Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice.

Mutations in SLURP1 cause mal de Meleda, a rare palmoplantar keratoderma (PPK). SLURP1 is a secreted protein that is expressed highly in keratinocytes but has also been identified elsewhere (e.g., spinal cord neurons). Here, we examined Slurp1-deficient mice (Slurp1(-/-)) created by replacing exon 2 with β-gal and neo cassettes. Slurp1(-/-) mice developed severe PPK characterized by increased keratinocyte proliferation, an accumulation of lipid droplets in the stratum corneum, and a water barrier defect. In addition, Slurp1(-/-) mice exhibited reduced adiposity, protection from obesity on a high-fat diet, low plasma lipid levels, and a neuromuscular abnormality (hind-limb clasping). Initially, it was unclear whether the metabolic and neuromuscular phenotypes were due to Slurp1 deficiency, because we found that the targeted Slurp1 mutation reduced the expression of several neighboring genes (e.g., Slurp2, Lypd2). We therefore created a new line of knockout mice (Slurp1X(-/-) mice) with a simple nonsense mutation in exon 2. The Slurp1X mutation did not reduce the expression of adjacent genes, but Slurp1X(-/-) mice exhibited all of the phenotypes observed in the original line of knockout mice. Thus, Slurp1 deficiency in mice elicits metabolic and neuromuscular abnormalities in addition to PPK

Editorial: on the road towards treatment of gastroparesis—accelerating, but do we get closer? Authors' reply

LINKED CONTENTThis article is linked to Kuo et al and Wuestenberghs & Gourcerol papers. To view these articles, visit https://doi.org/10.1111/apt.16344 and https://doi.org/10.1111/apt.1637

TLR2 and TLR4 as Potential Biomarkers of Environmental Particulate Matter Exposed Human Myeloid Dendritic Cells

In many subjects who are genetically susceptible to asthma, exposure to environmental stimuli may exacerbate their condition. However, it is unknown how the expression and function of a family of pattern-recognition receptors called toll-like receptors (TLR) are affected by exposure to particulate pollution. TLRs serve a critical function in alerting the immune system of tissue damage or infection—the so-called “danger signals”. We are interested in the role that TLRs play in directing appropriate responses by innate immunity, particularly dendritic cells (DC), after exposing them to particulate pollution. Dendritic cells serve a pivotal role in directing host immunity. Thus, we hypothesized that alterations in TLR expression could be further explored as potential biomarkers of effect related to DC exposure to particulate pollution. We show some preliminary data that indicates that inhaled particulate pollution acts directly on DC by down-regulating TLR expression and altering the activation state of DC. While further studies are warranted, we suggest that alterations in TLR2 and TLR4 expression should be explored as potential biomarkers of DC exposure to environmental particulate pollution

Synthesis of the elements in stars: forty years of progress

Forty years ago Burbidge, Burbidge, Fowler, and Hoyle combined what we would now call fragmentary evidence from nuclear physics, stellar evolution and the abundances of elements and isotopes in the solar system as well as a few stars into a synthesis of remarkable ingenuity. Their review provided a foundation for forty years of research in all of the aspects of low energy nuclear experiments and theory, stellar modeling over a wide range of mass and composition, and abundance studies of many hundreds of stars, many of which have shown distinct evidence of the processes suggested by B2FH. In this review we summarize progress in each of these fields with emphasis on the most recent developments

Strong-Coupling Expansions for Multiparticle Excitations: Continuum and Bound States

We present a new linked cluster expansion for calculating properties of multiparticle excitation spectra to high orders. We use it to obtain the two-particle spectra for systems of coupled spin-half dimers. We find that even for weakly coupled dimers the spectrum is very rich, consisting of many bound states. The number of bound states depends on both geometry of coupling and frustration. Many of the bound states can only be seen by going to sufficiently high orders in the perturbation theory, showing the extended character of the pair-attraction.Comment: 4 pages, 5 figure

