The representation of the country house in individual books and guides 1720-1845

During the eighteenth century a trend began for the publication of books devoted to the description of single country house; an early stage in the development of the country house guidebook. A survey of this largely unanalysed genre found it to be a much larger phenomenon than had previously been thought, with a peak in new publications later than has been suggested. The issue of the commission, details of production and uses and distribution of the guidebook are all previously neglected aspects of research. Analysis of these has given a greater insight into the context of production, and has shown the direct involvement of the house owner in many cases. In the secondary literature which does exist on this genre, the bias towards considering the contents of guidebook from the perspective of the tourists’ reception, or as an objective document, neglects the huge potential for analysis of the sub-agendas which were involved in these publications. These less overt potential messages included a justification of the country estate in general, as well as more individual markers which related to the house owner himself. This thesis has begun to rectify the lack of research into the guidebook, and to highlight this fruitful source of material on the eighteenth and early-nineteenth centuries. It has begun the innovative task of looking beyond guidebooks as merely a factual account of the estate, and to acknowledge that their objectivity is in question; the books were often nuanced towards given a particular impression and motivated by specific agendas. The house was represented both as an object of admiration in its own right but also used as a vehicle for the projection and display of the individual qualities and identity of the owner

PENERAPAN PRINSIP INTEGRATED GOOD CORPORATE GOVERNANCE-RISK MANAGEMENT - COMPLIANCE (IGRC) OLEH PT JOUSKA FINANSIAL INDONESIA DALAM PENGELOLAAN PORTOFOLIO EFEK DI PASAR MODAL

Trend investasi akhir-akhir ini semakin diminati oleh masyarakat yang mana masyarakat dapat membeli efek di pasar modal seperti saham, obligasi, atau surat berharga lainnya dengan harga terjangkau. PT. Jouska adalah perusahaan yang memanfaatkan momen mudahnya masyarakat membeli efek di pasar modal yang mana mereka berperan sebagai penasihat keuangan yang independent. Namun, ditengah jalan banyak klien mengeluhkan banyak kerugian dalam portofolionya setelah mengikuti rekomendasi PT. Jouska dan ternyata banyak pelanggaran yang dilakukan PT. Jouska. Berdasarkan uraian tersebut, peneliti mengkaji permasalahan berupa 1) Bagaimana pengelolaan portofolio efek oleh PT. Jouska Finansial Indonesia dikaitkan dengan ketentuan Pasar Modal, 2) Bagaimana implementasi prinsip Intergrated Good Corporate Governance-Risk Management-Compliance pada kegiatan usaha PT. Jouska Finansial Indonesia, dan 3) Bagaimana upaya pengawasan yang perlu dilakukan oleh Otoritas Jasa Keuangan (OJK) terhadap perusahaan efek dalam pengelolaan efek di Pasar Modal. Metode penelitian yang digunakan oleh peneliti yaitu deskriptif analitis yang mana menjelaskan peraturan yang berkaitan dengan fakta berupa data sekunder dan metode penelitian berupa yuridis normative yang mana penelitian ini mengkaji kaidah hukum, asas-asas, dan doktrin hukum positif. Tahap penelitian terdiri atas peneltian kepustakaan dan penelitian lapangan serta Teknik pengumpulan data berupa studi kepustakaan dan studi lapangan. Pada penelitian ini, analisis data yang digunakan yaitu yuridis kualitatif yang mana analisis dilakukan secara komprehensif, sistematis, dan holistic yang bertitik tolak pada teori-teori hukum, norma, asas dan peraturan perundang-undangan. Hasil penelitian yang dapat disimpulkan yaitu bahwa pengelolaan portofolio efek oleh PT. Jouska Finansial Indonesia tidak mengimplementasikan teori ekonomi Pancasila dan PT Jouska selaku perencana keuangan telah melanggar ketentuan dalam Pasal 30, 34, 35, 90 Undang-Undang Nomor 8 Tahun 1995 tentang Pasar Modal dan POJK mengenai Manajer Investasi dan Penasihat Investasi serta tidak mencerminkan keadilan ekonomi. Kemudian, PT. Jouska tidak mengimplementasikan prinsip IGRC yang mana dalam prinsip GCG tidak dilakukan dengan professional dan pada prinsip Risk Management tidak terdapat divisi manajemen risiko. Adapun, OJK dalam mengawasi perusahaan efek di pasar modal yaitu berfungsi menyelenggarakann pengaturan dan pengawasan yang terintegrasi pada sektor jasa keuangan dan dibantu peran masyarakat yang ikut melaporkan jika ada transaksi mencurigakan serta peran OJK perlu ditingkatkan kembali dalam hal preventif dan represif yang sudah ada SOPnya. Kata Kunci: Pasar Modal, Integrated Good Corporate Governance-Risk Management-Compliance (IGRC), Otoritas Jasa Keuanga

Summer temperature gradients in northwest Europe during the Lateglacial to early Holocene transition (15-8 ka BP) inferred from chironomid assemblages

