Irrigated greywater in an urban sub-division as a potential source of metals to soil, groundwater and surface water

Increased water demands in dry countries such as Australia, have led to increased adoption of various water reuse practices. Irrigation of greywater (all water discharged from the bathrooms, laundry and kitchen apart from toilet waste) is seen as a potential means of easing water demands; however, there is limited knowledge of how greywater irrigation impacts terrestrial and aquatic environments. This study compared four greywater irrigated residential lots to adjacent non-irrigated lots that acted as controls. Accumulation and potential impacts of metals in soil, groundwater and surface water, as a result of greywater irrigation, were assessed by comparing measured concentrations to national and international guidelines. Greywater increased concentrations of some metals in irrigated soil and resulted in As, B, Cr and Cu exceeding guidelines after only four years of irrigation. Movement of metals from the irrigation areas resulted in metal concentrations in groundwater (Al, As, Cr, Cu, Fe, Mn, Ni and Zn) and surface water (Cu, Fe and Zn) exceeding environmental quality guidelines again within four years. These results are unlikely to be universally applicable but indicate the need to consider metals in greywater in order to minimize potential adverse environmental effects from greywater irrigation

Electronic sculpting of ligand-GPCR subtype selectivity:the case of angiotensin II

GPCR subtypes possess distinct functional and pharmacological profiles, and thus development of subtype-selective ligands has immense therapeutic potential. This is especially the case for the angiotensin receptor subtypes AT1R and AT2R, where a functional negative control has been described and AT2R activation highlighted as an important cancer drug target. We describe a strategy to fine-tune ligand selectivity for the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl interactions. Through this strategy an AT2R high affinity (<i>K</i>_i = 3 nM) agonist analogue that exerted 18,000-fold higher selectivity for AT2R versus AT1R was obtained. We show that this compound is a negative regulator of AT1R signaling since it is able to inhibit MCF-7 breast carcinoma cellular proliferation in the low nanomolar range

Restriction fragment length polymorphisms distinguish among accessions of Ceratopteris thalictroides and C. richardii ( Parkeriaceae )

We have used cDNA clones as probes on Southern blots to detect restriction fragment length polymorphisms among seven Ceratopteris thalictroides accessions, three C. richardii accessions, and one putative interspecific hybrid. We found that the stringency of post-hybridization washes was a critical parameter affecting the quality of our blots; even with homologous cDNA sequences low stringency conditions resulted in a smear of signal, but high stringency washes gave blots with distinct bands. Most probes showed hybridization with four or more genomic fragments. Similarities in the number and size of fragments between and within species indicated that (i) C. richardii shows limited polymorphism among accessions tested, (ii) C. thalictroides is highly polymorphic, and (iii) Hawaiian accessions of C. thalictroides are divergent relative to their continental cohorts and among themselves. The putative interspecific hybrid did not group closely with either of these species.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41637/1/606_2004_Article_BF00939725.pd

The Atacama Cosmology Telescope: A Measurement of the 600< ell <8000 Cosmic Microwave Background Power Spectrum at 148 GHz

We present a measurement of the angular power spectrum of the cosmic microwave background (CMB) radiation observed at 148 GHz. The measurement uses maps with 1.4' angular resolution made with data from the Atacama Cosmology Telescope (ACT). The observations cover 228 square degrees of the southern sky, in a 4.2-degree-wide strip centered on declination 53 degrees South. The CMB at arcminute angular scales is particularly sensitive to the Silk damping scale, to the Sunyaev-Zel'dovich (SZ) effect from galaxy clusters, and to emission by radio sources and dusty galaxies. After masking the 108 brightest point sources in our maps, we estimate the power spectrum between 600 < \ell < 8000 using the adaptive multi-taper method to minimize spectral leakage and maximize use of the full data set. Our absolute calibration is based on observations of Uranus. To verify the calibration and test the fidelity of our map at large angular scales, we cross-correlate the ACT map to the WMAP map and recover the WMAP power spectrum from 250 < ell < 1150. The power beyond the Silk damping tail of the CMB is consistent with models of the emission from point sources. We quantify the contribution of SZ clusters to the power spectrum by fitting to a model normalized at sigma8 = 0.8. We constrain the model's amplitude ASZ < 1.63 (95% CL). If interpreted as a measurement of sigma8, this implies sigma8^SZ < 0.86 (95% CL) given our SZ model. A fit of ACT and WMAP five-year data jointly to a 6-parameter LCDM model plus terms for point sources and the SZ effect is consistent with these results.Comment: 15 pages, 8 figures. Accepted for publication in Ap