The effect of graphite and carbon black ratios on conductive ink performance

Conductive inks based on graphite and carbon black are used in a host of applications including energy storage, energy harvesting, electrochemical sensors and printed heaters. This requires accurate control of electrical properties tailored to the application; ink formulation is a fundamental element of this. Data on how formulation relates to properties have tended to apply to only single types of conductor at any time, with data on mixed types of carbon only empirical thus far. Therefore, screen printable carbon inks with differing graphite, carbon black and vinyl polymer content were formulated and printed to establish the effect on rheology, deposition and conductivity. The study found that at a higher total carbon loading ink of 29.4% by mass, optimal conductivity (0.029 Ω cm) was achieved at a graphite to carbon black ratio of 2.6 to 1. For a lower total carbon loading (21.7 mass %), this ratio was reduced to 1.8 to 1. Formulation affected viscosity and hence ink transfer and also surface roughness due to retention of features from the screen printing mesh and the inherent roughness of the carbon components, as well as the ability of features to be reproduced consistently

Imagining technology-enhanced learning with heritage artefacts: teacher-perceived potential of 2D and 3D heritage site visualisations

Background: There is much to be realised in the educational potential of national and world heritage sites. Such sites need to be supported in sharing their resources with a wide and international public, especially within formal education. Two-dimensional (2D) and three-dimensional (3D) heritage site visualisations could serve this need. Our study focuses on the teacher-perceived possibilities and benefits for education around such visualisations. Purpose: We describe how a group of UK teachers perceive the potential of cross-curricular learning that could arise from an Italian world heritage site. The teachers commented on 2D visualisations of artefacts from this site, as well as the design of a 3D immersive environment to serve educational purposes. We consider as follows: (1) how the cross-curricular teaching potential of such resources is perceived, and (2) what design features of a 3D immersive environment teachers suggest are needed for educational explorations. Sample: We recruited 10 teachers from the Midlands region of the UK and carried out semi-structured interviews. Methods: Interviews were transcribed and a thematic analysis applied to the conversations. Questioning was grounded in the examination of 2D and 3D visual resources. This provoked cross-curricular and educational design thinking. Results: Teacher responses highlighted a wide range of cross-curricular possibilities. However, they expressed a more ‘assimilative’ than ‘accommodative’ approach when relating resources to the curriculum. Such ‘assimilation’ involved seeing the site artefacts as raw material for more instrumental ‘curriculum activities’ (e.g. within art and design, geography, maths or literacy) rather than a more accommodative approach whereby curricular disciplines were exercised to make new meaning from the artefacts. In relation to 3D technology design, most teachers highlighted three technology features that would render it well matched to educational practice and three educational benefits over non-3D immersive environments. Conclusions: Teachers can easily imagine a rich range of opportunities to utilise 2D and 3D heritage site artefacts within the curriculum. However, the largely assimilative nature of this cross-curricular appropriation suggests the value of providing more guidance and support to teachers in the interpretation and application of artefacts. Their design suggestions can usefully inform construction of educational features within 3D immersive technologies that support heritage site experiences

Field Deployment of Prototype Antenna Tiles for the Mileura Widefield Array--Low Frequency Demonstrator

Experiments were performed with prototype antenna tiles for the Mileura Widefield Array--Low Frequency Demonstrator (MWA-LFD) to better understand the widefield, wideband properties of their design and to characterize the radio frequency interference (RFI) between 80 and 300 MHz at the site in Western Australia. Observations acquired during the six month deployment confirmed the predicted sensitivity of the antennas, sky-noise dominated system temperatures, and phase-coherent interferometric measurements. The radio spectrum is remarkably free of strong terrestrial signals, with the exception of two narrow frequency bands allocated to satellite downlinks and rare bursts due to ground-based transmissions being scattered from aircraft and meteor trails. Results indicate the potential of the MWA-LFD to make significant achievements in its three key science objectives: epoch of reionziation science, heliospheric science, and radio transient detection.Comment: Accepted by AJ. 17 pages with figure

