The Netherlands – Transatlantic litigation: the Bijlmer air crash case

Article reporting on the international litigation aspects of the crash of an El Al cargo plane into two apartment buildings in the south-eastern (“Bijlmer”) district of Amsterdam on Sunday 4 October 1992. Published in the Letter from … section of Amicus Curiae - Journal of the Institute of Advanced Legal Studies and its Society for Advanced Legal Studies. The Journal is produced by the Society for Advanced Legal Studies at the Institute of Advanced Legal Studies, University of London

Molecular misreading: The occurrence of frameshift proteins in different diseases

Neuronal homoeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the UPS (ubiquitin-proteasome system). As a result of molecular misreading, misframed UBB (ubiquitin B) (UBB+1) is generated. UBB+1 accumulates in the neuritic plaques and neurofibrillary tangles in all patients with AD (Alzheimer's disease) and in the neuronal and glial hallmarks of other tauopathies and in polyglutamine diseases such as Huntington's disease. UBB+1 is not present in synucleinopathies such as Parkinson's disease. We showed that UBB+1 causes UPS dysfunction, aggregation and apoptotic cell death. UBB+1 is also present in non-neurological cells, hepatocytes of the diseased liver and in muscles during inclusion body myositis. Other frequently occurring (age-related) diseases such as Type 2 (non-insulin-dependent) diabetes mellitus are currently under investigation. These findings point to the importance of the UPS in diseases and open new avenues for target identification of the main players of the UPS. Treatment of these diseases with tools (e.g. viral RNA interference constructs) to intervene with specific targets is the next step

The Netherlands – Transatlantic litigation: the Bijlmer air crash case

Article reporting on the international litigation aspects of the crash of an El Al cargo plane into two apartment buildings in the south-eastern (“Bijlmer”) district of Amsterdam on Sunday 4 October 1992. Published in the Letter from … section of Amicus Curiae - Journal of the Institute of Advanced Legal Studies and its Society for Advanced Legal Studies. The Journal is produced by the Society for Advanced Legal Studies at the Institute of Advanced Legal Studies, University of London

Dysfunction of Protein Quality control in Parkinsonism-Dementia complex of Guam

Guam parkinsonism-dementia complex (G-PDC) is an enigmatic neurodegenerative disease that is endemic to the Pacific island of Guam. G-PDC patients are clinically characterized by progressive cognitive impairment and parkinsonism. Neuropathologically, G-PDC is characterized by abundant neurofibrillary tangles, which are composed of hyperphosphorylated tau, marked deposition of 43-kDa TAR DNA-binding protein, and neuronal loss. Although both genetic and environmental factors have been implicated, the etiology and pathogenesis of G-PDC remain unknown. Recent neuropathological studies have provided new clues about the pathomechanisms involved in G-PDC. For example, deposition of abnormal components of the protein quality control system in brains of G-PDC patients indicates a role for proteostasis imbalance in the disease. This opens up promising avenues for new research on G-PDC and could have important implications for the study of other neurodegenerative disorders.ArticleFRONTIERS IN NEUROLOGY.9:173(2018)journal articl

Planetary Construction Zones in Occultation: Discovery of an Extrasolar Ring System Transiting a Young Sun-like Star and Future Prospects for Detecting Eclipses by Circumsecondary and Circumplanetary Disks

The large relative sizes of circumstellar and circumplanetary disks imply that they might be seen in eclipse in stellar light curves. We estimate that a survey of ~10^4 young (~10 Myr old) post-accretion pre-MS stars monitored for ~10 years should yield at least a few deep eclipses from circumplanetary disks and disks surrounding low mass companion stars. We present photometric and spectroscopic data for a pre-MS K5 star (1SWASP J140747.93-394542.6), a newly discovered ~0.9 Msun member of the ~16 Myr-old Upper Cen-Lup subgroup of Sco-Cen at a kinematic distance of 128 pc. SuperWASP and ASAS light curves for this star show a remarkably long, deep, and complex eclipse event centered on 29 April 2007. At least 5 multi-day dimming events of >0.5 mag are identified, with a >3.3 mag deep eclipse bracketed by two pairs of ~1 mag eclipses symmetrically occurring +-12 days and +-26 days before and after. Hence, significant dimming of the star was taking place on and off over at least a ~54 day period in 2007, and a strong >1 mag dimming event occurred over a ~12 day span. We place a firm lower limit on the period of 850 days (i.e. the orbital radius of the eclipser must be >1.7 AU and orbital velocity must be <22 km/s). The shape of the light curve is similar to the lop-sided eclipses of the Be star EE Cep. We suspect that this new star is being eclipsed by a low-mass object orbited by a dense inner disk, girded by at least 3 dusty rings of lower optical depth. Between these rings are at least two annuli of near-zero optical depth (i.e. gaps), possibly cleared out by planets or moons, depending on the nature of the secondary. For possible periods in the range 2.33-200 yr, the estimated total ring mass is ~8-0.4 Mmoon (if the rings have optical opacity similar to Saturn's rings), and the edge of the outermost detected ring has orbital radius ~0.4-0.09 AU.Comment: Astronomical Journal, in press, 13 figure

