The Housewife, the Vigilante and the Cigarette‐Smoking Man: The CIA

Reeling from the revelations about its operations in the 1970s, the CIA set up an Office of Public Affairs to improve its public image. Among its activities was greater engagement with television producers, but it largely failed to lead to more US drama series portraying the CIA in a better light. This article, however, analyses those few TV dramas that did characterize the CIA in the 1980s and 1990s – Scarecrow and Mrs King, The Equalizer and The X-Files. Each series gave a critique of the CIA and its practices while offering alternative pathways to redeeming the organization so that it could better serve US security and domestic safety. They are examples of how television dramas can ask questions, engage with critical issues in contemporary society, and push the boundaries of what we expect to see in our televisual entertainment. They may not have offered very much insight into what the CIA was actually doing globally, but their storylines did confront the public image of the CIA, question its ethos and its methods, and offer some alternative viewpoints on how the Agency might develop its role and approach. Each series attempted to push beyond stereotypes of the CIA and its agents, upset the usual balance between gender roles and refused to give the kind of closed, unambiguous viewpoints that so many US television dramas offered their audiences during the period. They contributed significantly to the cultural representation of the CIA as the Cold War drew to a close

The Aspergillus fumigatus sialidase is a KDNase: structural and mechanistic insights

Aspergillus fumigatus is a filamentous fungus that can cause severe respiratory disease in immunocompromised individuals. A putative sialidase from A. fumigatus was recently cloned and shown to be relatively poor in cleaving N-acetylneuraminic acid (Neu5Ac) in comparison to bacterial sialidases. Here we present the first crystal structure of a fungal sialidase. When the apo structure was compared to bacterial sialidase structures, the active site of the Aspergillus enzyme suggested that Neu5Ac would be a poor substrate due to a smaller pocket that normally accommodates the acetamido group of Neu5Ac in sialidases. A sialic acid with a hydroxyl in place of an acetamido group is 2-keto-3-deoxynononic acid (KDN). We show that KDN is the preferred substrate for the A. fumigatus sialidase and that A. fumigatus can utilise KDN as a sole carbon source. A 1.4Angstrom resolution crystal structure of the enzyme in complex with KDN reveals KDN in the active site in a boat conformation, and nearby a second binding site occupied by KDN in a chair conformation, suggesting that polyKDN may be a natural substrate. The enzyme is not inhibited by the sialidase transition state analogue 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (Neu5Ac2en) but is inhibited by the related KDN2en that we show bound to the enzyme in a 1.84Angstrom resolution crystal structure. Using a fluorinated KDN substrate, we present a 1.5Angstrom resolution structure of a covalently bound catalytic intermediate. The A. fumigatus sialidase is therefore a KDNase with a similar catalytic mechanism to Neu5Ac exosialidases, and this study represents the first structure of a KDNase

CureGN Study Rationale, Design, and Methods: Establishing a Large Prospective Observational Study of Glomerular Disease

Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death. Multicenter prospective cohort study. Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded. Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year. Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events. The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years’ initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year. Current follow-up can only detect large differences in ESKD and death outcomes. Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes