Frederik Kaiser en zijn pogingen tot hervorming van ‘het sterrekundig deel van onze zeevaart’

Frederik Kaiser and his efforts to reform the 'astronomical part of our navigation' From 1858 until his death in 1872 the Leyden astronomer Frederik Kaiser occupied the post of verifier of the Government's navigational instruments. Due to his efforts, new standards in particular for the instrumental aspects of the navigation technology were introduced. Long before his nomination Kaiser had argued unsuccessfully for such a reform. In this article is shown how and why finally his ideas were accepted. It is a first attempt to describe Kaiser's influence on the development of navigation technology in the Netherlands

‘Een procesverbaal van verhoor’

'A record of interrogation' This paper describes the influence of the leading Dutch astronomer in the nineteenth century, Frederik Kaiser (1808-1872), on the use of statistical methods in astronomy. In the absence of existing research traditions Kaiser modelled his investigations after the example set by Struve and Bessel. In this process statistical methods were introduced as a matter of course. Moreover, these methods were employed by Kaiser to introduce new regulations and standards in observational practice which throughout the nineteenth century dominated Dutch astronomical research. The analysis of the observational data thus became what Anton Pannekoek in his History of Astronomy (1951) called 'a record of interrogation'

Illustrating the phaenomena: celestial cartography in antiquity and the Middle Ages

In this volume all extant celestial maps and globes made before 1500 are described and analysed. It also discusses the astronomical sources involved in making these artefacts in antiquity, the Middle Ages, the Islamic world and the European Renaissance before 1500

In vivo significance of the G2 restriction point

Loss of activity of the retinoblastoma pathway is a common event in human cancer. Mouse models have revealed that tumorigenesis by loss of Rb was accelerated by concomitant loss of the cell cycle inhibitor p27KIP1. This has been attributed to reduced apoptosis and weakening of the G1 checkpoint. However, the role of p27KIP1 in a recently identified G2 restriction point may offer an alternative explanation for this synergy. Here, we have investigated the significance of the G2 restriction point in Rb-deficient pituitaries. We show that Rb loss in the pituitary gland activated the G2 restriction point, as evidenced by the appearance of cyclin B1-p27KIP1 complexes. Somewhat unexpectedly, these complexes remained present in Rb-deficient tumors. These results indicate that the G2 restriction point does operate in vivo. However, in the pituitary gland, this mechanism seems to retard rather than to prevent tumor growth

Unexpected moves: a conformational change in MutSα enables high-affinity DNA mismatch binding

The DNA mismatch repair protein MutSα recognizes wrongly incorporated DNA bases and initiates their correction during DNA replication. Dysfunctions in mismatch repair lead to a predisposition to cancer. Here, we study the homozygous mutation V63E in MSH2 that was found in the germline of a patient with suspected constitutional mismatch repair deficiency syndrome who developed colorectal cancer before the age of 30. Characterization of the mutant in mouse models, as well as slippage and repair assays, shows a mildly pathogenic phenotype. Using cryogenic electron microscopy and surface plasmon resonance, we explored the mechanistic effect of this mutation on MutSα function. We discovered that V63E disrupts a previously unappreciated interface between the mismatch binding domains (MBDs) of MSH2 and MSH6 and leads to reduced DNA binding. Our research identifies this interface as a 'safety lock' that ensures high-affinity DNA binding to increase replication fidelity. Our mechanistic model explains the hypomorphic phenotype of the V63E patient mutation and other variants in the MBD interface

Identification of Sequential Viral Escape Mutants Associated with Altered T-Cell Responses in a Human Immunodeficiency Virus Type 1-Infected Individual

Control of viremia in natural human immunodeficiency virus type 1 (HIV-1) infection in humans is associated with a virus-specific T-cell response. However, still much is unknown with regard to the extent of CD8(+) cytotoxic T-lymphocyte (CTL) responses required to successfully control HIV-1 infection and to what extent CTL epitope escape can account for rises in viral load and ultimate progression to disease. In this study, we chose to monitor through full-length genome sequence of replication-competent biological clones the modifications that occurred within predicted CTL epitopes and to identify whether the alterations resulted in epitope escape from CTL recognition. From an extensive analysis of 59 biological HIV-1 clones generated over a period of 4 years from a single individual in whom the viral load was observed to rise, we identified the locations in the genome of five CD8(+) CTL epitopes. Fixed mutations were identified within the p17, gp120, gp41, Nef, and reverse transcriptase genes. Using a gamma interferon ELIspot assay, we identified for four of the five epitopes with fixed mutations a complete loss of T-cell reactivity against the wild-type epitope and a partial loss of reactivity against the mutant epitope. These results demonstrate the sequential accumulation of CTL escape in a patient during disease progression, indicating that multiple combinations of T-cell epitopes are required to control viremia