1,843 research outputs found
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 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 dex and an interquartile range in
metallicity of dex. We construct a surface brightness map of M33 that
traces this feature to mags\,arcsec. At these low surface
brightness levels, the structure extends to projected radii of 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 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
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