703 research outputs found
Detection of non-melanoma skin cancer by in vivo fluorescence imaging with fluorocoxib A.
Non-melanoma skin cancer (NMSC) is the most common form of cancer in the US and its incidence is increasing. The current standard of care is visual inspection by physicians and/or dermatologists, followed by skin biopsy and pathologic confirmation. We have investigated the use of in vivo fluorescence imaging using fluorocoxib A as a molecular probe for early detection and assessment of skin tumors in mouse models of NMSC. Fluorocoxib A targets the cyclooxygenase-2 (COX-2) enzyme that is preferentially expressed by inflamed and tumor tissue, and therefore has potential to be an effective broadly active molecular biomarker for cancer detection. We tested the sensitivity of fluorocoxib A in a BCC allograft SCID hairless mouse model using a wide-field fluorescence imaging system. Subcutaneous allografts comprised of 1000 BCC cells were detectable above background. These BCC allograft mice were imaged over time and a linear correlation (R(2) = 0.8) between tumor volume and fluorocoxib A signal levels was observed. We also tested fluorocoxib A in a genetically engineered spontaneous BCC mouse model (Ptch1(+/-) K14-Cre-ER2 p53(fl/fl)), where sequential imaging of the same animals over time demonstrated that early, microscopic lesions (100 μm size) developed into visible macroscopic tumor masses over 11 to 17 days. Overall, for macroscopic tumors, the sensitivity was 88% and the specificity was 100%. For microscopic tumors, the sensitivity was 85% and specificity was 56%. These results demonstrate the potential of fluorocoxib A as an in vivo imaging agent for early detection, margin delineation and guided biopsies of NMSCs
Towards Neural Mixture Recommender for Long Range Dependent User Sequences
Understanding temporal dynamics has proved to be highly valuable for accurate
recommendation. Sequential recommenders have been successful in modeling the
dynamics of users and items over time. However, while different model
architectures excel at capturing various temporal ranges or dynamics, distinct
application contexts require adapting to diverse behaviors. In this paper we
examine how to build a model that can make use of different temporal ranges and
dynamics depending on the request context. We begin with the analysis of an
anonymized Youtube dataset comprising millions of user sequences. We quantify
the degree of long-range dependence in these sequences and demonstrate that
both short-term and long-term dependent behavioral patterns co-exist. We then
propose a neural Multi-temporal-range Mixture Model (M3) as a tailored solution
to deal with both short-term and long-term dependencies. Our approach employs a
mixture of models, each with a different temporal range. These models are
combined by a learned gating mechanism capable of exerting different model
combinations given different contextual information. In empirical evaluations
on a public dataset and our own anonymized YouTube dataset, M3 consistently
outperforms state-of-the-art sequential recommendation methods.Comment: Accepted at WWW 201
Ensemble reweighting using Cryo-EM particles
Cryo-electron microscopy (cryo-EM) has recently become a premier method for
obtaining high-resolution structures of biological macromolecules. However, it
is limited to biomolecular samples with low conformational heterogeneity, where
all the conformations can be well-sampled at many projection angles. While
cryo-EM technically provides single-molecule data for heterogeneous molecules,
most existing reconstruction tools cannot extract the full distribution of
possible molecular configurations. To overcome these limitations, we build on a
prior Bayesian approach and develop an ensemble refinement framework that
estimates the ensemble density from a set of cryo-EM particles by reweighting a
prior ensemble of conformations, e.g., from molecular dynamics simulations or
structure prediction tools. Our work is a general approach to recovering the
equilibrium probability density of the biomolecule directly in conformational
space from single-molecule data. To validate the framework, we study the
extraction of state populations and free energies for a simple toy model and
from synthetic cryo-EM images of a simulated protein that explores multiple
folded and unfolded conformations
Universality in the Screening Cloud of Dislocations Surrounding a Disclination
A detailed analytical and numerical analysis for the dislocation cloud
surrounding a disclination is presented. The analytical results show that the
combined system behaves as a single disclination with an effective fractional
charge which can be computed from the properties of the grain boundaries
forming the dislocation cloud. Expressions are also given when the crystal is
subjected to an external two-dimensional pressure. The analytical results are
generalized to a scaling form for the energy which up to core energies is given
by the Young modulus of the crystal times a universal function. The accuracy of
the universality hypothesis is numerically checked to high accuracy. The
numerical approach, based on a generalization from previous work by S. Seung
and D.R. Nelson ({\em Phys. Rev A 38:1005 (1988)}), is interesting on its own
and allows to compute the energy for an {\em arbitrary} distribution of
