559 research outputs found
The Application of FAST-NMR for the Identification of Novel Drug Discovery Targets
The continued success of genome sequencing projects has resulted in a wealth of information, but 40-50% of identified genes correspond to hypothetical proteins or proteins of unknown function. The Functional Annotation Screening Technology by NMR (FAST-NMR) screen was developed to assign a biological function for these unannotated proteins with a structure solved by the Protein Structure Initiative. FAST-NMR is based on the premise that a biological function can be described by a similarity in binding sites and ligand interactions with proteins of known function. The resulting co-structure and functional assignment may provide a starting point for a drug discovery effort
A Correlation between Protein Function and Ligand Binding Profiles
We report that proteins with the same function bind the same set of small molecules from a standardized chemical library. This observation led to a quantifiable and rapidly adaptable method for protein functional analysis using experimentally-derived ligand binding profiles. Ligand binding is measured using a high-throughput NMR ligand affinity screen with a structurally diverse chemical library. The method was demonstrated using a set of 19 proteins with a range of functions. A statistically significant similarity in ligand binding profiles was only observed between the two functionally identical albumins and between the five functionally similar amylases. This new approach is independent of sequence, structure or evolutionary information, and therefore, extends our ability to analyze and functionally annotate novel genes
Searching for Signatures of Cosmic Superstrings in the CMB
Because cosmic superstrings generically form junctions and gauge theoretic
strings typically do not, junctions may provide a signature to distinguish
between cosmic superstrings and gauge theoretic cosmic strings. In cosmic
microwave background anisotropy maps, cosmic strings lead to distinctive line
discontinuities. String junctions lead to junctions in these line
discontinuities. In turn, edge detection algorithms such as the Canny algorithm
can be used to search for signatures of strings in anisotropy maps. We apply
the Canny algorithm to simulated maps which contain the effects of cosmic
strings with and without string junctions. The Canny algorithm produces edge
maps. To distinguish between edge maps from string simulations with and without
junctions, we examine the density distribution of edges and pixels crossed by
edges. We find that in string simulations without Gaussian noise (such as
produced by the dominant inflationary fluctuations) our analysis of the output
data from the Canny algorithm can clearly distinguish between simulations with
and without string junctions. In the presence of Gaussian noise at the level
expected from the current bounds on the contribution of cosmic strings to the
total power spectrum of density fluctuations, the distinction between models
with and without junctions is more difficult. However, by carefully analyzing
the data the models can still be differentiated.Comment: 15 page
Perfluorooctanoic Acid–Induced Immunomodulation in Adult C57BL/6J or C57BL/6N Female Mice
BackgroundPerfluorooctanoic acid (PFOA), an environmentally persistent compound of regulatory concern, has been reported to reduce antibody responses in mice at a single dose.ObjectiveThe aim of this study was to evaluate PFOA effects on humoral and cellular immunity using standard assays for assessing immune function, and to derive dose–response data.MethodsC57BL/6J mice received 0 or 30 mg PFOA/kg/day for 10 days; half of the exposed groups were switched to vehicle and half continued on PFOA for five days. C57BL/6N mice received 0–30 mg/kg/day of PFOA in drinking water for 15 days. Mice were immunized with sheep red blood cells or sensitized to bovine serum albumin in Freund’s complete adjuvant on day 10 of exposure; immune responses were determined 1 day post-exposure.ResultsWe found that 30 mg PFOA/kg/day given for 10 or 15 days reduced IgM synthesis; serum collected 1 day postexposure contained 8.4 × 104 or 2.7 × 105 ng PFOA/mL, respectively. IgM synthesis was suppressed at exposures ≥ 3.75 mg PFOA/kg/day in a dose-dependent manner, and IgG titers were elevated at 3.75 and 7.5 mg PFOA/kg/day. Serum PFOA at 3.75 mg/kg/day was 7.4 × 104 ng/mL 1 day postexposure, or 150-fold greater than the levels reported in individuals living near a PFOA production site. Using a second-degree polynomial model, we calculated a benchmark dose of 3 mg/kg/day, with a lower bound (95% confidence limit) of 1.75 mg/kg/day. Cell-mediated function was not affected.ConclusionsIgM antibodies were suppressed after PFOA exposure. The margin of exposure for reduced IgM antibody synthesis was approximately 150 for highly exposed human populations
A lateral nanoflow assay reveals nanoplastic fluorescence heterogeneity
Colloidal nanoplastics present technological opportunities, environmental
concerns, and measurement challenges. To meet these challenges, we develop a
lateral nanoflow assay from sample-in to answer-out. Our measurement system
integrates complex nanofluidic replicas, super-resolution optical microscopy,
and comprehensive statistical analyses to measure polystyrene nanoparticles
that sorb and carry hydrophobic fluorophores. An elegant scaling of surface
forces within our silicone devices hydrodynamically automates the advection and
dominates the diffusion of the nanoparticles. Through steric interaction with
the replica structure, the particle size distribution reciprocally probes the
unknown limits of replica function. Multiple innovations in the integration and
calibration of device and microscope improve the accuracy of identifying single
nanoparticles and quantifying their diameters and fluorescence intensities. A
statistical model of the measurement approaches the information limit of the
system, discriminates size exclusion from surface adsorption, and reduces
nonideal data to return the particle size distribution with nanometer
resolution. A Bayesian statistical analysis of the dimensional and optical
properties of single nanoparticles reveals their fundamental structure-property
relationship. Fluorescence intensity shows a super-volumetric dependence,
scaling with nanoparticle diameter to nearly the fourth power and confounding
basic concepts of chemical sorption. Distributions of fluorescivity - the
product of the number density, absorption cross section, and quantum yield of
an ensemble of fluorophores - are ultrabroad and asymmetric, limiting ensemble
analysis and dimensional or chemical inference from fluorescence intensity.
