394 research outputs found
T1, diffusion tensor, and quantitative magnetization transfer imaging of the hippocampus in an Alzheimer's disease mouse model
Alzheimer's disease (AD) pathology causes microstructural changes in the brain. These changes, if quantified with magnetic resonance imaging (MRI), could be studied for use as an early biomarker for AD. The aim of our study was to determine if T1 relaxation, diffusion tensor imaging (DTI), and quantitative magnetization transfer imaging (qMTI) metrics could reveal changes within the hippocampus and surrounding white matter structures in ex vivo transgenic mouse brains overexpressing human amyloid precursor protein with the Swedish mutation. Delineation of hippocampal cell layers using DTI color maps allows more detailed analysis of T1-weighted imaging, DTI, and qMTI metrics, compared with segmentation of gross anatomy based on relaxation images, and with analysis of DTI or qMTI metrics alone. These alterations are observed in the absence of robust intracellular Aβ accumulation or plaque deposition as revealed by histology. This work demonstrates that multiparametric quantitative MRI methods are useful for characterizing changes within the hippocampal substructures and surrounding white matter tracts of mouse models of AD
Tissue eosinophilia: a morphologic marker for assessing stromal invasion in laryngeal squamous neoplasms
BACKGROUND: The assessment of tumor invasion of underlying benign stroma in neoplastic squamous proliferation of the larynx may pose a diagnostic challenge, particularly in small biopsy specimens that are frequently tangentially sectioned. We studied whether thresholds of an eosinophilic response to laryngeal squamous neoplasms provides an adjunctive histologic criterion for determining the presence of invasion. METHODS: Eighty-seven(n = 87) cases of invasive squamous cell carcinoma and preinvasive squamous neoplasia were evaluated. In each case, the number of eosinophils per high power field(eosinophils/hpf), and per 10 hpf in the tissue adjacent to the neoplastic epithelium, were counted and tabulated. For statistical purposes, the elevated eosinophils were defined and categorized as: focally and moderately elevated (5â9 eos/hpf), focally and markedly increased(>10/hpf), diffusely and moderately elevated(5â19 eos/10hpf), and diffusely and markedly increased (>20/10hpf). RESULTS: In the invasive carcinoma, eosinophil counts were elevated focally and /or diffusely, more frequently seen than in non-invasive neoplastic lesions. The increased eosinophil counts, specifically >10hpf, and >20/10hpf, were all statistically significantly associated with stromal invasion. Greater than 10 eosinophils/hpf and/or >20 eosinophils/10hpf had highest predictive power, with a sensitivity, specificity and positive predictive value of 82%, 93%, 96% and 80%, 100% and 100%, respectively. Virtually, greater than 20 eosinophils/10 hpf was diagnostic for tumor invasion in our series. CONCLUSION: Our study suggests for the first time that the elevated eosinophil count in squamous neoplasia of the larynx is a morphologic feature associated with tumor invasion. When the number of infiltrating eosinophils exceeds 10/hpf and or >20/10 hpf in a laryngeal biopsy with squamous neoplasia, it represents an indicator for the possibility of tumor invasion. Similarly, the presence of eosinophils meeting these thresholds in an excisional specimen should prompt a thorough evaluation for invasiveness, when evidence of invasion is absent, or when invasion is suspected by conventional criteria in the initial sections
Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1
Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJunâcFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ⤠7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases
Laser cooling of a nanomechanical oscillator into its quantum ground state
A patterned Si nanobeam is formed which supports co-localized acoustic and
optical resonances that are coupled via radiation pressure. Starting from a
bath temperature of T=20K, the 3.68GHz nanomechanical mode is cooled into its
quantum mechanical ground state utilizing optical radiation pressure. The
mechanical mode displacement fluctuations, imprinted on the transmitted cooling
laser beam, indicate that a final phonon mode occupancy of 0.85 +-0.04 is
obtained.Comment: 18 pages, 10 figure
Gravitational Radiation from Post-Newtonian Sources and Inspiralling Compact Binaries
The article reviews the current status of a theoretical approach to the
problem of the emission of gravitational waves by isolated systems in the
context of general relativity. Part A of the article deals with general
post-Newtonian sources. The exterior field of the source is investigated by
means of a combination of analytic post-Minkowskian and multipolar
approximations. The physical observables in the far-zone of the source are
described by a specific set of radiative multipole moments. By matching the
exterior solution to the metric of the post-Newtonian source in the near-zone
we obtain the explicit expressions of the source multipole moments. The
relationships between the radiative and source moments involve many non-linear
multipole interactions, among them those associated with the tails (and
tails-of-tails) of gravitational waves. Part B of the article is devoted to the
application to compact binary systems. We present the equations of binary
motion, and the associated Lagrangian and Hamiltonian, at the third
post-Newtonian (3PN) order beyond the Newtonian acceleration. The
gravitational-wave energy flux, taking consistently into account the
relativistic corrections in the binary moments as well as the various tail
effects, is derived through 3.5PN order with respect to the quadrupole
formalism. The binary's orbital phase, whose prior knowledge is crucial for
searching and analyzing the signals from inspiralling compact binaries, is
deduced from an energy balance argument.Comment: 109 pages, 1 figure; this version is an update of the Living Review
article originally published in 2002; available on-line at
http://www.livingreviews.org
Three little pieces for computer and relativity
Numerical relativity has made big strides over the last decade. A number of
problems that have plagued the field for years have now been mostly solved.
