Quantum whistling in superfluid 4He

Fundamental considerations predict that macroscopic quantum systems such as superfluids and the electrons in superconductors will exhibit oscillatory motion when pushed through a small constriction. Here we report the observation of these oscillations between two reservoirs of superfluid 4He partitioned by an array of nanometer-sized apertures. They obey the Josephson frequency equation and are coherent amongst all the apertures. This discovery at the relatively high temperature of 2K (2000 times higher than related phenomena in 3He) may pave the way for a new class of practical rotation sensors of unprecedented precision.Comment: 6 pages, 3 figures, to be published in Natur

Novel associations for hypothyroidism include known autoimmune risk loci

Hypothyroidism is the most common thyroid disorder, affecting about 5% of the general population. Here we present the first large genome-wide association study of hypothyroidism, in 2,564 cases and 24,448 controls from the customer base of 23andMe, Inc., a personal genetics company. We identify four genome-wide significant associations, two of which are well known to be involved with a large spectrum of autoimmune diseases: rs6679677 near _PTPN22_ and rs3184504 in _SH2B3_ (p-values 3.5e-13 and 3.0e-11, respectively). We also report associations with rs4915077 near _VAV3_ (p-value 8.3e-11), another gene involved in immune function, and rs965513 near _FOXE1_ (p-value 3.1e-14). Of these, the association with _PTPN22_ confirms a recent small candidate gene study, and _FOXE1_ was previously known to be associated with thyroid-stimulating hormone (TSH) levels. Although _SH2B3_ has been previously linked with a number of autoimmune diseases, this is the first report of its association with thyroid disease. The _VAV3_ association is novel. These results suggest heterogeneity in the genetic etiology of hypothyroidism, implicating genes involved in both autoimmune disorders and thyroid function. Using a genetic risk profile score based on the top association from each of the four genome-wide significant regions in our study, the relative risk between the highest and lowest deciles of genetic risk is 2.1

Environmental Factors in the Relapse and Recurrence of Inflammatory Bowel Disease:A Review of the Literature

The causes of relapse in patients with Crohn's disease (CD) and ulcerative colitis (UC) are largely unknown. This paper reviews the epidemiological and clinical data on how medications (non-steroidal anti-inflammatory drugs, estrogens and antibiotics), lifestyle factors (smoking, psychological stress, diet and air pollution) may precipitate clinical relapses and recurrence. Potential biological mechanisms include: increasing thrombotic tendency, imbalances in prostaglandin synthesis, alterations in the composition of gut microbiota, and mucosal damage causing increased permeability

Influence of leaf trichome type, and density on the host plant selection by the greenhouse whitefly, Trialeurodes vaporariorum (Hemiptera: Aleyrodidae)

Host selection by adult greenhouse whitefly Trialeurodes vaporariorum (Westwood) was assessed on two pelargonium plant cultivars, Pelargonium x domesticum (regal) and P. x hortorum (zonal) using Petri dish bioassay chambers in choice and no-choice tests. Plant characteristics which could influence the oviposition preference of the whitely i.e., type and density of trichomes on the abaxial leaf surface was determined. A strong host preference was observed for the regal compared to the zonal pelargonium by the adult whiteflies. In no-choice tests, adults laid a significantly higher number of eggs on regal than on zonal leaves both at 24 and 48 hours post-exposure, respectively. After exposure to the adult whitefly, the number of 42 eggs in choice tests were similar between cultivars at 24 hours, but were higher for regal at 48 and 72 hours. The total number of trichomes (sng: straight non-glandular + sg: straight glandular) per 0.50 cm2 44 was significantly less on regal (Mean ± SE sng + sg; 43.1 ± 1.5) than on zonal leaves (60.5 ± 1.2); however, the sng trichomes were significantly higher on the zonal (49.4 ± 0.96) than the regal leaves (28.6 ± 1.00). Also, the number of sg trichomes was slightly higher for the regal cultivar leaves compared to the zonal, being 14.4 ± 1.2 and 11.2 ± 0.5, respectively. Results suggest that the trichome density, type and the ability to express glandular exudates can affect adult whitefly Pelargonium cultivar preference and plays an important role in their host plant selection for oviposition

"Fortunate are those who take the first steps"? The psychosocial impact of novel drug development.