defects, on an {\em arbitrary geometry} with an arbitrary elastic {\em energy}
with very minor additional computational effort. Some implications for recent
experimental, computational and theoretical work are also discussed.Comment: 35 pages, 21 eps file
Theoretical interpretation of the experimental electronic structure of lens shaped, self-assembled InAs/GaAs quantum dots
We adopt an atomistic pseudopotential description of the electronic structure
of self-assembled, lens shaped InAs quantum dots within the ``linear
combination of bulk bands'' method. We present a detailed comparison with
experiment, including quantites such as the single particle electron and hole
energy level spacings, the excitonic band gap, the electron-electron, hole-hole
and electron hole Coulomb energies and the optical polarization anisotropy. We
find a generally good agreement, which is improved even further for a dot
composition where some Ga has diffused into the dots.Comment: 16 pages, 5 figures. Submitted to Physical Review
The fundamental pro-groupoid of an affine 2-scheme
A natural question in the theory of Tannakian categories is: What if you
don't remember \Forget? Working over an arbitrary commutative ring , we
prove that an answer to this question is given by the functor represented by
the \'etale fundamental groupoid \pi_1(\spec(R)), i.e.\ the separable
absolute Galois group of when it is a field. This gives a new definition
for \'etale \pi_1(\spec(R)) in terms of the category of -modules rather
than the category of \'etale covers. More generally, we introduce a new notion
of "commutative 2-ring" that includes both Grothendieck topoi and symmetric
monoidal categories of modules, and define a notion of for the
corresponding "affine 2-schemes." These results help to simplify and clarify
some of the peculiarities of the \'etale fundamental group. For example,
\'etale fundamental groups are not "true" groups but only profinite groups, and
one cannot hope to recover more: the "Tannakian" functor represented by the
\'etale fundamental group of a scheme preserves finite products but not all
products.Comment: 46 pages + bibliography. Diagrams drawn in Tik
Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure
Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure
Designing a patient-centered personal health record to promote preventive care
<p>Abstract</p> <p>Background</p> <p>Evidence-based preventive services offer profound health benefits, yet Americans receive only half of indicated care. A variety of government and specialty society policy initiatives are promoting the adoption of information technologies to engage patients in their care, such as personal health records, but current systems may not utilize the technology's full potential.</p> <p>Methods</p> <p>Using a previously described model to make information technology more patient-centered, we developed an interactive preventive health record (IPHR) designed to more deeply engage patients in preventive care and health promotion. We recruited 14 primary care practices to promote the IPHR to all adult patients and sought practice and patient input in designing the IPHR to ensure its usability, salience, and generalizability. The input involved patient usability tests, practice workflow observations, learning collaboratives, and patient feedback. Use of the IPHR was measured using practice appointment and IPHR databases.</p> <p>Results</p> <p>The IPHR that emerged from this process generates tailored patient recommendations based on guidelines from the U.S. Preventive Services Task Force and other organizations. It extracts clinical data from the practices' electronic medical record and obtains health risk assessment information from patients. Clinical content is translated and explained in lay language. Recommendations review the benefits and uncertainties of services and possible actions for patients and clinicians. Embedded in recommendations are self management tools, risk calculators, decision aids, and community resources - selected to match patient's clinical circumstances. Within six months, practices had encouraged 14.4% of patients to use the IPHR (ranging from 1.5% to 28.3% across the 14 practices). Practices successfully incorporated the IPHR into workflow, using it to prepare patients for visits, augment health behavior counseling, explain test results, automatically issue patient reminders for overdue services, prompt clinicians about needed services, and formulate personalized prevention plans.</p> <p>Conclusions</p> <p>The IPHR demonstrates that a patient-centered personal health record that interfaces with the electronic medical record can give patients a high level of individualized guidance and be successfully adopted by busy primary care practices. Further study and refinement are necessary to make information systems even more patient-centered and to demonstrate their impact on care.</p> <p>Trial Registration</p> <p>Clinicaltrials.gov identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00589173">NCT00589173</a></p
De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development
Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD
Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms
Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms
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