Assignment of the Human and Mouse Prion Protein Genes to Homologous Chromosomes

Purified preparations of scrapie prions contain one major macromolecule, designated prion protein (PrP). Genes encoding PrP are found in normal animals and humans but not within the infectious particles. The PrP gene was assigned to human chromosome 20 and the corresponding mouse chromosome 2 using somatic cell hybrids. In situ hybridization studies mapped the human PrP gene to band 20p12→pter. Our results should lead to studies of genetic loci syntenic with the PrP gene, which may play a role in the pathogenesis of prion diseases or other degenerative neurologic disorders

Angle and spin resolved Auger and photoelectron spectroscopy on Rb-layers by means of circularly polarized VUV radiation

Stoppmanns P, David R, Müller N, Heinzmann U. Angle and spin resolved Auger and photoelectron spectroscopy on Rb-layers by means of circularly polarized VUV radiation. Zeitschrift für Physik D: Atoms, Molecules and Clusters. 1994;30(2-3):251-253.Normal incidence circularly polarized VUV radiation with energies around 23 eV creates spin polarized photoelectrons from thick layers of Rb on Pt(111) and thus excites oriented 4[Rho] hole states. The preferential spin direction of the Auger electrons and its dependence upon the emission angle has been measured and is compared with the corresponding angular dependence of the primary photoelectron spin polarization also measured. Since the CVV Auger decay relates to a s2 pair of valence electrons, the cross comparison of results for photoelectrons and Auger electrons studies the questions on whether photoemission and Auger decay occur in sequence, assuming an independent two step model, and whether the valences-electrons couple to a singlet state configuration

Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations.

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma

A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.

Efst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinnIL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.Netherlands Asthma Foundation University Medical Center Groningen Ministry of Health and Environmental Hygiene of Netherlands Netherlands Asthma Stichting Astma Bestrijding BBMRI European Respiratory Society private and public research funds AstraZeneca ALK-Abello, Denmar

Meta-analysis identifies seven susceptibility loci involved in the atopic March

Eczema often precedes the development of asthma in a disease course called the a 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10 a'8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10 a'9). Additional susceptibility loci identified

Technical assistance to assess the potential of renewable liquid and gaseous transport fuels of non-biological origin (RFNBOs) as well as recycled carbon fuels (RCFs), to establish a methodology to determine the share of renewable energy from RFNBOs as well as to develop a framework on additionality in the transport sector

This report is a summary of the work conducted in Task 1 of the technical assistance to assess the potential of renewable fuels of non-biological origin (RFNBOs) and recycled carbon fuels (RCFs) to establish a methodology to determine the share of renewable energy from RFNBOs as well as to develop a framework on additionality in the transport sector. The goal of Task 1 within the entire project was the assessment of the deployment potential of RFNBOs and RCFs over the period from 2020 to 2050 in the EU transport sector. All relevant transport sub-sectors and modalities are considered: road transport, maritime and inland shipping, aviation, and railway. Furthermore, the competition for RFNBOs and RCFs between the transport sectors and other sectors and applications of RFNBOs is considered. A central result is the potential gross final consumption of RFNBOs and RCFs that would count towards the RES target in the transport sector. In addition, the needed resources and the arising costs for this deployment as well as the impacts on greenhouse gas emissions and local environments are analyzed. Finally, barriers to the deployment and options to overcome these are outlined

TGFβ Is Specifically Upregulated on Circulating CD14++ CD16+ and CD14+ CD16++ Monocytes in Patients with Atrial Fibrillation and Severe Atrial Fibrosis

