The low recombining pericentromeric region of barley restricts gene diversity and evolution but not gene expression

The low-recombining pericentromeric region of the barley genome contains roughly a quarter of the genes of the species, embedded in low-recombining DNA that is rich in repeats and repressive chromatin signatures. We have investigated the effects of pericentromeric region residency upon the expression, diversity and evolution of these genes. We observe no significant difference in average transcript level or developmental RNA specificity between the barley pericentromeric region and the rest of the genome. In contrast, all of the evolutionary parameters studied here show evidence of compromised gene evolution in this region. First, genes within the pericentromeric region of wild barley show reduced diversity and significantly weakened purifying selection compared with the rest of the genome. Second, gene duplicates (ohnolog pairs) derived from the cereal whole-genome duplication event ca. 60MYa have been completely eliminated from the barley pericentromeric region. Third, local gene duplication in the pericentromeric region is reduced by 29% relative to the rest of the genome. Thus, the pericentromeric region of barley is a permissive environment for gene expression but has restricted gene evolution in a sizeable fraction of barley's genes

Lead-free piezoelectric K0.5Bi0.5TiO3–Bi(Mg0.5Ti0.5)O3 ceramics with depolarisation temperatures up to ~220 C

The properties of K0.5Bi0.5TiO3-rich ceramic solid solutions in the system (1 - x)K0.5Bi0.5TiO3– xBi(Mg0.5Ti0.5)O3 are reported. The highest values of piezoelectric charge coefficient, d33, and field-induced strains are found in compositions located close to a compositional boundary between single-phase tetragonal and mixed tetragonal ? cubic perovskite phases. Maximum d33 values were *150 pC/N for x = 0.03, with positive strains of *0.25 %; the x = 0.04 composition had a d33 * 133 pC/N and strain of 0.35 % (bipolar electric field, 50 kV/ cm, 1 Hz). Depolarisation temperature Td is an important selection criterion for any lead-free piezoelectric for actuator or sensor applications. A Td of *220 C for x = 0.03 is *100 C higher than for the widely reported Na0.5Bi0.5TiO3–BaTiO3 system, yet d33 values and strains are similar, suggesting the new material is worthy of further attention as a lead-free piezoceramic for elevated temperature applications

Apolipoprotein E mediates evasion from hepatitis C virus−neutralizing antibodies

Background & Aims Efforts to develop an effective vaccine against hepatitis C virus (HCV) have been hindered by the propensity of the virus to evade host immune responses. HCV particles in serum and in cell culture associate with lipoproteins, which contribute to viral entry. Lipoprotein association has also been proposed to mediate viral evasion of the humoral immune response, though the mechanisms are poorly defined. Methods We used small interfering RNAs to reduce levels of apolipoprotein E (apoE) in cell culture−derived HCV−producing Huh7.5-derived hepatoma cells and confirmed its depletion by immunoblot analyses of purified viral particles. Before infection of naïve hepatoma cells, we exposed cell culture−derived HCV strains of different genotypes, subtypes, and variants to serum and polyclonal and monoclonal antibodies isolated from patients with chronic HCV infection. We analyzed the interaction of apoE with viral envelope glycoprotein E2 and HCV virions by immunoprecipitation. Results Through loss-of-function studies on patient-derived HCV variants of several genotypes and subtypes, we found that the HCV particle apoE allows the virus to avoid neutralization by patient-derived antibodies. Functional studies with human monoclonal antiviral antibodies showed that conformational epitopes of envelope glycoprotein E2 domains B and C were exposed after depletion of apoE. The level and conformation of virion-associated apoE affected the ability of the virus to escape neutralization by antibodies. Conclusions In cell-infection studies, we found that HCV-associated apoE helps the virus avoid neutralization by antibodies against HCV isolated from chronically infected patients. This method of immune evasion poses a challenge for the development of HCV vaccines

Metabolic gatekeeper function of B-lymphoid transcription factors.

B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK. Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor), TXNIP (encoding a glucose-feedback sensor) and CNR2 (encoding a cannabinoid receptor) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation

The Advanced Compton Telescope

The Advanced Compton Telescope (ACT), the next major step in gamma-ray astronomy, will probe the fires where chemical elements are formed by enabling high-resolution spectroscopy of nuclear emission from supernova explosions. During the past two years, our collaboration has been undertaking a NASA mission concept study for ACT. This study was designed to (1) transform the key scientific objectives into specific instrument requirements, (2) to identify the most promising technologies to meet those requirements, and (3) to design a viable mission concept for this instrument. We present the results of this study, including scientific goals and expected performance, mission design, and technology recommendations

Effects of antenatal betamethasone on preterm human and mouse ductus arteriosus: comparison with baboon data.

BackgroundAlthough studies involving preterm infants ≤34 weeks gestation report a decreased incidence of patent ductus arteriosus after antenatal betamethasone, studies involving younger gestation infants report conflicting results.MethodsWe used preterm baboons, mice, and humans (≤276/7 weeks gestation) to examine betamethasone's effects on ductus gene expression and constriction both in vitro and in vivo.ResultsIn mice, betamethasone increased the sensitivity of the premature ductus to the contractile effects of oxygen without altering the effects of other contractile or vasodilatory stimuli. Betamethasone's effects on oxygen sensitivity could be eliminated by inhibiting endogenous prostaglandin/nitric oxide signaling. In mice and baboons, betamethasone increased the expression of several developmentally regulated genes that mediate oxygen-induced constriction (K+ channels) and inhibit vasodilator signaling (phosphodiesterases). In human infants, betamethasone increased the rate of ductus constriction at all gestational ages. However, in infants born ≤256/7 weeks gestation, betamethasone's contractile effects were only apparent when prostaglandin signaling was inhibited, whereas at 26-27 weeks gestation, betamethasone's contractile effects were apparent even in the absence of prostaglandin inhibitors.ConclusionsWe speculate that betamethasone's contractile effects may be mediated through genes that are developmentally regulated. This could explain why betamethasone's effects vary according to the infant's developmental age at birth

