Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height.

The biological processes controlling human growth are diverse, complex and poorly understood. Genetic factors are important and human height has been shown to be a highly polygenic trait to which common and rare genetic variation contributes. Weaver syndrome is a human overgrowth condition characterised by tall stature, dysmorphic facial features, learning disability and variable additional features. We performed exome sequencing in four individuals with Weaver syndrome, identifying a mutation in the histone methyltransferase, EZH2, in each case. Sequencing of EZH2 in additional individuals with overgrowth identified a further 15 mutations. The EZH2 mutation spectrum in Weaver syndrome shows considerable overlap with the inactivating somatic EZH2 mutations recently reported in myeloid malignancies. Our data establish EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth

No-Bang Quantum State of the Cosmos

A quantum state of the entire cosmos (universe or multiverse) is proposed which is the equal mixture of the Giddings-Marolf states that are asymptotically single de Sitter spacetimes in both past and future and are regular on the throat or neck of minimal three-volume. That is, states are excluded that have a big bang or big crunch or which split into multiple asymptotic de Sitter spacetimes. (For simplicity, transitions between different values of the cosmological constant are assumed not to occur, though different positive values are allowed.) The entropy of this mixed state appears to be of the order of the three-fourths power of the Bekenstein-Hawking A/4 entropy of de Sitter spacetime. Most of the component pure states do not have rapid inflation, but when an inflaton is present and the states are weighted by the volume at the end of inflation, a much smaller number of states may dominate and give a large amount of inflation and hence may agree with observations.Comment: 18 pages, LaTeX, updated with a few new qualifications and reference

Frost flowers growing in the Arctic ocean‐atmosphere–sea ice–snow interface: 2. Mercury exchange between the atmosphere, snow, and frost flowers

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95146/1/jgrd17360.pd

Explore the concept of “light” and its interaction with matter: an inquiry-based science education project in primary school

The exploration process leading to the understanding of physical phenomena, such as light and its interaction with matter, raises great interest and curiosity in children. However, in most primary schools, children rarely have the opportunity to conduct science activities in which they can engage in an enquiry process even if by the action of the teacher. In this context, we have organised several in-service teacher training courses and carried out several pedagogic interventions in Portuguese primary schools, with the aim of promoting inquirybased science education. This article describes one of those projects, developed with a class of the third grade, which explored the curricular topic “Light Experiments”. Various activities were planned and implemented, during a total of ten hours spread over five lessons. The specific objectives of this paper are: to illustrate and analyse the teaching and learning process promoted in the classroom during the exploration of one of these lessons, and to assess children’s learning three weeks after the lessons. The results suggest that children made significant learning which persisted. We conclude discussing some processes that stimulated children’ learning, including the importance of teacher questioning in scaffolding children's learning and some didactic implications for teacher training.CIEC – Research Centre on Child Studies, IE, UMinho (FCT R&D unit 317), Portuga

Association of a Deletion of GSTT2B with an Altered Risk of Oesophageal Squamous Cell Carcinoma in a South African Population: A Case-Control Study

Polymorphisms in the Glutathione S-transferase genes are associated with altered risks in many cancers, but their role in oesophageal cancer is unclear. Recently a 37-kb deletion polymorphism of GSTT2B that reduces expression of GSTT2 has been described. We evaluated the influence of the GSTT1 and GSTT2B deletion polymorphisms, and the GSTP1 Ile105Val polymorphism (rs1695) on susceptibility to oesophageal squamous cell carcinoma (OSCC) in the Black and Mixed Ancestry populations of South Africa.The GSTT1, GSTT2B and GSTP1 variants were genotyped in 562 OSCC cases and 907 controls, and tested for association with OSCC and for interaction with smoking and alcohol consumption. Linkage disequilibrium (LD) between the deletions at GSTT1 and GSTT2B was determined, and the haplotypes tested for association with OSCC. Neither the GSTT1 deletion nor the GSTP1 Ile105Val polymorphism was associated with OSCC risk in the Black or Mixed Ancestry populations. The GSTT2B deletion was not associated with OSCC risk in the Black population, but was associated with reduced risk of OSCC in the Mixed Ancestry population (OR=0.71; 95% CI 0.57-0.90, p=0.004). Case-only analysis showed no interaction between the GST polymorphisms and smoking or alcohol consumption. LD between the neighboring GSTT1 and GSTT2B deletions was low in both populations (r(2)(Black)=0.04; r(2)(MxA)=0.07), thus these deletions should be assessed independently for effects on disease risk.Although there was no association between the GSTT1 deletion polymorphism or the GSTP1 Ile105Val polymorphism with OSCC, our results suggest that the presence of the recently described GSTT2B deletion may have a protective effect on the risk of OSCC in the Mixed Ancestry South African population. This is the first report of the contribution of the GSTT2B deletion to cancer risk

