Identification and characterization of non-coding RNAs and their associated proteins involved in cellular stress responses

We have designed two new experimental approaches to overcome limitations of previously established methods. Their usefulness, however, turned out to be limited and we were unable to provide a reliable improvement to existing methodologies. Secondly, we provided an extensive atlas of the transcriptional landscape of MCF-7 cells during the DDR. We employed three different high-throughput RNA sequencing approaches to provide a comprehensive analysis of the transcriptome. Our efforts led to identification of differentially expressed transcripts regardless of their polyadenylation or stability, or towards their presence in existing genome annotations. We have provided a foundation for future functional studies of lncRNAs potentially involved in DDR and investigated four lncRNAs upregulated in this condition in more detail. Thirdly, we have provided a new important insight into regulatory mechanism of DDX3 – a protein, which has been previously reported to associate with lncRNAs and is implicated in both DDR and tumorigenesis. We have described the nature of DDX3-lncRNAs interactions on a transcriptome-wide scale and furthered our understanding of DDX3 mediated regulation of translation. We have determined the global effects of DDX3 depletion on the abundance of mRNAs and their translation efficiency. In combination with the analysis of DDX3-mRNA binding specificity those results show that the protein is required for translation initiation on subset of mRNAs harboring structured 5’ UTRs

Fragmented Legislatures and the Budget: Analyzing Presidential Democracies

What impact does party fragmentation have on the likelihood of democracies to run a fiscal deficit? Past research is almost unanimous in finding that as the number of parties in a country\u27s legislature or government grows, so does its probability of overspending. However, this finding is based largely on parliamentary systems, and there is no reason to believe that it should hold when executives are independent. In this article, I develop a theory for the impact of legislative fragmentation on budgetary politics in presidential democracies. I argue that unified presidential systems should tend most toward fiscal solvency but that increasing fragmentation should actually facilitate budget balancing when government is divided. The logic is that presidents, who are likely to prefer balanced budgets due to their broad constituencies, will be better able to craft acceptable governing coalitions from divided legislatures than from ones controlled by a single opposing party. They will also be better able to circumvent such fragmented legislatures should a coalition prove impossible. I test these propositions quantitatively in all presidential democracies from 1976 to 2007. The results provide support for the theory and highlight the contrasting impact of legislative fragmentation on public policy in presidential vs. parliamentary systems

Coronaviruses: Is Sialic Acid a Gate to the Eye of Cytokine Storm? From the Entry to the Effects

Coronaviruses (CoVs) are a diverse family of the enveloped human and animal viruses reported as causative agents for respiratory and intestinal infections. The high pathogenic potential of human CoVs, including SARS-CoV, MERS-CoV and SARS-CoV-2, is closely related to the invasion mechanisms underlying the attachment and entry of viral particles to the host cells. There is increasing evidence that sialylated compounds of cellular glycocalyx can serve as an important factor in the mechanism of CoVs infection. Additionally, the sialic acid-mediated cross-reactivity with the host immune lectins is known to exert the immune response of different intensity in selected pathological stages. Here, we focus on the last findings in the field of glycobiology in the context of the role of sialic acid in tissue tropism, viral entry kinetics and immune regulation in the CoVs infections

Sialic Acid-Siglec Axis as Molecular Checkpoints Targeting of Immune System: Smart Players in Pathology and Conventional Therapy

The sialic acid-based molecular mimicry in pathogens and malignant cells is a regulatory mechanism that leads to cross-reactivity with host antigens resulting in suppression and tolerance in the immune system. The interplay between sialoglycans and immunoregulatory Siglec receptors promotes foreign antigens hiding and immunosurveillance impairment. Therefore, molecular targeting of immune checkpoints, including sialic acid-Siglec axis, is a promising new field of inflammatory disorders and cancer therapy. However, the conventional drugs used in regular management can interfere with glycome machinery and exert a divergent effect on immune controlling systems. Here, we focus on the known effects of standard therapies on the sialoglycan-Siglec checkpoint and their importance in diagnosis, prediction, and clinical outcomes

The Paired Siglecs in Brain Tumours Therapy: The Immunomodulatory Effect of Dexamethasone and Temozolomide in Human Glioma In Vitro Model