Tildacerfont in Adults With Classic Congenital Adrenal Hyperplasia: Results from Two Phase 2 Studies

Context: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is typically treated with lifelong supraphysiologic doses of glucocorticoids (GCs). Tildacerfont, a corticotropin-releasing factor type-1 receptor antagonist, may reduce excess androgen production, allowing for GC dose reduction. Objective: Assess tildacerfont safety and efficacy. Design and setting: Two Phase 2 open-label studies. Patients: Adults with 21OHD. Intervention: Oral tildacerfont 200 to 1000 mg once daily (QD) (n = 10) or 100 to 200 mg twice daily (n = 9 and 7) for 2 weeks (Study 1), and 400 mg QD (n = 11) for 12 weeks (Study 2). Main outcome measure: Efficacy was evaluated by changes from baseline at 8 am in adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), and androstenedione (A4) according to baseline A4 ≤ 2× upper limit of normal (ULN) or A4 > 2× ULN. Safety was evaluated using adverse events (AEs) and laboratory assessments. Results: In Study 1, evaluable participants with baseline A4 > 2× ULN (n = 11; 19-67 years, 55% female) had reductions from baseline in ACTH (-59.4% to -28.4%), 17-OHP (-38.3% to 0.3%), and A4 (-24.2% to -18.1%), with no clear dose response. In Study 2, participants with baseline A4 > 2× ULN (n = 5; 26-63 years, 40% female) had ~80% maximum mean reductions in biomarker levels. ACTH and A4 were normalized for 60% and 40%, respectively. In both studies, participants with baseline A4 ≤ 2× ULN maintained biomarker levels. AEs (in 53.6% of patients overall) included headache (7.1%) and upper respiratory tract infection (7.1%). Conclusions: For patients with 21OHD, up to 12 weeks of oral tildacerfont reduced or maintained key hormone biomarkers toward normal

Plasmodium falciparum gametocyte dynamics in areas of different malaria endemicity

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to identify and compare factors associated with <it>Plasmodium falciparum </it>gametocyte carriage in three regions of differing malaria endemicity.</p> <p>Methods</p> <p>Retrospective data from Thailand, The Gambia and Tanzania were used. The data came from large prospective field-based clinical trials, which investigated gametocyte carriage after different anti-malarial drug treatments.</p> <p>Results</p> <p>Gametocytaemia was detected during the observation period in 12% of patients (931 out of 7548) in Thailand, 34% (683 out of 2020) in The Gambia, and 31% (430 out of 1400) in Tanzania (p < 0.001). Approximately one third (33%, 680/2044) of the patients with gametocytaemia during the observation period, already had patent gametocytaemia at enrolment (day 0 or day 1): 35% (318/931) in Thailand, 37% (250/683) in The Gambia, 26% (112/430) in Tanzania. Maximum gametocytaemia was usually observed on or before the seventh day after starting treatment (93% in Thailand, 70% in Tanzania and 78% in The Gambia). Lowest gametocyte carriage rates were observed following treatment with artemisinin derivatives, while sulphadoxine-pyrimethamine (SP) was associated with significantly greater development of gametocytaemia than other drug treatments (p < 0.001). The duration of gametocyte carriage was shorter in Thailand by 86% and Tanzania by 65% than in The Gambia. Gametocyte carriage was 27% longer among people presenting with anaemia, and was shorter in duration among patients who received artemisinin derivatives, by 27% in Thailand and by 71% in Tanzania and The Gambia.</p> <p>Conclusion</p> <p>This study confirms the independent association of gametocytaemia with anaemia, and the significantly lower prevalence and duration of gametocyte carriage following treatment with an artemisinin derivative. The large differences in gametocyte carriage rates between regions with different levels of malaria transmission suggest that drug interventions to prevent transmission will have different effects in different places.</p