The raster temperature data was interpolated from site temperature data estimated from Chironomid records using Kriging. Temperatures are in Degrees Centigrage. The dataset covers all of Northern Europe including Iceland and Scandanavia.</span

Fevipiprant (QAW039), a slowly dissociating CRTh2 antagonist with the potential for improved clinical efficacy

Here we describe the pharmacologic properties of a series of clinically relevant chemoattractant receptor-homologous molecules expressed on T-helper type 2 (CRTh2) receptor antagonists, including fevipiprant (NVP-QAW039 or QAW039), which is currently in development for the treatment of allergic diseases. [3H]-QAW039 displayed high affinity for the human CRTh2 receptor (1.14 ± 0.44 nM) expressed in Chinese hamster ovary cells, the binding being reversible and competitive with the native agonist prostaglandin D2 (PGD2). The binding kinetics of QAW039 determined directly using [3H]-QAW039 revealed mean kinetic on (kon) and off (koff) values for QAW039 of 4.5 × 107 M-1min-1 and 0.048 minute-1, respectively. Importantly, the koff of QAW039 (half-life = 14.4 minutes) was >7-fold slower than the slowest reference compound tested, AZD-1981. In functional studies, QAW039 behaved as an insurmountable antagonist of PGD2-stimulated [35S]-GTPγS activation, and its effects were not fully reversed by increasing concentrations of PGD2 after an initial 15-minute incubation period. This behavior is consistent with its relatively slow dissociation from the human CRTh2 receptor. In contrast for the other ligands tested this time-dependent effect on maximal stimulation was fully reversed by the 15-minute time point, whereas QAW039's effects persisted for >180 minutes. All CRTh2 antagonists tested inhibited PGD2-stimulated human eosinophil shape change, but importantly QAW039 retained its potency in the whole-blood shape-change assay relative to the isolated shape change assay, potentially reflective of its relatively slower off rate from the CRTh2 receptor. QAW039 was also a potent inhibitor of PGD2-induced cytokine release in human Th2 cells. Slow CRTh2 antagonist dissociation could provide increased receptor coverage in the face of pathologic PGD2 concentrations, which may be clinically relevant

Isoform-Specific Biased Agonism of Histamine H 3 Receptor Agonists s

ABSTRACT The human histamine H 3 receptor (hH 3 R) is subject to extensive gene splicing that gives rise to a large number of functional and nonfunctional isoforms. Despite the general acceptance that G protein-coupled receptors can adopt different ligand-induced conformations that give rise to biased signaling, this has not been studied for the H 3 R; further, it is unknown whether splice variants of the same receptor engender the same or differential biased signaling. Herein, we profiled the pharmacology of histamine receptor agonists at the two most abundant hH 3 R splice variants (hH 3 R 445 and hH 3 R 365 ) across seven signaling endpoints. Both isoforms engender biased signaling, notably for 4-[3-(benzyloxy)propyl]-1H-imidazole (proxyfan) [e.g., strong bias toward phosphorylation of glycogen synthase kinase 3b (GSK3b) via the full-length receptor] and its congener 3-(1H-imidazol-4-yl)propyl-(4-iodophenyl)-methyl ether (iodoproxyfan), which are strongly consistent with the former&apos;s designation as a &quot;protean&quot; agonist. The 80 amino acid IL3 deleted isoform hH 3 R 365 is more permissive in its signaling than hH 3 R 445 : 2-(1H-imidazol-5-yl)ethyl imidothiocarbamate (imetit), proxyfan, and iodoproxyfan were all markedly biased away from calcium signaling, and principal component analysis of the full data set revealed divergent profiles for all five agonists. However, most interesting was the identification of differential biased signaling between the two isoforms. Strikingly, hH 3 R 365 was completely unable to stimulate GSK3b phosphorylation, an endpoint robustly activated by the full-length receptor. To the best of our knowledge, this is the first quantitative example of differential biased signaling via isoforms of the same G proteincoupled receptor that are simultaneously expressed in vivo and gives rise to the possibility of selective pharmacological targeting of individual receptor splice variants

Discovery of fevipiprant (NVP-QAW039), a potent and selective DP2 receptor antagonist for treatment of asthma

Further optimization of an initial DP2 receptor antagonist clinical candidate NVPQAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2- (trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma

Creating and curating an archive: Bury St Edmunds and its Anglo-Saxon past

This contribution explores the mechanisms by which the Benedictine foundation of Bury St Edmunds sought to legitimise and preserve their spurious pre-Conquest privileges and holdings throughout the Middle Ages. The archive is extraordinary in terms of the large number of surviving registers and cartularies which contain copies of Anglo-Saxon charters, many of which are wholly or partly in Old English. The essay charts the changing use to which these ancient documents were put in response to threats to the foundation's continued enjoyment of its liberties. The focus throughout the essay is to demonstrate how pragmatic considerations at every stage affects the development of the archive and the ways in which these linguistically challenging texts were presented, re-presented, and represented during the Abbey’s history