Functional characterisation of novel NR5A1 variants reveals multiple complex roles in Disorders of Sex Development

Variants in the NR5A1 gene encoding SF1 have been described in a diverse spectrum of disorders of sex development (DSD). Recently, we reported the use of a targeted gene panel for DSD where we identified 15 individuals with a variant in NR5A1, nine of which are novel. Here, we examine the functional effect of these changes in relation to the patient phenotype. All novel variants tested had reduced trans-activational activity, while several had altered protein level, localization, or conformation. In addition, we found evidence of new roles for SF1 protein domains including a region within the ligand binding domain that appears to contribute to SF1 regulation of Mu¨llerian development. There was little correlation between the severity of the phenotype and the nature of the NR5A1 variant. We report two familial cases of NR5A1 deficiency with evidence of variable expressivity; we also report on individuals with oligogenic inheritance. Finally, we found that the nature of the NR5A1 variant does not inform patient outcomes (including pubertal androgenization and malignancy risk). This study adds nine novel pathogenic NR5A1 variants to the pool of diagnostic variants. It highlights a greater need for understanding the complexity of SF1 function and the additional factors that contribute

The Atacama Cosmology Telescope (ACT): Beam Profiles and First SZ Cluster Maps

The Atacama Cosmology Telescope (ACT) is currently observing the cosmic microwave background with arcminute resolution at 148 GHz, 218 GHz, and 277 GHz. In this paper, we present ACT's first results. Data have been analyzed using a maximum-likelihood map-making method which uses B-splines to model and remove the atmospheric signal. It has been used to make high-precision beam maps from which we determine the experiment's window functions. This beam information directly impacts all subsequent analyses of the data. We also used the method to map a sample of galaxy clusters via the Sunyaev-Zel'dovich (SZ) effect, and show five clusters previously detected with X-ray or SZ observations. We provide integrated Compton-y measurements for each cluster. Of particular interest is our detection of the z = 0.44 component of A3128 and our current non-detection of the low-redshift part, providing strong evidence that the further cluster is more massive as suggested by X-ray measurements. This is a compelling example of the redshift-independent mass selection of the SZ effect.Comment: 16 pages, 10 figures. Accepted for publication in ApJS. See Marriage et al. (arXiv:1010.1065) and Menanteau et al. (arXiv:1006.5126) for additional cluster result

Ligand-Induced Modulation of the Free-Energy Landscape of G Protein-Coupled Receptors Explored by Adaptive Biasing Techniques

Extensive experimental information supports the formation of ligand-specific conformations of G protein-coupled receptors (GPCRs) as a possible molecular basis for their functional selectivity for signaling pathways. Taking advantage of the recently published inactive and active crystal structures of GPCRs, we have implemented an all-atom computational strategy that combines different adaptive biasing techniques to identify ligand-specific conformations along pre-determined activation pathways. Using the prototypic GPCR β2-adrenergic receptor as a suitable test case for validation, we show that ligands with different efficacies (either inverse agonists, neutral antagonists, or agonists) modulate the free-energy landscape of the receptor by shifting the conformational equilibrium towards active or inactive conformations depending on their elicited physiological response. Notably, we provide for the first time a quantitative description of the thermodynamics of the receptor in an explicit atomistic environment, which accounts for the receptor basal activity and the stabilization of different active-like states by differently potent agonists. Structural inspection of these metastable states reveals unique conformations of the receptor that may have been difficult to retrieve experimentally

How achievable are COVID-19 clinical trial recruitment targets? A UK observational cohort study and trials registry analysis

