498 research outputs found
Lung Screening Benefits and Challenges: A Review of The Data and Outline for Implementation
Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for almost a fifth of all cancer-related deaths. Annual computed tomographic lung cancer screening (CTLS) detects lung cancer at earlier stages and reduces lung cancer-related mortality among high-risk individuals. Many medical organizations, including the U.S. Preventive Services Task Force, recommend annual CTLS in high-risk populations. However, fewer than 5% of individuals worldwide at high risk for lung cancer have undergone screening. In large part, this is owing to delayed implementation of CTLS in many countries throughout the world. Factors contributing to low uptake in countries with longstanding CTLS endorsement, such as the United States, include lack of patient and clinician awareness of current recommendations in favor of CTLS and clinician concerns about CTLS-related radiation exposure, false-positive results, overdiagnosis, and cost. This review of the literature serves to address these concerns by evaluating the potential risks and benefits of CTLS. Review of key components of a lung screening program, along with an updated shared decision aid, provides guidance for program development and optimization. Review of studies evaluating the population considered "high-risk" is included as this may affect future guidelines within the United States and other countries considering lung screening implementation
Secular evolution versus hierarchical merging: galaxy evolution along the Hubble sequence, in the field and rich environments
In the current galaxy formation scenarios, two physical phenomena are invoked
to build disk galaxies: hierarchical mergers and more quiescent external gas
accretion, coming from intergalactic filaments. Although both are thought to
play a role, their relative importance is not known precisely. Here we consider
the constraints on these scenarios brought by the observation-deduced star
formation history on the one hand, and observed dynamics of galaxies on the
other hand: the high frequency of bars and spirals, the high frequency of
perturbations such as lopsidedness, warps, or polar rings.
All these observations are not easily reproduced in simulations without
important gas accretion. N-body simulations taking into account the mass
exchange between stars and gas through star formation and feedback, can
reproduce the data, only if galaxies double their mass in about 10 Gyr through
gas accretion. Warped and polar ring systems are good tracers of this
accretion, which occurs from cold gas which has not been virialised in the
system's potential. The relative importance of these phenomena are compared
between the field and rich clusters. The respective role of mergers and gas
accretion vary considerably with environment.Comment: 18 pages, 8 figures, review paper to "Penetrating Bars through Masks
of Cosmic Dust: the Hubble Tuning Fork Strikes a New Note", Pilanesberg, ed.
D. Block et al., Kluwe
Smart homes and their users:a systematic analysis and key challenges
Published research on smart homes and their users is growing exponentially, yet a clear understanding of who these users are and how they might use smart home technologies is missing from a field being overwhelmingly pushed by technology developers. Through a systematic analysis of peer-reviewed literature on smart homes and their users, this paper takes stock of the dominant research themes and the linkages and disconnects between them. Key findings within each of nine themes are analysed, grouped into three: (1) views of the smart home-functional, instrumental, socio-technical; (2) users and the use of the smart home-prospective users, interactions and decisions, using technologies in the home; and (3) challenges for realising the smart home-hardware and software, design, domestication. These themes are integrated into an organising framework for future research that identifies the presence or absence of cross-cutting relationships between different understandings of smart homes and their users. The usefulness of the organising framework is illustrated in relation to two major concerns-privacy and control-that have been narrowly interpreted to date, precluding deeper insights and potential solutions. Future research on smart homes and their users can benefit by exploring and developing cross-cutting relationships between the research themes identified
A Mild Form of SLC29A3 Disorder: A Frameshift Deletion Leads to the Paradoxical Translation of an Otherwise Noncoding mRNA Splice Variant
We investigated two siblings with granulomatous histiocytosis prominent in the nasal area, mimicking rhinoscleroma and Rosai-Dorfman syndrome. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous frameshift deletion in SLC29A3, which encodes human equilibrative nucleoside transporter-3 (hENT3). Germline mutations in SLC29A3 have been reported in rare patients with a wide range of overlapping clinical features and inherited disorders including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, and Faisalabad histiocytosis. With the exception of insulin-dependent diabetes and mild finger and toe contractures in one sibling, the two patients with nasal granulomatous histiocytosis studied here displayed none of the many SLC29A3-associated phenotypes. This mild clinical phenotype probably results from a remarkable genetic mechanism. The SLC29A3 frameshift deletion prevents the expression of the normally coding transcripts. It instead leads to the translation, expression, and function of an otherwise noncoding, out-of-frame mRNA splice variant lacking exon 3 that is eliminated by nonsense-mediated mRNA decay (NMD) in healthy individuals. The mutated isoform differs from the wild-type hENT3 by the modification of 20 residues in exon 2 and the removal of another 28 amino acids in exon 3, which include the second transmembrane domain. As a result, this new isoform displays some functional activity. This mechanism probably accounts for the narrow and mild clinical phenotype of the patients. This study highlights the ‘rescue’ role played by a normally noncoding mRNA splice variant of SLC29A3, uncovering a new mechanism by which frameshift mutations can be hypomorphic
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A high-resolution map of human evolutionary constraint using 29 mammals.