Clinical Utility of Random Anti–Tumor Necrosis Factor Drug–Level Testing and Measurement of Antidrug Antibodies on the Long-Term Treatment Response in Rheumatoid Arthritis

Objective: To investigate whether antidrug antibodies and/or drug non-trough levels predict the long-term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.  Methods: A total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme-linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non-trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.  Results: Among patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.  Conclusion: Pharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months

Touch and contact during COVID-19:Insights from queer digital spaces

The aim of this conceptual paper is to discuss the transformation of socialisation processes due to the digitalisation of entertainment and community formation during COVID-19. More specifically, we focus on alternative modes of touch and contact within the context of queer digital entertainment spaces and question how the world is shaped and sensed in a (post-) COVID-19 era. Inspired by the work of Karen Barad on a quantum theory of queer intimacies, we highlight that the rise of hybridised experiences in-between physical and digital spaces captures a series of spatio-temporal, material and symbolic dimensions of touch and contact. We conclude by drawing implications for the future of organisations and work

A polarimetrically oriented X-ray stare at the accreting pulsar EXO 2030+375

Accreting X-ray pulsars (XRPs) are presumably ideal targets for polarization measurements, as their high magnetic field strength is expected to polarize the emission up to a polarization degree of ~80%. However, such expectations are being challenged by recent observations of XRPs with the Imaging X-ray Polarimeter Explorer (IXPE). Here we report on the results of yet another XRP, EXO 2030+375, observed with IXPE and contemporarily monitored with Insight-HXMT and SRG/ART-XC. In line with recent results obtained with IXPE for similar sources, analysis of the EXO 2030+375 data returns a low polarization degree of 0%-3% in the phase-averaged study and variation in the range 2%-7% in the phase-resolved study. Using the rotating vector model we constrain the geometry of the system and obtain a value for the magnetic obliquity of ~$60^{\circ}$. Considering also the estimated pulsar inclination of ~$130^{\circ}$, this indicates that the magnetic axis swings close to the observer line of sight. Our joint polarimetric, spectral and timing analysis hint to a complex accreting geometry where magnetic multipoles with asymmetric topology and gravitational light bending significantly affect the observed source behavior.Comment: A&A accepted. Proofs versio

X-ray polarimetry of the accreting pulsar GX 301-2

The phase- and energy-resolved polarization measurements of accreting X-ray pulsars (XRPs) allow us to test different theoretical models of their emission, as well as to provide an avenue to determine the emission region geometry. We present the results of the observations of the XRP GX 301-2 performed with the Imaging X-ray Polarimetry Explorer (IXPE). GX 301-2 is a persistent XRP with one of the longest known spin periods of ~680 s. A massive hyper-giant companion star Wray 977 supplies mass to the neutron star via powerful stellar winds. We do not detect significant polarization in the phase-averaged data using spectro-polarimetric analysis, with the upper limit on the polarization degree (PD) of 2.3% (99% confidence level). Using the phase-resolved spectro-polarimetric analysis we get a significant detection of polarization (above 99% c.l.) in two out of nine phase bins and marginal detection in three bins, with a PD ranging between ~3% and ~10%, and a polarization angle varying in a very wide range from ~0 deg to ~160 deg. Using the rotating vector model we obtain constraints on the pulsar geometry using both phase-binned and unbinned analysis getting excellent agreement. Finally, we discuss possible reasons for a low observed polarization in GX 301-2.Comment: 10 pages, 10 figures, submitted to A&

IXPE Observations of the Quintessential Wind-accreting X-Ray Pulsar Vela X-1

The radiation from accreting X-ray pulsars was expected to be highly polarized, with some estimates for the polarization degree of up to 80%. However, phase-resolved and energy-resolved polarimetry of X-ray pulsars is required in order to test different models and to shed light on the emission processes and the geometry of the emission region. Here we present the first results of the observations of the accreting X-ray pulsar Vela X-1 performed with the Imaging X-ray Polarimetry Explorer. Vela X-1 is considered to be the archetypal example of a wind-accreting, high-mass X-ray binary system, consisting of a highly magnetized neutron star accreting matter from its supergiant stellar companion. The spectropolarimetric analysis of the phase-averaged data for Vela X-1 reveals a polarization degree (PD) of 2.3% ± 0.4% at the polarization angle (PA) of −47.°3 ± 5.°4. A low PD is consistent with the results obtained for other X-ray pulsars and is likely related to the inverse temperature structure of the neutron star atmosphere. The energy-resolved analysis shows the PD above 5 keV reaching 6%–10% and a ∼90° difference in the PA compared to the data in the 2–3 keV range. The phase-resolved spectropolarimetric analysis finds a PD in the range 0%–9% with the PA varying between −80° and 40°