OBJECTIVES: To analyse enrolment to interventional trials during the first wave of the COVID-19 pandemic in England and describe the barriers to successful recruitment in the circumstance of a further wave or future pandemics. DESIGN: We analysed registered interventional COVID-19 trial data and concurrently did a prospective observational study of hospitalised patients with COVID-19 who were being assessed for eligibility to one of the RECOVERY, C19-ACS or SIMPLE trials. SETTING: Interventional COVID-19 trial data were analysed from the clinicaltrials.gov and International Standard Randomized Controlled Trial Number databases on 12 July 2020. The patient cohort was taken from five centres in a respiratory National Institute for Health Research network. Population and modelling data were taken from published reports from the UK government and Medical Research Council Biostatistics Unit. PARTICIPANTS: 2082 consecutive admitted patients with laboratory-confirmed SARS-CoV-2 infection from 27 March 2020 were included. MAIN OUTCOME MEASURES: Proportions enrolled, and reasons for exclusion from the aforementioned trials. Comparisons of trial recruitment targets with estimated feasible recruitment numbers. RESULTS: Analysis of trial registration data for COVID-19 treatment studies enrolling in England showed that by 12 July 2020, 29 142 participants were needed. In the observational study, 430 (20.7%) proceeded to randomisation. 82 (3.9%) declined participation, 699 (33.6%) were excluded on clinical grounds, 363 (17.4%) were medically fit for discharge and 153 (7.3%) were receiving palliative care. With 111 037 people hospitalised with COVID-19 in England by 12 July 2020, we determine that 22 985 people were potentially suitable for trial enrolment. We estimate a UK hospitalisation rate of 2.38%, and that another 1.25 million infections would be required to meet recruitment targets of ongoing trials. CONCLUSIONS: Feasible recruitment rates, study design and proliferation of trials can limit the number, and size, that will successfully complete recruitment. We consider that fewer, more appropriately designed trials, prioritising cooperation between centres would maximise productivity in a further wave

Superspreaders drive the largest outbreaks of hospital onset COVID-19 infections.

SARS-CoV-2 is notable both for its rapid spread, and for the heterogeneity of its patterns of transmission, with multiple published incidences of superspreading behaviour. Here, we applied a novel network reconstruction algorithm to infer patterns of viral transmission occurring between patients and health care workers (HCWs) in the largest clusters of COVID-19 infection identified during the first wave of the epidemic at Cambridge University Hospitals NHS Foundation Trust, UK. Based upon dates of individuals reporting symptoms, recorded individual locations, and viral genome sequence data, we show an uneven pattern of transmission between individuals, with patients being much more likely to be infected by other patients than by HCWs. Further, the data were consistent with a pattern of superspreading, whereby 21% of individuals caused 80% of transmission events. Our study provides a detailed retrospective analysis of nosocomial SARS-CoV-2 transmission, and sheds light on the need for intensive and pervasive infection control procedures

Incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel

<p>Abstract</p> <p>Background</p> <p>To determine the incidence of reversible amenorrhea in women with breast cancer undergoing adjuvant anthracycline-based chemotherapy with or without docetaxel.</p> <p>Methods</p> <p>We studied the incidence and duration of amenorrhea induced by two chemotherapy regimens: (i) 6 cycles of 5-fluorouracil 500 mg/m², epirubicin 100 mg/m²and cyclophosphamide 500 mg/m²on day 1 every 3 weeks (6FEC) and (ii) 3 cycles of FEC 100 followed by 3 cycles of docetaxel 100 mg/m²on day 1 every 3 weeks (3FEC/3D). Reversible amenorrhea was defined as recovery of regular menses and, where available (101 patients), premenopausal hormone values (luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol) in the year following the end of chemotherapy.</p> <p>Results</p> <p>One hundred and fifty-four premenopausal patients were included: 84 treated with 6FEC and 70 with 3FEC/3D. The median age was 43.5 years (range: 28–58) in the 6FEC arm and 44 years (range: 29–53) in the 3FEC/3D arm. Seventy-eight percent of patients were treated in the context of the PACS 01 trial. The incidence of chemotherapy-induced amenorrhea at the end of chemotherapy was similar in the two groups: 93 % in the 6FEC arm and 92.8 % in the 3FEC/3D arm. However, in the year following the end of chemotherapy, more patients recovered menses in the 3FEC/3D arm than in the 6FEC arm: 35.5 % versus 23.7 % (p = 0.019). Among the 101 patients for whom hormone values were available, 43 % in the 3FEC/3D arm and 29 % in the 6FEC arm showed premenopausal levels one year after the end of chemotherapy (p < 0.01). In the 3FEC/3D group, there was a statistically significant advantage in disease-free survival (DFS) for patients who were still amenorrheic after one year, compared to patients who had recovered regular menses (p = 0.0017).</p> <p>Conclusion</p> <p>Our study suggests that 3FEC/3D treatment induces more reversible amenorrhea than 6FEC. The clinical relevance of these findings needs to be investigated further.</p