Analysis of paleomagnetic data: a tribute to Hans Zijderveld. Introduction

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43920/1/11288_2004_Article_147505.pd

Post-Eocene coupled oroclines in the Talesh (NW Iran): paleomagnetic constraints

The Talesh Mountains (NW Iran) witnessed a long deformation history from the Triassic Cimmerian orogeny to the ongoing Arabia-Eurasia collision. This protracted multi-stage deformation has generated a remarkably curved orogen with a puzzling kinematic and deformational history. In this study, we investigate the origin of the Talesh curvature through paleomagnetic analyses on rocks of Paleozoic, Mesozoic and Cenozoic age. Our results indicate that at least two major, large-scale, vertical-axis-rotations took place since the Late Cretaceous: 1) a pre-Eocene 73° ± 17° clockwise rotation and 2) post-Eocene differential rotations that formed the Z-shaped mountain belt within a crustal-scale shear zone. The latter involved an increasing amount of clockwise (CW) rotation from south (16°) to north (48°). The orocline formation likely started during the Oligocene where an approximately east-west oriented mountain belt was buckled by the Arabia-Eurasia collision, with Arabia acting as a rigid indenter and the South Caspian basin as a rigid backstop. We hypothesise that the NE-SW oriented Aras and Lahijan fault zones, inherited from transform faults related to the Mesozoic opening of the Caspian-Black Sea back-arc, accommodated the coupled orocline formation

Dissecting distinct proteolytic activities of FMDV Lpro implicates cleavage and degradation of RLR signaling proteins, not its deISGylase/DUB activity, in type I interferon suppression

Author summary Outbreaks of the picornavirus foot-and-mouth disease virus (FMDV) have significant consequences for animal health and product safety and place a major economic burden on the global livestock industry. Understanding how this notorious animal pathogen suppresses the antiviral type I interferon (IFN-alpha/beta) response may help to develop countermeasures to control FMDV infections. FMDV suppresses the IFN-alpha/beta response through the activity of its Leader protein (L-pro), a protease that can cleave host cell proteins. L(pro)was also shown to have deubiquitinase and deISGylase activity, raising the possibility that L(pro)suppresses IFN-alpha/beta by removing ubiquitin and/or ISG15, two posttranslational modifications that can regulate the activation, interactions and localization of (signaling) proteins. Here, we show that TBK1 and MAVS, two signaling proteins that are important for activation of IFN-alpha/beta gene transcription, are cleaved by L-pro. By generating L(pro)mutants lacking either of these two activities, we demonstrate that L-pro's ability to cleave signaling proteins, but not its deubiquitination/deISGylase activity, correlates with suppression of IFN-beta gene transcription. The type I interferon response is an important innate antiviral pathway. Recognition of viral RNA by RIG-I-like receptors (RLRs) activates a signaling cascade that leads to type I interferon (IFN-alpha/beta) gene transcription. Multiple proteins in this signaling pathway (e.g. RIG-I, MDA5, MAVS, TBK1, IRF3) are regulated by (de)ubiquitination events. Most viruses have evolved mechanisms to counter this antiviral response. The leader protease (L-pro) of foot-and-mouth-disease virus (FMDV) has been recognized to reduce IFN-alpha/beta gene transcription; however, the exact mechanism is unknown. The proteolytic activity of L(pro)is vital for releasing itself from the viral polyprotein and for cleaving and degrading specific host cell proteins, such as eIF4G and NF-kappa B. In addition, L(pro)has been demonstrated to have deubiquitination/deISGylation activity. L-pro's deubiquitination/deISGylation activity and the cleavage/degradation of signaling proteins have both been postulated to be important for reduced IFN-alpha/beta gene transcription. Here, we demonstrate that TBK1, the kinase that phosphorylates and activates the transcription factor IRF3, is cleaved by L(pro)in FMDV-infected cells as well as in cells infected with a recombinant EMCV expressing L-pro.In vitrocleavage experiments revealed that L(pro)cleaves TBK1 at residues 692-694. We also observed cleavage of MAVS in HeLa cells infected with EMCV-L-pro, but only observed decreasing levels of MAVS in FMDV-infected porcine LFPK alpha V beta 6 cells. We set out to dissect L-pro's ability to cleave RLR signaling proteins from its deubiquitination/deISGylation activity, to determine their relative contributions to the reduction of IFN-alpha/beta gene transcription. The introduction of specific mutations, of which several were based on the recently published structure of L(pro)in complex with ISG15, allowed us to identify specific amino acid substitutions that separate the different proteolytic activities of L-pro. Characterization of the effects of these mutations revealed that L-pro's ability to cleave RLR signaling proteins but not its deubiquitination/deISGylation activity correlates with the reduced IFN-beta gene transcription

Examining the distribution and impact of single nucleotide polymorphisms in the capsular locus of Streptococcus pneumoniae serotype 19A

Streptococcus pneumoniae serotype 19A prevalence has increased after implementation of PCV7 and PCV10 vaccines. In this study, we have provided, with high accuracy, the genetic diversity of the 19A serotype in a cohort of Dutch invasive pneumococcal disease patients and asymptomatic carriers obtained in the period 2004-2016. Whole genomes of the 338 pneumococcal isolates in this cohort were sequenced and their capsule (cps) loci compared to examine the diversity and determine the impact on the production of CPS sugar precursors and CPS shedding. We discovered 79 types with a unique CPS locus sequence. Most variation was observed in the rmlB and rmlD genes of the TDP-Rha synthesis pathway, and in the wzg gene, of unknown function. Interestingly, gene variation in the cps locus was conserved in multiple alleles. Using RmlB and RmlD protein models, we predict that enzymatic function is not affected by the single nucleotide polymorphisms as identified. To determine if RmlB and RmlD function was affected, we analyzed nucleotide sugar levels using UHPLC-MS. CPS precursors differed between 19A cps locus subtypes, including TDP-Rha, but no clear correlation was observed. Also, a significant difference in multiple nucleotide sugar levels was observed between phylogenetically branched groups. Because of indications of a role for Wzg in capsule shedding, we analyzed if this was affected. No clear indication of a direct role in shedding was found. We thus describe genotypic variety in rmlB, rmlD and wzg in serotype 19A the Netherlands, for which we have not discovered an associated phenotype

Dielectric material options for integrated capacitors

Future MIM capacitor generations will require significantly increased specific capacitances by utilization of high-k dielectric materials. In order to achieve high capacitance per chip area, these dielectrics have to be deposited in three-dimensional capacitor structures by ALD or AVD (atomic vapor deposition) process techniques. In this study eight dielectric materials, which can be deposited by these techniques and exhibit the potential to reach k-values of over 50 were identified, prepared and characterized as single films and stacked film systems. To primarily focus on a material comparison, preliminary processes were used for film deposition on planar test devices. Measuring leakage current density versus the dielectric constant k shows that at low voltages (=1 V) dielectrics with k-values up to 100 satisfy the typical leakage current density specification o

Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.

BackgroundMucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.MethodsThis 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.ResultsThe two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.ConclusionsLaronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made