This progress has transformed numerical relativity into a powerful tool to
explore fundamental problems in physics and astrophysics, and I present here
three representative examples. These "three little pieces" reflect a personal
choice and describe work that I am particularly familiar with. However, many
more examples could be made.Comment: 42 pages, 11 figures. Plenary talk at "Relativity and Gravitation:
100 Years after Einstein in Prague", June 25 - 29, 2012, Prague, Czech
Republic. To appear in the Proceedings (Edition Open Access). Collects
results appeared in journal articles [72,73, 122-124
Coverage, Adherence and Costs of Intermittent Preventive Treatment of Malaria in Children Employing Different Delivery Strategies in Jasikan, Ghana
BACKGROUND: Intermittent preventive treatment of malaria in children (IPTc) involves the administration of a course of anti-malarial drugs at specified time intervals to children at risk of malaria regardless of whether or not they are known to be infected. IPTc provides a high level of protection against uncomplicated and severe malaria, with monthly sulphadoxine-pyrimethamine plus amodiaquine (SP&AQ) and sulphadoxine-pyrimethamine plus piperaquine being the most efficacious regimens. A key challenge is the identification of a cost-effective delivery strategy. METHODS: A community randomized trial was undertaken in Jasikan district, Ghana to assess IPTc effectiveness and costs using SP&AQ delivered in three different ways. Twelve villages were randomly selected to receive IPTc from village health workers (VHWs) or facility-based nurses working at health centres' outpatient departments (OPD) or EPI outreach clinics. Children aged 3 to 59 months-old received one IPT course (three doses) in May, June, September and October. Effectiveness was measured in terms of children covered and adherent to a course and delivery costs were calculated in financial and economic terms using an ingredient approach from the provider perspective. RESULTS: The economic cost per child receiving at least the first dose of all 4 courses was US4.93 by OPD nurses and US7.56 and US$8.51 when IPTc was delivered by VHWs or facility-based nurses respectively. The main cost driver for the VHW delivery was supervision, reflecting resources used for travelling to more remote communities rather than more intense supervision, and for OPD and EPI delivery, it was the opportunity cost of the time spent by nurses in dispensing IPTc. CONCLUSIONS: VHWs achieve higher IPTc coverage and adherence at lower costs than facility-based nurses in Jasikan district, Ghana. TRIAL REGISTRATION: ClinicalTrials.gov NCT00119132
Longitudinal multi-centre brain imaging studies: guidelines and practical tips for accurate and reproducible imaging endpoints and data sharing
Abstract Background Research involving brain imaging is important for understanding common brain diseases. Study endpoints can include features and measures derived from imaging modalities, providing a benchmark against which other phenotypical data can be assessed. In trials, imaging data provide objective evidence of beneficial and adverse outcomes. Multi-centre studies increase generalisability and statistical power. However, there is a lack of practical guidelines for the set-up and conduct of large neuroimaging studies. Methods We address this deficit by describing aspects of study design and other essential practical considerations that will help researchers avoid common pitfalls and data loss. Results The recommendations are grouped into seven categories: (1) planning, (2) defining the imaging endpoints, developing an imaging manual and managing the workflow, (3) performing a dummy run and testing the analysis methods, (4) acquiring the scans, (5) anonymising and transferring the data, (6) monitoring quality, and (7) using structured data and sharing data. Conclusions Implementing these steps will lead to valuable and usable data and help to avoid imaging data wastage
Brane-World Gravity
The observable universe could be a 1+3-surface (the "brane") embedded in a
1+3+\textit{d}-dimensional spacetime (the "bulk"), with Standard Model
particles and fields trapped on the brane while gravity is free to access the
bulk. At least one of the \textit{d} extra spatial dimensions could be very
large relative to the Planck scale, which lowers the fundamental gravity scale,
possibly even down to the electroweak ( TeV) level. This revolutionary
picture arises in the framework of recent developments in M theory. The
1+10-dimensional M theory encompasses the known 1+9-dimensional superstring
theories, and is widely considered to be a promising potential route to quantum
gravity. At low energies, gravity is localized at the brane and general
relativity is recovered, but at high energies gravity "leaks" into the bulk,
behaving in a truly higher-dimensional way. This introduces significant changes
to gravitational dynamics and perturbations, with interesting and potentially
testable implications for high-energy astrophysics, black holes, and cosmology.
Brane-world models offer a phenomenological way to test some of the novel
predictions and corrections to general relativity that are implied by M theory.
This review analyzes the geometry, dynamics and perturbations of simple
brane-world models for cosmology and astrophysics, mainly focusing on warped
5-dimensional brane-worlds based on the Randall--Sundrum models. We also cover
the simplest brane-world models in which 4-dimensional gravity on the brane is
modified at \emph{low} energies -- the 5-dimensional Dvali--Gabadadze--Porrati
models. Then we discuss co-dimension two branes in 6-dimensional models.Comment: A major update of Living Reviews in Relativity 7:7 (2004)
"Brane-World Gravity", 119 pages, 28 figures, the update contains new
material on RS perturbations, including full numerical solutions of
gravitational waves and scalar perturbations, on DGP models, and also on 6D
models. A published version in Living Reviews in Relativit
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