Multiple histone modifications in euchromatin promote heterochromatin formation by redundant mechanisms in Saccharomyces cerevisiae

<p>Abstract</p> <p>Background</p> <p>Methylation of lysine 79 on histone H3 by Dot1 is required for maintenance of heterochromatin structure in yeast and humans. However, this histone modification occurs predominantly in euchromatin. Thus, Dot1 affects silencing by indirect mechanisms and does not act by the recruitment model commonly proposed for histone modifications. To better understand the role of H3K79 methylation gene silencing, we investigated the silencing function of Dot1 by genetic suppressor and enhancer analysis and examined the relationship between Dot1 and other global euchromatic histone modifiers.</p> <p>Result</p> <p>We determined that loss of H3K79 methylation results in a partial silencing defect that could be bypassed by conditions that promote targeting of Sir proteins to heterochromatin. Furthermore, the silencing defect in strains lacking Dot1 was dependent on methylation of H3K4 by Set1 and histone acetylation by Gcn5, Elp3, and Sas2 in euchromatin. Our study shows that multiple histone modifications associated with euchromatin positively modulate the function of heterochromatin by distinct mechanisms. Genetic interactions between Set1 and Set2 suggested that the H3K36 methyltransferase Set2, unlike most other euchromatic modifiers, negatively affects gene silencing.</p> <p>Conclusion</p> <p>Our genetic dissection of Dot1's role in silencing in budding yeast showed that heterochromatin formation is modulated by multiple euchromatic histone modifiers that act by non-overlapping mechanisms. We discuss how euchromatic histone modifiers can make negative as well as positive contributions to gene silencing by competing with heterochromatin proteins within heterochromatin, within euchromatin, and at the boundary between euchromatin and heterochromatin.</p

Assessment of resolution and intercenter reproducibility of results of genotyping Staphylococcus aureus by pulsed-field gel electrophoresis of SmaI macrorestriction fragments: a multicenter study

Twenty well-characterized isolates of methicillin-resistant Staphylococcus aureus were used to study the optimal resolution and interlaboratory reproducibility of pulsed-field gel electrophoresis (PFGE) of DNA macrorestriction fragments. Five identical isolates (one PFGE type), 5 isolates that produced related PFGE subtypes, and 10 isolates with unique PFGE patterns were analyzed blindly in 12 different laboratories by in-house protocols. In several laboratories a standardized PFGE protocol with a commercial kit was applied successfully as well. Eight of the centers correctly identified the genetic homogeneity of the identical isolates by both the in-house and standard protocols. Four of 12 laboratories failed to produce interpretable data by the standardized protocol, due to technical problems (primarily plug preparation). With the five rel

High Level Architecture (HLA) federation with Umbra and OPNET federates.

Network-centric systems that depend on mobile wireless ad hoc networks for their information exchange require detailed analysis to support their development. In many cases, this critical analysis is best provided with high-fidelity system simulations that include the effects of network architectures and protocols. In this research, we developed a high-fidelity system simulation capability using an HLA federation. The HLA federation, consisting of the Umbra system simulator and OPNET Modeler network simulator, provides a means for the system simulator to both affect, and be affected by, events in the network simulator. Advances are also made in increasing the fidelity of the wireless communication channel and reducing simulation run-time with a dead reckoning capability. A simulation experiment is included to demonstrate the developed modeling and simulation capability

Dot1 binding induces chromatin rearrangements by histone methylation-dependent and -independent mechanisms

<p>Abstract</p> <p>Background</p> <p>Methylation of histone H3 lysine 79 (H3K79) by Dot1 is highly conserved among species and has been associated with both gene repression and activation. To eliminate indirect effects and examine the direct consequences of Dot1 binding and H3K79 methylation, we investigated the effects of targeting Dot1 to different positions in the yeast genome.</p> <p>Results</p> <p>Targeting Dot1 did not activate transcription at a euchromatic locus. However, chromatin-bound Dot1 derepressed heterochromatin-mediated gene silencing over a considerable distance. Unexpectedly, Dot1-mediated derepression was established by both a H3K79 methylation-dependent and a methylation-independent mechanism; the latter required the histone acetyltransferase Gcn5. By monitoring the localization of a fluorescently tagged telomere in living cells, we found that the targeting of Dot1, but not its methylation activity, led to the release of a telomere from the repressive environment at the nuclear periphery. This probably contributes to the activity-independent derepression effect of Dot1.</p> <p>Conclusions</p> <p>Targeting of Dot1 promoted gene expression by antagonizing gene repression through both histone methylation and chromatin relocalization. Our findings show that binding of Dot1 to chromatin can positively affect local gene expression by chromatin rearrangements over a considerable distance.</p