopsy. No severe adverse events were observed. EVX-01 elicited long-lasting EVX-01-specific T-cell responses in all patients. Competitive manufacturing time was demonstrated. EVX-01 was shown to be safe and able to elicit immune responses targeting tumor neoantigens with encouraging early indications of a clinical and meaningful antitumor efficacy, warranting further study.
Background:
As the patents of originator biologics are expiring, biosimilar versions are becoming available for the treatment of inflammatory bowel disease (IBD). However, published switch studies of ...the first infliximab biosimilar, CT-P13, have delivered ambiguous results that could be interpreted as showing a trend towards inferior effectiveness in Crohn’s disease (CD) compared with ulcerative colitis (UC). The aim of this study was to investigate the effectiveness and safety of switching IBD patients from treatment with Remicade to CT-P13.
Methods:
In this prospective observational cohort study, all adult IBD patients on Remicade treatment, at four hospitals, were switched to CT-P13. The primary endpoint was change in clinical disease activity at 2, 6, and 12 months after the switch. Secondary endpoints were subgroup analyses of patients with and without concomitant immunomodulators; changes in biomarkers, quality of life, drug trough levels and anti-drug antibodies (ADAbs); and adverse events.
Results:
A total of 313 IBD patients were switched (195 CD; 118 UC). There were no significant changes in clinical disease activity, quality of life, biomarkers (except a small but significant increase in albumin in CD) including F-calprotectin, drug trough levels, or proportion of patients in remission. Disease worsening rates were 14.0% for CD and 13.8% for UC; and 2.7% developed ADAbs and 2.2% developed serious adverse events.
Conclusions:
This is the largest study of switched IBD patients published to date, and it demonstrates that switching from Remicade to CT-P13 may be done with preserved therapeutic effectiveness and safety in both CD and UC.
•A new kind of sorbent for SPME of triazoles.•High tendency toward the adsorption of triazoles.•Easy preparation of sorbent and easy operation.•Showing high pre-concentration factor, high extraction ...percentage, low LOQ and cheapness.•Stability with time and possibility regeneration and reusing many times.
An environmentally friendly method which is based on preparation and use of a new composite consisting of poly 3-aminophenol and graphene oxide for solid-phase microextraction of triazole fungicides from natural water and juices is introduced. The composite was synthesized by in-situ polymerization of 3-aminophenol and graphene oxide in weak alkaline media. By using the obtained results from the characterization, a suitable mechanism for polymerization and a proper structure for the polymer were proposed. Under optimal conditions, there are linear relationships between concentration of triazoles and their HPLC peak areas in the range of 0.5–100 µg L−1. The recovery percentages, pre-concentration factors and LOQ for all triazoles were 95.2–98.0%, about 200 and 0.2–0.4 µg L−1, respectively. The offered method was applied for extraction and determination of triazoles from natural water, some juices and it represents a promising alternative method for analysis of triazoles.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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