Novel drug development offers people with cystic fibrosis exciting opportunities but is not without challenges. Currently, there is an understandable emphasis on protecting patients' physical health when developing treatments. However, there appears to be little consideration of how novel drug development impacts on psychosocial wellbeing, or the downstream consequences of this. Using an illustrative case and reviewing the literature we explore themes regarding the psychosocial impact of trial participation and novel drug development and identify areas requiring further research. Through this, we hope to prepare healthcare professionals to better understand the needs of their patients in this rapidly evolving landscape

A PSTOL-like gene, TaPSTOL, controls a number of agronomically important traits in wheat

Background Phosphorus (P) is an essential macronutrient for plant growth, and is required in large quantities by elite varieties of crops to maintain yields. Approximately 70% of global cultivated land suffers from P deficiency, and it has recently been estimated that worldwide P resources will be exhausted by the end of this century, increasing the demand for crops more efficient in their P usage. A greater understanding of how plants are able to maintain yield with lower P inputs is, therefore, highly desirable to both breeders and farmers. Here, we clone the wheat (Triticum aestivum L.) homologue of the rice PSTOL gene (OsPSTOL), and characterize its role in phosphate nutrition plus other agronomically important traits. Results TaPSTOL is a single copy gene located on the short arm of chromosome 5A, encoding a putative kinase protein, and shares a high level of sequence similarity to OsPSTOL. We re-sequenced TaPSTOL from 24 different wheat accessions and (3) three T. durum varieties. No sequence differences were detected in 26 of the accessions, whereas two indels were identified in the promoter region of one of the durum wheats. We characterised the expression of TaPSTOL under different P concentrations and demonstrated that the promoter was induced in root tips and hairs under P limiting conditions. Overexpression and RNAi silencing of TaPSTOL in transgenic wheat lines showed that there was a significant effect upon root biomass, flowering time independent of P treatment, tiller number and seed yield, correlating with the expression of TaPSTOL. However this did not increase PUE as elevated P concentration in the grain did not correspond to increased yields. Conclusions Manipulation of TaPSTOL expression in wheat shows it is responsible for many of the previously described phenotypic advantages as OsPSTOL except yield. Furthermore, we show TaPSTOL contributes to additional agronomically important traits including flowering time and grain size. Analysis of TaPSTOL sequences from a broad selection of wheat varieties, encompassing 91% of the genetic diversity in UK bread wheat, showed that there is very little genetic variation in this gene, which would suggest that this locus may have been under high selection pressure

Respective impacts of Arctic sea ice decline and increasing greenhouse gases concentration on Sahel precipitation

The impact of climate change on Sahel precipitation is uncertain and has to be widely documented. Recently, it has been shown that Arctic sea ice loss leverages the global warming effects worldwide, suggesting a potential impact of Arctic sea ice decline on tropical regions. However, defining the specific roles of increasing greenhouse gases (GHG) concentration and declining Arctic sea ice extent on Sahel climate is not straightforward since the former impacts the latter. We avoid this dependency by analysing idealized experiments performed with the CNRM-CM5 coupled model. Results show that the increase in GHG concentration explains most of the Sahel precipitation change. We found that the impact due to Arctic sea ice loss depends on the level of atmospheric GHG concentration. When the GHG concentration is relatively low (values representative of 1980s), then the impact is moderate over the Sahel. However, when the concentration in GHG is levelled up, then Arctic sea ice loss leads to increased Sahel precipitation. In this particular case the ocean-land meridional gradient of temperature strengthens, allowing a more intense monsoon circulation. We linked the non-linearity of Arctic sea ice decline impact with differences in temperature and sea level pressure changes over the North Atlantic Ocean. We argue that the impact of the Arctic sea ice loss will become more relevant with time, in the context of climate change

Antarctic last interglacial isotope peak in response to sea ice retreat not ice-sheet collapse

