The third helix of the homeodomain of paired class homeodomain proteins acts as a recognition helix both for DNA and protein interactions

The transcription factor Pax6 is essential for the development of the eyes and the central nervous system of vertebrates and invertebrates. Pax6 contains two DNA-binding domains; an N-terminal paired domain and a centrally located homeodomain. We have previously shown that the vertebrate paired-less isoform of Pax6 (Pax6ΔPD), and several other homeodomain proteins, interact with the full-length isoform of Pax6 enhancing Pax6-mediated transactivation from paired domain-DNA binding sites. By mutation analyses and molecular modeling we now demonstrate that, surprisingly, the recognition helix for specific DNA binding of the homeodomains of Pax6 and Chx10 interacts with the C-terminal RED subdomain of the paired domain of Pax6. Basic residues in the recognition helix and the N-terminal arm of the homeodomain form an interaction surface that binds to an acidic patch involving residues in helices 1 and 2 of the RED subdomain. We used fluorescence resonance energy transfer assays to demonstrate such interactions between Pax6 molecules in the nuclei of living cells. Interestingly, two mutations in the homeodomain recognition helix, R57A and R58A, reduced protein–protein interactions, but not DNA binding of Pax6ΔPD. These findings suggest a critical role for the recognition helix and N-terminal arm of the paired class homeodomain in protein–protein interactions

Structural and functional characterization of salmon STAT1, STAT2 and IRF9 homologs sheds light on interferon signaling in teleosts

Mammalian IRF9 and STAT2, together with STAT1, form the ISGF3 transcription factor complex, which is critical for type I interferon (IFN)-induced signaling, while IFNγ stimulation is mediated by homodimeric STAT1 protein. Teleost fish are known to possess most JAK and STAT family members, however, description of their functional activity in lower vertebrates is still scarce. In the present study we have identified two different STAT2 homologs and one IRF9 homolog from Atlantic salmon (Salmo salar). Both proteins have domain-like structures with functional motifs that are similar to higher vertebrates, suggesting that they are orthologs to mammalian STAT2 and IRF9. The two identified salmon STAT2s, named STAT2a and STAT2b, showed high sequence identity but were divergent in their transactivation domain (TAD). Like STAT1, ectopically expressed STAT2a and b were shown to be tyrosine phosphorylated by type I IFNs and, interestingly, also by IFNγ. Microscopy analyses demonstrated that STAT2 co-localized with STAT1a in the cytoplasm of unstimulated cells, while IFNa1 and IFNγ stimulation seemed to favor their nuclear localization. Overexpression of STAT2a or STAT2b together with STAT1a activated a GAS-containing reporter gene construct in IFNγ-stimulated cells. The highest induction of GAS promoter activation was found in IFNγ-stimulated cells transfected with IRF9 alone. Taken together, these data suggest that salmon STAT2 and IRF9 may have a role in IFNγ-induced signaling and promote the expression of GAS-driven genes in bony fish. Since mammalian STAT2 is primarily an ISGF3 component and not involved in IFNγ signaling, our finding features a novel role for STAT2 in fish

Aggregation and Representation in the European Parliament Party Groups

While members of the European Parliament are elected in national constituencies, their votes are determined by the aggregation of MEPs in multinational party groups. The uncoordinated aggregation of national party programmes in multinational EP party groups challenges theories of representation based on national parties and parliaments. This article provides a theoretical means of understanding representation by linking the aggregation of dozens of national party programmes in different EP party groups to the aggregation of groups to produce the parliamentary majority needed to enact policies. Drawing on an original data source of national party programmes, the EU Profiler, the article shows that the EP majorities created by aggregating MEP votes in party groups are best explained by cartel theories. These give priority to strengthening the EP’s collective capacity to enact policies rather than voting in accord with the programmes they were nationally elected to represent