The paired sialic acid-binding immunoglobulin like lectins (Siglecs) are characterized by similar cellular distribution and ligand recognition but opposing signalling functions attributed to different intracellular sequences. Since sialic acid—Siglec axis are known to control immune homeostasis, the imbalance between activatory and inhibitory mechanisms of glycan-dependent immune control is considered to promote pathology. The role of sialylation in cancer is described, however, its importance in immune regulation in gliomas is not fully understood. The experimental and clinical observation suggest that dexamethasone (Dex) and temozolomide (TMZ), used in the glioma management, alter the immunity within the tumour microenvironment. Using glioma-microglia/monocytes transwell co-cultures, we investigated modulatory action of Dex/TMZ on paired Siglecs. Based on real-time PCR and flow cytometry, we found changes in SIGLEC genes and their products. These effects were accompanied by altered cytokine profile and immune cells phenotype switching measured by arginases expression. Additionally, the exposure to Dex or TMZ increased the binding of inhibitory Siglec-5 and Siglec-11 fusion proteins to glioma cells. Our study suggests that the therapy-induced modulation of the interplay between sialoglycans and paired Siglecs, dependently on patient’s phenotype, is of particular signification in the immune surveillance in the glioma management and may be useful in glioma patient’s therapy plan verification

The Paired Siglecs in Brain Tumours Therapy: The Immunomodulatory Effect of Dexamethasone and Temozolomide in Human Glioma In Vitro Model

The paired sialic acid-binding immunoglobulin like lectins (Siglecs) are characterized by similar cellular distribution and ligand recognition but opposing signalling functions attributed to different intracellular sequences. Since sialic acid—Siglec axis are known to control immune homeostasis, the imbalance between activatory and inhibitory mechanisms of glycan-dependent immune control is considered to promote pathology. The role of sialylation in cancer is described, however, its importance in immune regulation in gliomas is not fully understood. The experimental and clinical observation suggest that dexamethasone (Dex) and temozolomide (TMZ), used in the glioma management, alter the immunity within the tumour microenvironment. Using glioma-microglia/monocytes transwell co-cultures, we investigated modulatory action of Dex/TMZ on paired Siglecs. Based on real-time PCR and flow cytometry, we found changes in SIGLEC genes and their products. These effects were accompanied by altered cytokine profile and immune cells phenotype switching measured by arginases expression. Additionally, the exposure to Dex or TMZ increased the binding of inhibitory Siglec-5 and Siglec-11 fusion proteins to glioma cells. Our study suggests that the therapy-induced modulation of the interplay between sialoglycans and paired Siglecs, dependently on patient’s phenotype, is of particular signification in the immune surveillance in the glioma management and may be useful in glioma patient’s therapy plan verification

Majoritarian Electoral Systems and Consumer Power: Price-Level Evidence from the OECD

ABSTRACT: A straightforward extension of the standard Stigler-Peltzman model of regulation, coupled with a Taagepera-Shugart analysis of electoral-system effects, suggests: (a) that the greater seat-vote elasticities of majoritarian electoral systems will tilt policy in favor of consumers, while proportional systems should strengthen producers; and (b) that the pro-consumer bias of majoritarian systems should be manifested in systematically lower prices. Empirical tests, controlling for the structural determinants of national price levels established in the earlier "law of one price" literature, establish majoritarian electoral systems as a significant and robust predictor, lowering national price levels in the mean OECD country by approximately ten percent

DDX3 depletion represses translation of mRNAs with complex 5' UTRs.

DDX3 is an RNA chaperone of the DEAD-box family that regulates translation. Ded1, the yeast ortholog of DDX3, is a global regulator of translation, whereas DDX3 is thought to preferentially affect a subset of mRNAs. However, the set of mRNAs that are regulated by DDX3 are unknown, along with the relationship between DDX3 binding and activity. Here, we use ribosome profiling, RNA-seq, and PAR-CLIP to define the set of mRNAs that are regulated by DDX3 in human cells. We find that while DDX3 binds highly expressed mRNAs, depletion of DDX3 particularly affects the translation of a small subset of the transcriptome. We further find that DDX3 binds a site on helix 16 of the human ribosomal rRNA, placing it immediately adjacent to the mRNA entry channel. Translation changes caused by depleting DDX3 levels or expressing an inactive point mutation are different, consistent with different association of these genetic variant types with disease. Taken together, this work defines the subset of the transcriptome that is responsive to DDX3 inhibition, with relevance for basic biology and disease states where DDX3 is altered