Re-entrant relaxor ferroelectric behaviour in Nb-doped BiFeO 3 –BaTiO 3 ceramics †

BiFeO3–BaTiO3 (BF–BT) solid solutions exhibit great promise as the basis for high temperature piezoelectric transducers and energy storage dielectrics, but the fundamental mechanisms governing their functional properties require further clarification. In the present study, both pure and niobium-doped 0.7BF–0.3BT ceramics are synthesized by solid state reaction and their structure–property relationships are systematically investigated. It is shown that substituting a low concentration of Ti with Nb at a level of 0.5 at% increases the resistivity of BF–BT ceramics and facilitates ferroelectric switching at high electric field levels. Stable planar piezoelectric coupling factor values are achieved with a variation from 0.35 to 0.45 over the temperature range from 100 to 430 °C. In addition to the ferroelectric-paraelectric phase transformation at the Curie point (∼430 °C), a frequency-dependent relaxation of the dielectric permittivity and associated loss peak are observed over the temperature range from −50 to +150 °C. These effects are correlated with anomalous enhancement of the remanent polarization and structural (rhombohedral) distortion with increasing temperature, indicating the occurrence of a re-entrant relaxor ferroelectric transformation on cooling. The results of the study provide new insight into the thermal evolution of structure and the corresponding functional properties in BF–BT and related solid solutions

Core-shell Grain Structures and Dielectric Properties of Na0.5K0.5NbO3-LiTaO3-BiScO3 Piezoelectric Ceramics.

The origins of distinctive compositional dependence of relative permittivity, ɛr, in the Pb-free piezoelectric system (1-x)Na0.5K0.5NbO3-xLiTaO3, x≤ 10 mol.% modified with BiScO3 have been revealed using transmission electron microscopy with energy dispersive X-ray analysis (TEM-EDX). As the LiTaO3 content increased the Curie peak at ~370°C in ɛr –T plots became more diffuse, and at x= 5 mol.% an additional higher temperature peak occurred. TEM-EDX analysis showed the change in dielectric properties at x= 5 mol.% was due to a change in microstructure: micron-scale grains were replaced by submicron grains exhibiting core-shell chemical segregation. The outer shell was similar to the target solid solution composition, slightly enriched in Bi, Sc and Ta, whilst the core approximated to (Na, K, Li)NbO3 and was responsible for the additional dielectric peak. Examples of a novel three-tier metastable grain structure were observed for certain compositions

Top research priorities in liver and gallbladder disorders in the UK

OBJECTIVES: There is a mismatch between research questions considered important by patients, carers and healthcare professionals and the research performed in many fields of medicine. The non-alcohol-related liver and gallbladder disorders priority setting partnership was established to identify the top research priorities in the prevention, diagnostic and treatment of gallbladder disorders and liver disorders not covered by the James-Lind Alliance (JLA) alcohol-related liver disease priority setting partnership. DESIGN: The methods broadly followed the principles of the JLA guidebook. The one major deviation from the JLA methodology was the final step of identifying priorities: instead of prioritisation by group discussions at a consensus workshop involving stakeholders, the prioritisation was achieved by a modified Delphi consensus process. RESULTS: A total of 428 unique valid diagnostic or treatment research questions were identified. A literature review established that none of these questions were considered 'answered' that is, high-quality systematic reviews suggest that further research is not required on the topic. The Delphi panel achieved consensus (at least 80% Delphi panel members agreed) that a research question was a top research priority for six questions. Four additional research questions with highest proportion of Delphi panel members ranking the question as highly important were added to constitute the top 10 research priorities. CONCLUSIONS: A priority setting process involving patients, carers and healthcare professionals has been used to identify the top 10priority areas for research related to liver and gallbladder disorders. Basic, translational, clinical and public health research are required to address these uncertainties

The effect of interplanetary scintillation on epoch of reionization power spectra

© 2015. The American Astronomical Society. All rights reserved. Interplanetary Scintillation (IPS) induces intensity fluctuations in small angular size astronomical radio sources via the distortive effects of spatially and temporally varying electron density associated with outflows from the Sun. These radio sources are a potential foreground contaminant signal for redshifted HI emission from the Epoch of Reionization (EoR) because they yield time-dependent flux density variations in bright extragalactic point sources. Contamination from foreground continuum sources complicates efforts to discriminate the cosmological signal from other sources in the sky. In IPS, at large angles from the Sun applicable to EoR observations, weak scattering induces spatially and temporally correlated fluctuations in the measured flux density of sources in the field, potentially affecting the detectability of the EoR signal by inducing non-static variations in the signal strength. In this work, we explore the impact of interplanetary weak scintillation on EoR power spectrum measurements, accounting for the instrumental spatial and temporal sampling. We use published power spectra of electron density fluctuations and parameters of EoR experiments to derive the IPS power spectrum in the wavenumber phase space of EoR power spectrum measurements. The contrast of IPS power to expected cosmological power is used as a metric to assess the impact of IPS. We show that IPS has a spectral structure different from power from foregrounds alone, but the additional leakage into the EoR observation parameter space is negligible under typical IPS conditions, unless data are used from deep within the foreground contamination region