The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease
Science Programs for a 2 m-class Telescope at Dome C, Antarctica: PILOT, the Pathfinder for an International Large Optical Telescope
The cold, dry and stable air above the summits of the Antarctic plateau
provides the best ground-based observing conditions from optical to sub-mm
wavelengths to be found on the Earth. PILOT is a proposed 2 m telescope, to be
built at Dome C in Antarctica, able to exploit these conditions for conducting
astronomy at optical and infrared wavelengths. While PILOT is intended as a
pathfinder towards the construction of future grand-design facilities, it will
also be able to undertake a range of fundamental science investigations in its
own right. This paper provides the performance specifications for PILOT,
including its instrumentation. It then describes the kinds of science projects
that it could best conduct. These range from planetary science to the search
for other solar systems, from star formation within the Galaxy to the star
formation history of the Universe, and from gravitational lensing caused by
exo-planets to that produced by the cosmic web of dark matter. PILOT would be
particularly powerful for wide-field imaging at infrared wavelengths, achieving
near-diffraction limited performance with simple tip-tilt wavefront correction.
PILOT would also be capable of near-diffraction limited performance in the
optical wavebands, as well be able to open new wavebands for regular ground
based observation; in the mid-IR from 17 to 40 microns and in the sub-mm at 200
microns.Comment: 74 pages, 14 figures, PASA, in pres
Amyloid-Associated Nucleic Acid Hybridisation
Nucleic acids promote amyloid formation in diseases including Alzheimer's
and Creutzfeldt-Jakob disease. However, it remains unclear whether the close
interactions between amyloid and nucleic acid allow nucleic acid secondary
structure to play a role in modulating amyloid structure and function. Here we
have used a simplified system of short basic peptides with alternating
hydrophobic and hydrophilic amino acid residues to study nucleic acid - amyloid
interactions. Employing biophysical techniques including X-ray fibre
diffraction, circular dichroism spectroscopy and electron microscopy we show
that the polymerized charges of nucleic acids concentrate and enhance the
formation of amyloid from short basic peptides, many of which would not
otherwise form fibres. In turn, the amyloid component binds nucleic acids and
promotes their hybridisation at concentrations below their solution
Kd, as shown by time-resolved FRET studies. The
self-reinforcing interactions between peptides and nucleic acids lead to the
formation of amyloid nucleic acid (ANA) fibres whose properties are distinct
from their component polymers. In addition to their importance in disease and
potential in engineering, ANA fibres formed from prebiotically-produced peptides
and nucleic acids may have played a role in early evolution, constituting the
first entities subject to Darwinian evolution
Nonheritable Cellular Variability Accelerates the Evolutionary Processes of Cancer
Heritable genetic or epigenetic changes in cells are thought to drive tumor development, metastasis, and drug resistance. This essay discusses the possibility that nonheritable phenotypic variability contributes to the evolution of cancer, suggesting new approaches to treatment
Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice
Background: Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a ‘‘cognitive enhancer’ ’ and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia. Methodology/Principal Findings: Through the use of stereological counting methods, we observed a significant reduction (,20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc. Additionally, exposure to either 1 mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopaminergic neurons to the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Unbiased gene screening employing Affymetrix GeneChipH HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2, and th in the substantia nigr
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