Activity of the lipoxygenase inhibitor 1-phenyl-3-pyrazolidinone (phenidone) and derivatives on the inhibition of adhesion molecule expression on human umbilical vascular endothelial cells

Leukocyte adhesion contributes to perfusion abnormalities and tissue damage during trauma, shock or overwhelming inflammation. This study was performed to determine whether the lipoxygenase inhibitor phenidone and derivatives decrease the expression of adhesion molecules on tumor necrosis factor-α (TNF-α) stimulated endothelial cells and attenuate leukocyte-endothelial interactions under flow in vitro. TNF-α stimulated human umbilical venous endothelial cells (HUVECs) were incubated with phenidone, 4-methyl-phenidone, 4-4-dimethyl-phenidone, 5-methyl-phenidone, 5-phenyl-phenidone, and 5-methyl-1,(2,5-di-chloro-phenyl)-3-pyrazolidone. We tested the inhibition of adhesion molecule expression at different inhibitor concentrations before, during, and after the stimulation of HUVECs. The inhibition of endothelial cell expression on HUVECs was measured by flow cytometry. Rolling and firm adhesion of leukocytes to pretreated endothelium was examined in a parallel plate flow chamber. Phenidone inhibited the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and endothelial-leukocyte adhesion molecule-1 on HUVECs when added prior to HUVEC stimulation. The inhibitory effect of phenidone was still observed when added simultaneously, but not when added after HUVEC stimulation. 4-4-dimethyl-phenidone and 5-phenyl-phenidone inhibited the expression of adhesion molecules more effectively than phenidone. The attenuation of leukocyte rolling under flow conditions was also significantly more effective with 4-4-dimethyl-phenidone than with phenidone. Lipoxygenase inhibitors might be of therapeutically interest for the treatment of overwhelming systemic inflammation during shock, trauma, and sepsis

Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/- mice

Objective FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG1 variants or chromosomal microaberrations in 14q12. The study aimed at assessing the scope of structural cerebral anomalies revealed by neuroimaging to delineate the genotype and neuroimaging phenotype associations. Methods We compiled 34 patients with a heterozygous (likely) pathogenic FOXG1 variant. Qualitative assessment of cerebral anomalies was performed by standardized re-analysis of all 34 MRI data sets. Statistical analysis of genetic, clinical and neuroimaging data were performed. We quantified clinical and neuroimaging phenotypes using severity scores. Telencephalic phenotypes of adult Foxg1+/- mice were examined using immunohistological stainings followed by quantitative evaluation of structural anomalies. Results Characteristic neuroimaging features included corpus callosum anomalies (82%), thickening of the fornix (74%), simplified gyral pattern (56%), enlargement of inner CSF spaces (44%), hypoplasia of basal ganglia (38%), and hypoplasia of frontal lobes (29%). We observed a marked, filiform thinning of the rostrum as recurrent highly typical pattern of corpus callosum anomaly in combination with distinct thickening of the fornix as a characteristic feature. Thickening of the fornices was not reported previously in FOXG1 syndrome. Simplified gyral pattern occurred significantly more frequently in patients with early truncating variants. Higher clinical severity scores were significantly associated with higher neuroimaging severity scores. Modeling of Foxg1 heterozygosity in mouse brain recapitulated the associated abnormal cerebral morphology phenotypes, including the striking enlargement of the fornix. Interpretation Combination of specific corpus callosum anomalies with simplified gyral pattern and hyperplasia of the fornices is highly characteristic for FOXG1 syndrome.Peer reviewe

The population genomic legacy of the second plague pandemic

Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%–40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th–19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics.publishedVersio

The population genomic legacy of the second plague pandemic

Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%-40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th-19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics

The Surface Array planned for IceCube-Gen2

IceCube-Gen2, the extension of the IceCube Neutrino Observatory, will feature three main components: an optical array in the deep ice, a large-scale radio array in the shallow ice and firn, and a surface detector above the optical array. Thus, IceCube-Gen2 will not only be an excellent detector for PeV neutrinos, but also constitutes a unique setup for the measurement of cosmic-ray air showers, where the electromagnetic component and low-energy muons are measured at the surface and high-energy muons are measured in the ice. As for ongoing enhancement of IceCube’s current surface array, IceTop, we foresee a combination of elevated scintillation and radio detectors for the Gen2 surface array, aiming at high measurement accuracy for air showers. The science goals are manifold: The in-situ measurement of the cosmic-ray flux and mass composition, as well as more thorough tests of hadronic interaction models, will improve the understanding of muons and atmospheric neutrinos detected in the ice, in particular, regarding prompt muons. Moreover, the surface array provides a cosmic-ray veto for the in-ice detector and contributes to the calibration of the optical and radio arrays. Last but not least, the surface array will make major contributions to cosmic-ray science in the energy range of the transition from Galactic to extragalactic sources. The increased sensitivities for photons and for cosmic-ray anisotropies at multi-PeV energies provide a chance to solve the puzzle of the origin of the most energetic Galactic cosmic rays and will serve IceCube’s multimessenger mission

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements