Preliminary trend monitoring system data manager's guide

The functions and data base structures that the data base manager will be responsible for maintaining are documented. All normal and error sequences are included

Carolingian imperial authority : consolidation to dissolution, 751-870

Abstract from public.pdf.This thesis examines the development and breakdown of Carolingian imperial authority from the reign of Pepin the Short (751-768) to the death of Lothar I in 855. This work incorporates a variety of source materials, including narrative, diplomatic, numismatic, and visual evidence. While most scholarship has focused on the figures of Charlemagne and Louis the Pious, this thesis attempts to shed light on the strength of the imperial authority by examining the much neglected figure of Lothar, Louis the Pious' eldest son and coemperor. Lothar has been a controversial figure in Carolingian history. His seizure of power in 833 has colored him as an ungrateful, troublesome son, and the failure of his kingdom, Middle Francia, has made him out to be an ineffective ruler. Though Middle Francia existed for such a short period of time (843-870/5), its ruler should not be overlooked as a critical player in the Carolingian disintegration both before the Treaty of Verdun (843) and after. The tendency in modern scholarship, however, has been to focus on Louis the Pious and his struggle with rebellious magnates or the subsequent reigns of Charles the Bald and Louis the German, as the early beginnings of European state formation. Lothar has only been a matter of concern when discussing the general narrative of events between 828 and 843, primarily focusing on the Frankish Civil War (840-843)

Investigating the structural and functional characteristics of coproporphyrin ferrochelatase

Heme is an essential cofactor in most organisms, this includes bacteria and mammals. The coproporphyrin-dependent heme biosynthesis pathway is specific to Gram positive bacteria and was only discovered in 2015. Before this discovery Gram positive bacteria were assumed to synthesise heme using the same heme synthesis pathway as mammals. As a result, the enzymes within this pathway have not been fully characterised and provide novel targets for antibiotics. Experiments were completed to investigate the protein-protein interactions between HemH and HemQ, two consecutive enzymes in the pathway as they are covalently linked in P. acnes. This used SEC and showed that truncations for the P. acnes HemH-Q protein (HemHL and HemQS) interacted 1:1 whereas other non-covalently linked HemH and HemQ proteins didn’t have observable protein-protein interactions. Kinetic investigation of the wildtype B. subtilis and S. aureus HemH proteins with their endogenous substrate (coproporphyrin) was completed as previous kinetic analysis of B. subtilis HemH used analogues of protoporphyrin IX in the kinetic assays. A combination of spectroscopic techniques were utilised and they show that the two proteins are very active and behave in a broadly similar way to each other. Stopped flow fluorescence spectroscopy proved a useful tool for in depth kinetic investigation into the enzymatic mechanism of coproporphyrin ferrochelatase. Rates constants for enzyme/porphyrin isomerisation, metal chelation and binding constants for substrate binding were estimated using this technique. Finally, functionally important B. subtilis HemH active site mutants (K87A, H88A, E264A/Q) were characterised using similar techniques described for wildtype characterisation. K87A/H88A and E264A/Q are on the non-conserved and conserved active site face, respectively. This shows that whilst K87A, E264A/Q are relatively inactive they are capable of binding coproporphyrin and activity is diminished after binding. H88A has activity comparable to wildtype with weakened coproporphyrin binding and better at iron binding and chelation. This research could provide details for rational drug design of antibiotics that specifically target Gram positive bacteria

An Oversight Agenda for Customs and Border Protection: Americas Largest, Least Accountable Law Enforcement Agency

The nation's largest law enforcement agency, U.S. Customs and Border Protection (CBP), is also its least transparent and accountable. The need for oversight and reform is pressing: Along the border, there have been numerous examples of CBP encounters leading to civilian deaths.This report proposes a bottom-up, good governance approach to reforms, and identifies six discrete needs for oversight which have in common a focus on changing CBP culture. It steers clear of border-policy debates by focusing on increased professionalism and transparency, as well as on improved processes for addressing misconduct. These oversight topics address a culture of impunity that must be — or at least must become — unacceptable to every CBP leader, officer, and agent among the many who do serve honorably

Mutations in TGM6 induce the unfolded protein response in SCA35

Spinocerebellar ataxia type 35 (SCA35) is a rare autosomal-dominant neurodegenerative disease caused by mutations in the TGM6 gene, which codes for transglutaminase 6 (TG6). Mutations in TG6 induce cerebellar degeneration by an unknown mechanism. We identified seven patients bearing new mutations in TGM6. To gain insights into the molecular basis of mutant TG6-induced neurotoxicity, we analyzed all of the seven new TG6 mutants and the five TG6 mutants previously linked to SCA35. We found that wild-type (TG6-WT) mainly localized to the nucleus and perinuclear area, whereas five TG6 mutations showed nuclear depletion, increased accumulation in the perinuclear area, insolubility and loss of enzymatic function. Aberrant accumulation of these TG6 mutants in the perinuclear area led to activation of the unfolded protein response (UPR), suggesting that specific TG6 mutants elicit an endoplasmic reticulum (ER) stress response. Mutations associated with activation of the UPR caused death of primary neurons and reduced the survival of novel D. melanogaster models of SCA35. These results indicate that mutations differently impacting on TG6 function cause neuronal dysfunction and death through diverse mechanisms and highlight the UPR as a potential therapeutic target for patient treatment

Patrician landscapes and the picturesque in Nottinghamshire c.1750-c.1850

This article considers the Dukeries estates of north Nottinghamshire in the hey-day of aristocratic power and prestige, from the mid-Georgian to the mid-Victorian period. It poses a contrast between visitors’ impressions of the area as one of constancy and continuity, a point of reassurance in an age of political and social upheaval, and the reality of internal changes from within. Closely crowded as these estates were, their aristocratic owners competed with one another to fashion the most economically viable and aesthetically pleasing symbol of status and power. The article pays close attention to the hold which picturesque principles exercised on individual owners and considers the role of plantation, animals and water in parkland management and improvement. Finally, the article considers the extent to which the estates were sites of contestation; owners attempted to keep unwanted plebeian incursions at bay, whilst carefully controlling access on set-piece occasions such as coming-of-age festivities