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Heterozygous activin receptor-like kinase 1 (ALK1) mutations are associated with two vascular diseases: hereditary hemorrhagic telangiectasia (HHT) and more rarely pulmonary arterial hypertension (PAH). Here, we aimed to understand the impact of ALK1 mutations on BMP9 and BMP10 transcriptomic responses in endothelial cells. Endothelial colony-forming cells (ECFCs) and microvascular endothelial cells (HMVECs) carrying loss of function ALK1 mutations were isolated from newborn HHT and adult PAH donors, respectively. RNA-sequencing was performed on each type of cells compared to controls following an 18 h stimulation with BMP9 or BMP10. In control ECFCs, BMP9 and BMP10 stimulations induced similar transcriptomic responses with around 800 differentially expressed genes (DEGs). ALK1-mutated ECFCs unexpectedly revealed highly similar transcriptomic profiles to controls, both at the baseline and upon stimulation, and normal activation of Smad1/5 that could not be explained by a compensation in cell-surface ALK1 level. Conversely, PAH HMVECs revealed strong transcriptional dysregulations compared to controls with > 1200 DEGs at the baseline. Consequently, because our study involved two variables, ALK1 genotype and BMP stimulation, we performed two-factor differential expression analysis and identified 44 BMP9-dysregulated genes in mutated HMVECs, but none in ECFCs. Yet, the impaired regulation of at least one hit, namely lunatic fringe (LFNG), was validated by RT-qPCR in three different ALK1-mutated endothelial models. In conclusion, ALK1 heterozygosity only modified the BMP9/BMP10 regulation of few genes, including LFNG involved in NOTCH signaling. Future studies will uncover whether dysregulations in such hits are enough to promote HHT/PAH pathogenesis, making them potential therapeutic targets, or if second hits are necessary.

Background Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular dysplasia resulting in visceral arteriovenous malformations and smaller mucocutaneous telangiectasia. Most patients experience recurrent nosebleeds and become anemic without iron supplementation. However, thousands may require anticoagulation for conditions such as venous thromboembolism and/or atrial fibrillation. Over decades, tolerance data has been published for almost 200 HHT-affected users of warfarin and heparins, but there are no published data for the newer direct oral anticoagulants (DOACs) in HHT. Methods To provide such data, a retrospective audit was conducted across the eight HHT centres of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), in Denmark, France, Germany, Italy, the Netherlands and the UK. Results Although HHT Centres had not specifically recommended the use of DOACs, 32 treatment episodes had been initiated by other clinicians in 28 patients reviewed at the Centres, at median age 65 years (range 30–84). Indications were for atrial fibrillation (16 treatment episodes) and venous thromboembolism (16 episodes). The 32 treatment episodes used Apixaban ( n  = 15), Rivaroxaban ( n  = 14), and Dabigatran ( n  = 3). HHT nosebleeds increased in severity in 24/32 treatment episodes (75%), leading to treatment discontinuation in 11 (34.4%). Treatment discontinuation was required for 4/15 (26.7%) Apixaban episodes and 7/14 (50%) Rivaroxaban episodes. By a 4 point scale of increasing severity, there was a trend for Rivaroxaban to be associated with a greater bleeding risk both including and excluding patients who had used more than one agent (age-adjusted coefficients 0.61 (95% confidence intervals 0.11, 1.20) and 0.74 (95% confidence intervals 0.12, 1.36) respectively. Associations were maintained after adjustment for gender and treatment indication. Extreme hemorrhagic responses, worse than anything experienced previously, with individual nosebleeds lasting hours requiring hospital admissions, blood transfusions and in all cases treatment discontinuation, occurred in 5/14 (35.7%) Rivaroxaban episodes compared to 3/15 (20%) Apixaban episodes and published rates of ~ 5% for warfarin and heparin. Conclusions Currently, conventional heparin and warfarin remain first choice anticoagulants in HHT. If newer anticoagulants are considered, although study numbers are small, at this stage Apixaban appears to be associated with lesser bleeding risk than Rivaroxaban.