Several studies have suggested that sea-level rise during the last interglacial implies retreat of the West Antarctic Ice Sheet (WAIS). The prevalent hypothesis is that the retreat coincided with the peak Antarctic temperature and stable water isotope values from 128,000 years ago (128 ka); very early in the last interglacial. Here, by analysing climate model simulations of last interglacial WAIS loss featuring water isotopes, we show instead that the isotopic response to WAIS loss is in opposition to the isotopic evidence at 128 ka. Instead, a reduction in winter sea ice area of 65±7% fully explains the 128 ka ice core evidence. Our finding of a marked retreat of the sea ice at 128 ka demonstrates the sensitivity of Antarctic sea ice extent to climate warming

A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis

BACKGROUND: Cystic fibrosis (CF) is a chronic, life-limiting disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene leading to abnormal airway surface ion transport, chronic lung infections, inflammation and eventual respiratory failure. With the exception of the small-molecule potentiator, ivacaftor (Kalydeco®, Vertex Pharmaceuticals, Boston, MA, USA), which is suitable for a small proportion of patients, there are no licensed therapies targeting the basic defect. The UK Cystic Fibrosis Gene Therapy Consortium has taken a cationic lipid-mediated CFTR gene therapy formulation through preclinical and clinical development. OBJECTIVE: To determine clinical efficacy of the formulation delivered to the airways over a period of 1 year in patients with CF. DESIGN: This was a randomised, double-blind, placebo-controlled Phase IIb trial of the CFTR gene–liposome complex pGM169/GL67A. Randomisation was performed via InForm™ version 4.6 (Phase Forward Incorporated, Oracle, CA, USA) and was 1 : 1, except for patients in the mechanistic subgroups (2 : 1). Allocation was blinded by masking nebuliser chambers. SETTINGS: Data were collected in the clinical and scientific sites and entered onto a trial-specific InForm, version 4.6 database. PARTICIPANTS: Patients with CF aged ≥ 12 years with forced expiratory volume in the first second (FEV1) between 50% and 90% predicted and any combination of CFTR mutations. The per-protocol group (≥ 9 doses) consisted of 54 patients receiving placebo (62 randomised) and 62 patients receiving gene therapy (78 randomised). INTERVENTIONS: Subjects received 5 ml of nebulised pGM169/G67A (active) or 0.9% saline (placebo) at 28 (±5)-day intervals over 1 year. MAIN OUTCOME MEASURES: The primary end point was the relative change in percentage predicted FEV1 over the 12-month period. A number of secondary clinical outcomes were assessed alongside safety measures: other spirometric values; lung clearance index (LCI) assessed by multibreath washout; structural disease on computed tomography (CT) scan; the Cystic Fibrosis Questionnaire – Revised (CFQ-R), a validated quality-of-life questionnaire; exercise capacity and monitoring; systemic and sputum inflammatory markers; and adverse events (AEs). A mechanistic study was performed in a subgroup in whom transgene deoxyribonucleic acid (DNA) and messenger ribonucleic acid (mRNA) was measured alongside nasal and lower airway potential difference. RESULTS: There was a significant (p = 0.046) treatment effect (TE) of 3.7% [95% confidence interval (CI) 0.1% to 7.3%] in the primary end point at 12 months and in secondary end points, including forced vital capacity (FVC) (p = 0.031) and CT gas trapping (p = 0.048). Other outcomes, although not reaching statistical significance, favoured active treatment. Effects were noted by 1 month and were irrespective of sex, age or CFTR mutation class. Subjects with a more severe baseline FEV1 had a FEV1 TE of 6.4% (95% CI 0.8% to 12.1%) and greater changes in many other secondary outcomes. However, the more mildly affected group also demonstrated benefits, particularly in small airway disease markers such as LCI. The active group showed a significantly (p = 0.032) greater bronchial chloride secretory response. No difference in treatment-attributable AEs was seen between the placebo and active groups. CONCLUSIONS: Monthly application of the pGM169/GL67A gene therapy formulation was associated with an improvement in lung function, other clinically relevant parameters and bronchial CFTR function, compared with placebo. LIMITATIONS: Although encouraging, the improvement in FEV1 was modest and was not accompanied by detectable improvement in patients’ quality of life. FUTURE WORK: Future work will focus on attempts to increase efficacy by increasing dose or frequency, the coadministration of a CFTR potentiator, or the use of modified viral vectors capable of repeated administration. TRIAL REGISTRATION: ClinicalTrials.gov NCT01621867