Digital transformations and the archival nature of surrogates

Large-scale digitization is generating extraordinary collections of visual and textual surrogates, potentially endowed with transcendent long-term cultural and research values. Understanding the nature of digital surrogacy is a substantial intellectual opportunity for archival science and the digital humanities, because of the increasing independence of surrogate collections from their archival sources. The paper presents an argument that one of the most significant requirements for the long-term access to collections of digital surrogates is to treat digital surrogates as archival records that embody traces of their fluid lifecycles and therefore are worthy of management and preservation as archives. It advances a theory of the archival nature of surrogacy founded on longstanding notions of archival quality, the traces of their source and the conditions of their creation, and the functional ‘‘work of the archive.’’ The paper presents evidence supporting a ‘‘secondary provenance’’ derived from re-digitization, re-ingestion of multiple versions, and de facto replacement of the original sources. The design of the underlying research that motivates the paper and summary findings are reported separately. The research has been supported generously by the US Institute of Museum and Library Services.Institute for Museum and Library ServicesPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111825/1/J26 Conway Digital Transformations 2014-pers.pdfDescription of J26 Conway Digital Transformations 2014-pers.pdf : Main articl

Pax6 Represses Androgen Receptor-Mediated Transactivation by Inhibiting Recruitment of the Coactivator SPBP

The androgen receptor (AR) has a central role in development and maintenance of the male reproductive system and in the etiology of prostate cancer. The transcription factor Pax6 has recently been reported to act as a repressor of AR and to be hypermethylated in prostate cancer cells. SPBP is a transcriptional regulator that previously has been shown to enhance the activity of Pax6. In this study we have identified SPBP to act as a transcriptional coactivator of AR. We also show that Pax6 inhibits SPBP-mediated enhancement of AR activity on the AR target gene probasin promoter, a repression that was partly reversed by increased expression of SPBP. Enhanced expression of Pax6 reduced the amount of SPBP associated with the probasin promoter when assayed by ChIP in HeLa cells. We mapped the interaction between both AR and SPBP, and AR and Pax6 to the DNA-binding domains of the involved proteins. Further binding studies revealed that Pax6 and SPBP compete for binding to AR. These results suggest that Pax6 represses AR activity by displacing and/or inhibiting recruitment of coactivators to AR target promoters. Understanding the mechanism for inhibition of AR coactivators can give rise to molecular targeted drugs for treatment of prostate cancer

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Introduction:Taking Bourdieu further into studies of Organizations and Management

This introduction presents an overview of the key concepts discussed in the subsequent chapters of this book. The book discusses the pressures imposed on managers and staff resulting from the ideological purchase of neoliberal ideas by nation-states. It also discusses the new institutions and Bourdieu’s field theory. The book analyses the importance of social capital in the form of ‘wasta’ in the context of the insurance sector in Jordan, as a resource for employment and career advancement. It deals with how professional fields, in change and transition, have become contested due to ongoing struggles over legitimate forms of capital, and the consequences this might have on the habitus of individuals/professionals within the field. The book focuses on the emerging health promotion strategies within work organizations, related to developments in the wider field, which can be associated with improved working conditions and welfare, yet it may also result in bodily performance pressures imposed on staff

In the Midst of a Storm:Forging Future Paths for Bourdieu-inspired Organizational and Management Studies

The chapters in this volume have shown how organizations and their internal dynamics are related to the broader fields surrounding them at specific moments in history. Building on their contributions, the aims of this chapter are to offer examples of the interconnectedness of the COVID-19 crisis as it relates to key management and organization studies (MOS) themes. In particular, the concepts of transnational field, crisis and hysteresis are applied as central tools in studying the limits of strict organizational and meso-level analysis and offering MOS scholars Bourdieu-inspired alternatives for studying the affects of COVID-19 and the ways forward. We argue that the COVID-19 pandemic, as a major crisis across transnational fields, serves as a window offering insights into the multiple dimensions and interconnectedness of organizational life in relation to broader changes in society. We demonstrate how such crisis challenges or changes the rules of the game, doxa and the nature, distribution and conversion of cultural, social and economic capital within organizational and professional fields. The COVID-19 crisis has led to increased mortality rates in most countries, widespread unemployment and increased issues of inequality and precarity. But simultaneously the crisis has produced new and innovative job types and mass employment. We offer some suggestions as to how Bourdieu-inspired research can investigate the impact of such changes on organizations in the longer term in fundamental areas such as culture, leadership, communication, digitalization and working conditions

In the midst of a storm: forging future paths for Bourdieu inspired Organizational and Management Studies

No abstract available