A new parasitic, mixed-field, neutron-dominated irradiation station has been recently commissioned at the European Laboratory for Particle Physics (CERN). The station is installed within the neutron time-of-flight (n_TOF) facility, taking advantage of the secondary radiation produced by the neutron spallation target, with neutrons ranging from 0.025 eV to several hundreds of MeV. The new station allows radiation damage studies to be performed in irradiation conditions that are closer to the ones encountered during the operation of particle accelerators; the irradiation tests carried out in the station will be complementary to the standard tests on materials, usually performed with gamma sources. Samples will be exposed to neutron-dominated doses in the MGy range per year, with minimal impact on the n_TOF facility operation. The station has 24 irradiation positions, each hosting up to100cm3of sample material. In view of its proximity to the n_TOF target, inside protective shielding, the irradiation station and its operating procedures have been carefully developed taking into account the safety of personnel and to avoid any unwanted impact on the operation of the n_TOF facility and experiments. Due to the residual radioactivity of the whole area around the n_TOF target and of the irradiated samples, access to the irradiation station is forbidden to human operators even when the n_TOF facility is not in operation. Robots are used for the remote installation and retrieval of the samples, and other optimizations of the handling procedures were developed in compliance with radiation protection regulations and the aim of minimizing doses to personnel. The sample containers were designed to be radiation tolerant, compatible with remote handling, and subject to detailed risk analysis and testing during their development. The whole life cycle of the irradiated materials, including their post-irradiation examinations and final disposal, was considered and optimized.

Genetic link to obesity Obesity is a highly heritable disorder but the genetic associations reported to date account for only a small percentage of the inherited variation in body mass index. Two groups report deletions on chromosome16p11.2 that may explain part of the 'missing heritability' in terms of 'high-penetrance' mutations that are rare but when present are very often associated with severe obesity. This is in contrast to more common gene defects that are less closely associated with clinical symptoms. Bochukova et al . identified rare recurrent copy number variants in 300 patients with severe early-onset obesity, caused by deletions involving several genes including SH2B1 , known to be involved in leptin and insulin signalling. Many of the patients also suffered neurodevelopmental disorders. Walters et al . identified deletions of at least 593 kilobases on chromosome 16p11.2 in 31 patients with a previously unrecognized type of extreme obesity. The strategy they used to identify the lesion — using small well-phenotyped cohorts of extreme phenotypes with targeted follow-up in genome-wide association studies and population cohorts — shows promise as a means of identifying 'missing heritability' in complex metabolic diseases more generally. Recently, numerous single nucleotide polymorphisms have been identified as being associated with obesity, but these loci together account for only a small fraction of the known heritable component. Here, an association is reported between rare deletions of at least 593 kilobases at 16p11.2 and a highly penetrant form of obesity. The strategy used of combining study of extreme phenotypes with targeted follow-up is promising for identifying missing heritability in obesity. Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western ‘obesogenic’ environment and a strong genetic contribution 1 . Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component 1 . Thus, the ‘common disease, common variant’ hypothesis is increasingly coming under challenge 2 . Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) ≥ 40 kg m -2 or BMI standard deviation score ≥ 4; P = 6.4 × 10 -8 , odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3 ). The most productive approach may therefore be to combine the ‘power of the extreme’ 4 in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

The beam dump facility (BDF) is a project for a new facility at CERN dedicated to high intensity beam dump and fixed target experiments. Currently in its design phase, the first aim of the facility is to search for light dark matter and hidden sector models with the Search for Hidden Particles (SHiP) experiment. At the core of the facility sits a dense target/dump, whose function is to absorb safely the400GeV/cSuper Proton Synchrotron (SPS) beam and to maximize the production of charm and beauty mesons. An average power of 300 kW will be deposited on the target, which will be subjected to unprecedented conditions in terms of temperature, structural loads and irradiation. In order to provide a representative validation of the target design, a prototype target has been designed, manufactured, and tested under the SPS fixed-target proton beam during 2018, up to an average beam power of 50 kW, corresponding to 350 kJ per pulse. The present contribution details the target prototype design and experimental setup, as well as a first evaluation of the measurements performed during beam irradiation. The analysis of the collected data suggests that a representative reproduction of the operational conditions of the beam dump facility target was achieved during the prototype tests, which will be complemented by a postirradiation examination campaign during 2020.