These results reset expectations for optimizing nanoplastic products,
understanding nanoplastic byproducts, and applying nanoplastic standards
POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism
Objective: Mitochondrial dysfunction plays a key role in the pathophysiology of neurodegenerative disorders such as ataxia and Parkinson's disease. We describe an extended Belgian pedigree where seven individuals presented with adult-onset cerebellar ataxia, axonal peripheral ataxic neuropathy, and tremor, in variable combination with parkinsonism, seizures, cognitive decline, and ophthalmoplegia. We sought to identify the underlying molecular etiology and characterize the mitochondrial pathophysiology of this neurological syndrome.
Methods: Clinical, neurophysiological, and neuroradiological evaluations were conducted. Patient muscle and cultured fibroblasts underwent extensive analyses to assess mitochondrial function. Genetic studies including genome-wide sequencing were conducted.
Results: Hallmarks of mitochondrial dysfunction were present in patients' tissues including ultrastructural anomalies of mitochondria, mosaic cytochrome c oxidase deficiency, and multiple mtDNA deletions. We identified a splice acceptor variant in POLG2, c.970-1G>C, segregating with disease in this family and associated with a concomitant decrease in levels of POLG2 protein in patient cells.
Interpretation: This work extends the clinical spectrum of POLG2 deficiency to include an overwhelming, adult-onset neurological syndrome that includes cerebellar syndrome, peripheral neuropathy, tremor, and parkinsonism. We therefore suggest to include POLG2 sequencing in the evaluation of ataxia and sensory neuropathy in adults, especially when it is accompanied by tremor or parkinsonism with white matter disease. The demonstration that deletions of mtDNA resulting from autosomal-dominant POLG2 variant lead to a monogenic neurodegenerative multicomponent syndrome provides further evidence for a major role of mitochondrial dysfunction in the pathomechanism of nonsyndromic forms of the component neurodegenerative disorders
Virtual Screening of acyclovir derivatives as potential antiviral agents: design, synthesis, and biological evaluation of new acyclic nucleoside ProTides
Following our findings on the anti-human immunodeficiency virus (HIV) activity of acyclovir (ACV) phosphate prodrugs, we herein report the ProTide approach applied to a series of acyclic nucleosides aimed at the identification of novel and selective antiviral, in particular anti-HIV agents. Acyclic nucleoside analogues used in this study were identified through a virtual screening using HIV-reverse transcriptase (RT), adenylate/guanylate kinase, and human DNA polymerase γ. A total of 39 new phosphate prodrugs were synthesized and evaluated against HIV-1 (in vitro and ex vivo human tonsillar tissue system) and human herpes viruses. Several ProTide compounds showed substantial potency against HIV-1 at low micromolar range while the parent nucleosides were not effective. Also, pronounced inhibition of herpesvirus replication was observed. A carboxypeptidase-mediated hydrolysis study was performed for a selection of compounds to assess the formation of putative metabolites and support the biological activity observed
On the Generation of a Scale-Invariant Spectrum of Adiabatic Fluctuations in Cosmological Models with a Contracting Phase
In Pre-Big-Bang and in Ekpyrotic Cosmology, perturbations on cosmological
scales today are generated from quantum vacuum fluctuations during a phase when
the Universe is contracting (viewed in the Einstein frame). The backgrounds
studied to date do not yield a scale invariant spectrum of adiabatic
fluctuations. Here, we present a new contracting background model (neither of
Pre-Big-Bang nor of the Ekpyrotic form) involving a single scalar field coupled
to gravity in which a scale-invariant spectrum of curvature fluctuations and
gravitational waves results. The equation of state of this scalar field
corresponds to cold matter. We demonstrate that if this contracting phase can
be matched via a nonsingular bounce to an expanding Friedmann cosmology, the
scale-invariance of the curvature fluctuations is maintained. We also find new
background solutions for Pre-Big-Bang and for Ekpyrotic cosmology, which
involve two scalar fields with exponential potentials with background values
which are evolving in time. We comment on the difficulty of obtaining a
scale-invariant spectrum of adiabatic fluctuations with background solutions
which have been studied in the past.Comment: 8 pages, revised version without the section on perturbations,
matching the version published on Phys. Rev. D. For cosmological
perturbations in the two field model see astro-ph/021127
Reducing the impact of physical inactivity: evidence to support the case for targeting people with chronic mental and physical conditions
Background :
Recent evidence suggests that small increases in the physical activity of those considered least active can have a bigger health impact than raising levels of those already achieving or close to achieving recommendations. Profiling the characteristics of those who are least active allows for appropriate targeting of interventions. This study therefore examined the characteristics of people in the lowest physical activity bracket.
Methods :
Data were taken from the Collaboration for Leadership in Applied Health Research and Care (CLAHRC) funded ‘South Yorkshire Cohort’, a longitudinal observational dataset of residents of South Yorkshire, England. Five separate outcomes based on a shortened version of the GPPAQ were used to represent the lowest levels of physical activity. Potential predictors examined were age, sex, body mass index, ethnicity, chronic conditions, current employment and deprivation. Descriptive statistics and logistic regression were conducted.
Results :
Individuals with chronic mental and physical conditions (fatigue, insomnia, anxiety, depression, diabetes, breathing problems, high blood pressure, heart disease, stroke and cancer) were more likely to report the lowest levels of physical activity across all five outcomes. Demographic variations were also observed.
Conclusions :
Targeting people with chronic mental and physical conditions has the potential to reduce the impact of physical inactivity.</p
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