Quantifying biogenic bias in screening libraries.

In lead discovery, libraries of 10(6) molecules are screened for biological activity. Given the over 10(60) drug-like molecules thought possible, such screens might never succeed. The fact that they do, even occasionally, implies a biased selection of library molecules. We have developed a method to quantify the bias in screening libraries toward biogenic molecules. With this approach, we consider what is missing from screening libraries and how they can be optimized

Observation of small scale structure using sextupole lensing

Weak gravitational lensing seeks to determine shear by measuring induced quadrupole (elliptical) shapes in background galaxy images. Small impact parameter (a few kpc) gravitational lensing by foreground core masses between 2 10^{9} and 2 10^{12} M_\odot will additionally induce a sextupole shape with the quadrupole and sextupole minima aligned. This correlation in relative orientation of the quadrupole and sextupole provides a sensitive method to identify images which have been slightly curved by lensing events. A general theoretical framework for sextupole lensing is developed which includes several low order coefficients in a general lensing map. Tools to impute map coefficients from the galaxy images are described and applied to the north Hubble deep field. Instrumental PSFs, camera charge diffusion, and image composition methods are modelled in the coefficient determination process. Estimates of Poisson counting noise for each galaxy are used to cut galaxies with signals too small to reliably establish curvature. Curved galaxies are found to be spatially clumped, as would be expected if the curving were due to small impact parameter lensing by localized ensembles of dark matter haloes. Simulations provide an estimate of the total required lensing mass and the acceptable mass range of the constituent haloes. The overdensities and underdensities of visible galaxies and their locations in the Hubble foreground is found to be consistent with our observations and their interpretation as lensing events.Comment: 40 pages, 44 figure

The Chemical Basis of Pharmacology

ABSTRACT: Molecular biology now dominates pharmacology so thoroughly that it is difficult to recall that only a generation ago the field was very different. To understand drug action today, we characterize the targets through which they act and new drug leads are discovered on the basis of target structure and function. Until the mid-1980s the information often flowed in reverse: investigators began with organic molecules and sought targets, relating receptors not by sequence or structure but by their ligands. Recently, investigators have returned to this chemical view of biology, bringing to it systematic and quantitative methods of relating targets by their ligands. This has allowed the discovery of new targets for established drugs, suggested the bases for their side effects, and predicted the molecular targets underlying phenotypic screens. The bases for these new methods, some of their successes and liabilities, and new opportunities for their use are described. So dominant has the molecular biology view of pharmacology become that it is difficult to remember that even 25 years ago it was little more than an aspiration. Today we understand the activity of drugs and reagents first through the specific, clonable receptor molecules with which they interact. To understan

Development and Validation of Molecular Markers for \u3cem\u3ePhytophthora medicaginis\u3c/em\u3e Resistance in Lucerne

Resistance to Phytophthora medicaginis is an essential attribute to incorporate into lucerne (Medicago sativa) cultivars which are likely to be grown on heavy soils or in conditions where the soil remains excessively wet for prolonged periods. Current breeding strategies rely on recurrent phenotypic selection to maintain adequate levels of resistance in newly developed synthetic cultivars. However, little is known about the source or mechanism(s) of genetic resistance operating in the cultivar. A genetic linkage map was generated from a tetraploid M. sativa population using SSR markers anchored to existing genetic and physical maps. Large effect QTL were identified on linkage groups 2, 5, 6 and 7, each of which contributed between 11-30% of the phenotypic variation. Evaluation of the marker-trait associations in another sampling of the same population was undertaken, using a different isolate of P. medicaginis. The findings indicate that in the lucerne genotype examined in this study, a network of interactions involving at least three common loci, contribute to resistance to P. medicaginis. An alignment of the resistance loci identified in this study with those previously identified provided a framework for cataloguing the diversity of resistance loci present in lucerne, and will be used to guide future lucerne breeding efforts

Management of Children With Chronic Wet Cough and Protracted Bacterial Bronchitis CHEST Guideline and Expert Panel Report

BACKGROUND: Wet or productive cough is common in children with chronic cough. We formulated recommendations based on systematic reviews related to the management of chronic wet cough in children (aged METHODS: We used the CHEST expert cough panel\u27s protocol for systematic reviews and the American College of Chest Physicians (CHEST) methodologic guidelines and GRADE framework (the Grading of Recommendations Assessment, Development and Evaluation). Data from the systematic reviews in conjunction with patients\u27 values and preferences and the clinical context were used to form recommendations. Delphi methodology was used to obtain consensus for the recommendations/suggestions made. RESULTS: Combining data from the systematic reviews, we found high-quality evidence in children aged 4 weeks\u27 duration) wet/productive cough that using appropriate antibiotics improves cough resolution, and further investigations (eg, flexible bronchoscopy, chest CT scans, immunity tests) should be undertaken when specific cough pointers (eg, digital clubbing) are present. When the wet cough does not improve following 4 weeks of antibiotic treatment, there is moderate-quality evidence that further investigations should be considered to look for an underlying disease. New recommendations include the recognition of the clinical diagnostic entity of protracted bacterial bronchitis. CONCLUSIONS: Compared with the 2006 Cough Guidelines, there is now high-quality evidence for some, but not all, aspects of the management of chronic wet cough in specialist settings. However, further studies (particularly in primary health) are required