Among 353 patients with hereditary hemorrhagic telangiectasia retrospectively analyzed during the period 1985-2005, we identified 67 cases of severe infection that affected 48 patients (13.6%). Extracerebral infections accounted for 67% of all infections, and most involved Staphylococcus aureus and were associated with prolonged epistaxis. Cerebral infections accounted for 33% of all infections, were mainly due to multiple and anaerobic bacteria, and were associated with the presence of pulmonary arteriovenous malformations and a short duration of epistaxis.

Background Hereditary hemorrhagic telangiectasia (HHT) is a multisystemic inherited vascular dysplasia that leads to nosebleeds and visceral arteriovenous malformations (AVMs). Anti-angiogenic drugs thalidomide and bevacizumab have been increasingly used off-label with variable results. The HHT working group within the ERN for Rare Multisystemic Vascular Diseases (VASCERN), developed a questionnaire-based retrospective capture of adverse events (AEs) classified using the Common Terminology Criteria for Adverse Events. Results Sixty-nine HHT patients received bevacizumab, 37 (50.6%) for high output cardiac failure/hepatic AVMs, and 32 (49.4%) for bleeding; the 69 patients received bevacizumab for a mean of 11 months for a total of 63.8 person/years treatment. 67 received thalidomide, all for epistaxis and/or gastrointestinal bleeding; they received thalidomide for a mean of 13.4 months/patient for a total of 75 person/years treatment. AEs were reported in 58 patients, 33 with bevacizumab, 37 with thalidomide. 32 grade 1–3 AEs related to bevacizumab were reported with an average incidence rate of 50 per 100 person-years. 34 grade 1–3 AEs related to thalidomide were reported with an average incidence rate of 45.3 per 100 person-years. Bevacizumab AEs were more common in females (27 AEs in 46 women) than males (6 in 23, p  < 0.001). Thalidomide AEs occurred at more similar rates in males (25 AEs in 41 men, 60.9%) and females (12 in 26 (46.2%), but were more common in ENG patients (17 in 17) than in ACVRL1 (14 in 34, p  < 0.0001). For bevacizumab, the most common reports were of joint pains (7/69, 10%), headache (3/69, 4.4%) and proteinuria (2/69, 3%), and for thalidomide, peripheral neuropathy (12/67, 18%); drowsiness (8/67, 12%); and dizziness (6/67, 9%). Fatal adverse events were more common in males ( p  = 0.009), and in patients with ENG pathogenic variants ( p  = 0.012). One fatal AE was possibly related to bevacizumab (average incidence rate: 1.5 per 100 person-years); 3 fatal AEs were possibly related to thalidomide (average incidence rate: 4 per 100 person-years). Conclusions With potential increase in use of Bevacizumab and Thalidomide in HHT patients, data presented support appropriate weighing of the toxicities which can arise in HHT settings and the practice recommendations for their prevention and management.

In patients with hereditary hemorrhagic telangiectasia, treatment with engasertib reduced nosebleed frequency and duration over 12 weeks, with mild reversible rash as the most common drug-related side effect.

This paper is dedicated to the preparation of thin film with a strong perpendicular to the film plane magnetic anisotropy, behaviour of great interest for spintronics. Single-crystalline [Co/Ni] (111) superlattices have been grown by molecular beam epitaxy. The epitaxial growth of Co and Ni was controlled by using reflection high energy diffraction (RHEED), allowing us to get an accurate control of the thicknesses . The superlattices magnetic properties were studied using magnetometry. All of them exhibit strong perpendicular to the plane magnetic anisotropy. The maximum of magneto-crystalline anisotropy is obtained for one cobalt mo nolayer. A simple model which takes into account surface and volume anisotropy explains the evolution of perpendicular anisotropy in these layers.