Background/Aims: Fibrotic remodeling of the atria plays a key role in the pathogenesis of atrial fibrillation (AF). As little is known about the contribution of circulating monocytes in atrial remodeling and the pathophysiology of AF, we investigated profibrotic factors in different subsets of circulating monocytes obtained from patients with atrial fibrillation undergoing catheter ablation. Methods: A 3D high density voltage mapping was performed in sinus rhythm to evaluate the extent of low-voltage areas (LVAs) in the atria of 71 patients with persistent AF. Low-voltage was defined as signals of < 0.5mV during sinus rhythm. Prior to ablation, blood was drawn and monocytes were analyzed by FACS. Based on the expression of CD14 and CD16, three subgroups including CD14++ CD16- (‘classical’), CD14++ CD16+ (‘intermediate’), and CD14+ CD16++ (‘non-classical’) were analyzed for the expression of TGFb, CD147, and MMP-9, representing pivotal profibrotic pathways in myocardial remodeling. Results: Expression of TGFb was increased in CD14+ monocytes of patients with extensive LVAs compared to patients with a low extend of LVAs. While CD14++ CD16- monocytes showed no difference, CD14++ CD16+ and CD14+ CD16++ monocytes showed a strong increase of TGFb abundance. Although CD147 and MMP-9 are strongly associated with myocardial fibrosis, we found no difference in expression between the two groups in any monocyte subsets. Conclusion: TGFb is specifically upregulated on CD14++ CD16+ and CD14+ CD16++ monocytes in patients with extensive LVAs undergoing catheter ablation

Identification of conserved immune-related adverse event risk factors and clinical outcomes in a pan-immunotherapy data mart

BackgroundCancer immunotherapy (CIT) often triggers immune-related adverse events (irAEs). Analysis of irAEs in large checkpoint inhibitor (CPI) trials has enhanced their management and demonstrated their prognostic value for treatment outcome. However, data on irAEs in non-standard CITs are limited, and systematic exploration is lacking. Identifying predictive biomarkers for irAEs in these therapies is still emerging and essential for improving patient care.MethodsWe established a harmonized data mart from 27 early-phase CIT trials, encompassing 14 molecules with diverse mechanisms across various cancer indications. This dataset includes 3,608 patients, both CPI-naïve and CPI-experienced, with detailed information on clinical data, tumor characteristics, soluble biomarkers, and genome-wide genotyping. We examined the occurrence of different irAEs and CIT molecules concerning incidence, severity, and onset. A meta-analysis was conducted to assess the association between risk factors and the time to onset of irAEs. Finally, we explored the predictive value of irAEs for clinical outcomes, specifically measured by progression-free survival (PFS).ResultsOur analysis reveals significant variation in irAE incidence and kinetics across CIT molecules. Common irAEs include hepatitis, rash, acute kidney injuries, and hypothyroidism, with hepatitis often severe and others mild. Hepatitis is frequently associated with immunocytokine treatment, while T-cell bispecifics are linked to organ-specific toxicities. Hepatic metastases correlate with hepatitis but inversely with rash; elevated liver enzymes are associated with hepatitis, and high ferritin levels with acute kidney injury risk. Higher myeloid cell counts are associated with reduced rash likelihood. No tumor microenvironment associations were found, and polygenic risk scores show limited utility in our setting. Rash correlates with improved outcomes, whereas hepatitis is associated with a poorer prognosis, independent of baseline prognostic state assessed by the Real World Prognostic score.ConclusionsThese findings highlight the complexity of immune toxicities in early-phase trials, emphasizing the importance of the CIT class, as well as the roles of tumor burden, metastasis sites, and systemic immune state in the development of irAEs. Additionally, the observed association between skin toxicities and improved PFS suggests that skin toxicity could serve as a marker of systemic immune activation across immunotherapy contexts

Study of Human RIG-I Polymorphisms Identifies Two Variants with an Opposite Impact on the Antiviral Immune Response

International audienceBACKGROUND: RIG-I is a pivotal receptor that detects numerous RNA and DNA viruses. Thus, its defectiveness may strongly impair the host antiviral immunity. Remarkably, very little information is available on RIG-I single-nucleotide polymorphisms (SNPs) presenting a functional impact on the host response. METHODOLOGY/PRINCIPAL FINDINGS: Here, we studied all non-synonymous SNPs of RIG-I using biochemical and structural modeling approaches. We identified two important variants: (i) a frameshift mutation (P(229)fs) that generates a truncated, constitutively active receptor and (ii) a serine to isoleucine mutation (S(183)I), which drastically inhibits antiviral signaling and exerts a down-regulatory effect, due to unintended stable complexes of RIG-I with itself and with MAVS, a key downstream adapter protein. CONCLUSIONS/SIGNIFICANCE: Hence, this study characterized P(229)fs and S(183)I SNPs as major functional RIG-I variants and potential genetic determinants of viral susceptibility. This work also demonstrated that serine 183 is a residue that critically regulates RIG-I-induced antiviral signaling