Spatial Variations of Jovian Tropospheric Ammonia via Ground-Based Imaging

Optical bandpass-filter observations can be simply processed to determine similar horizontal ammonia distributions above the Jovian cloud tops as mid-infrared and microwave observations. Current understanding of this distribution and its relationship to aerosol opacity, cloud-top pressure, and circulation is provided by atmospheric retrieval models using observations from major ground-based facilities and spacecraft. These techniques recover high fidelity information on the ammonia distribution but are limited in spatial and temporal coverage. Part of this coverage gap - upper tropospheric abundance - can be bridged by using continuum-divided ammonia and methane absorption images as suggested by Combes and Encrenaz [1979]. In 2020-21, Jupiter was imaged in the 645 nm ammonia absorption band and adjacent continuum bands, demonstrating that the spatially-resolved optical depth in that band could be determined with a 0.28-m Schmidt-Cassegrain telescope (SCT). In 2022, a 620 nm filter was added to include methane absorption images in the same wavelength range. Methane abundance provides a constant reference against which to determine the ammonia abundance, specifically the column-averaged mole fraction above the clouds. VLT/MUSE results are compared to these SCT results and those from the TEXES mid-infrared spectrometer used on the IRTF and the Gemini telescopes. Meridional and longitudinal features are examined, including the Equatorial Zone (EZ) ammonia enhancement, the North Equatorial Belt (NEB) depletion, depletion above the Great Red Spot (GRS), and suggested enhancements over bright plumes in the northern EZ. This work demonstrates meaningful ammonia monitoring that can provide synoptic coverage and continuity between spacecraft or major ground-based facility campaigns.Comment: 23 pages, 8 figure

Neural modelling, control and optimisation of an industrial grinding process

This paper describes the development of neural model-based control strategies for the optimisation of an industrial aluminium substrate disk grinding process. The grindstone removal rate varies considerably over a stone life and is a highly nonlinear function of process variables. Using historical grindstone performance data, a NARX-based neural network model is developed. This model is then used to implement a direct inverse controller and an internal model controller based on the process settings and previous removal rates. Preliminary plant investigations show that thickness defects can be reduced by 50% or more, compared to other schemes employed

Neural modelling, control and optimisation of an industrial grinding process

This paper describes the development of neural model-based control strategies for the optimisation of an industrial aluminium substrate disk grinding process. The grindstone removal rate varies considerably over a stone life and is a highly nonlinear function of process variables. Using historical grindstone performance data, a NARX-based neural network model is developed. This model is then used to implement a direct inverse controller and an internal model controller based on the process settings and previous removal rates. Preliminary plant investigations show that thickness defects can be reduced by 50% or more, compared to other schemes employed

The photometric properties of a vast stellar substructure in the outskirts of M33

We have surveyed $\sim40$sq.degrees surrounding M33 with CFHT MegaCam in the g and i filters, as part of the Pan-Andromeda Archaeological Survey. Our observations are deep enough to resolve the top 4mags of the red giant branch population in this galaxy. We have previously shown that the disk of M33 is surrounded by a large, irregular, low-surface brightness substructure. Here, we quantify the stellar populations and structure of this feature using the PAndAS data. We show that the stellar populations of this feature are consistent with an old population with $\sim-1.6$dex and an interquartile range in metallicity of $\sim0.5$dex. We construct a surface brightness map of M33 that traces this feature to $\mu_V\simeq33$mags\,arcsec$^{-2}$. At these low surface brightness levels, the structure extends to projected radii of $\sim40$kpc from the center of M33 in both the north-west and south-east quadrants of the galaxy. Overall, the structure has an "S-shaped" appearance that broadly aligns with the orientation of the HI disk warp. We calculate a lower limit to the integrated luminosity of the structure of $-12.7\pm0.5$mags, comparable to a bright dwarf galaxy such as Fornax or AndII and slightly less than $1\$ of the total luminosity of M33. Further, we show that there is tentative evidence for a distortion in the distribution of young stars near the edge of the HI disk that occurs at similar azimuth to the warp in HI. The data also hint at a low-level, extended stellar component at larger radius that may be a M33 halo component. We revisit studies of M33 and its stellar populations in light of these new results, and we discuss possible formation scenarios for the vast stellar structure. Our favored model is that of the tidal disruption of M33 in its orbit around M31.Comment: Accepted for publication in ApJ. 17 figures. ApJ preprint forma