327 research outputs found
Higher nucleoporin-Importinβ affinity at the nuclear basket increases nucleocytoplasmic import.
Several in vitro studies have shown the presence of an affinity gradient in nuclear pore complex proteins for the import receptor Importinβ, at least partially contributing to nucleocytoplasmic transport, while others have historically argued against the presence of such a gradient. Nonetheless, the existence of an affinity gradient has remained an uncharacterized contributing factor. To shed light on the affinity gradient theory and better characterize how the existence of such an affinity gradient between the nuclear pore and the import receptor may influence the nucleocytoplasmic traffic, we have developed a general-purpose agent based modeling (ABM) framework that features a new method for relating rate constants to molecular binding and unbinding probabilities, and used our ABM approach to quantify the effects of a wide range of forward and reverse nucleoporin-Importinβ affinity gradients. Our results indicate that transport through the nuclear pore complex is maximized with an effective macroscopic affinity gradient of 2000 µM, 200 µM and 10 µM in the cytoplasmic, central channel and nuclear basket respectively. The transport rate at this gradient is approximately 10% higher than the transport rate for a comparable pore lacking any affinity gradient, which has a peak transport rate when all nucleoporins have an affinity of 200 µM for Importinβ. Furthermore, this optimal ratio of affinity gradients is representative of the ratio of affinities reported for the yeast nuclear pore complex--suggesting that the affinity gradient seen in vitro is highly optimized
Comparing Fifty Natural Languages and Twelve Genetic Languages Using Word Embedding Language Divergence (WELD) as a Quantitative Measure of Language Distance
We introduce a new measure of distance between languages based on word
embedding, called word embedding language divergence (WELD). WELD is defined as
divergence between unified similarity distribution of words between languages.
Using such a measure, we perform language comparison for fifty natural
languages and twelve genetic languages. Our natural language dataset is a
collection of sentence-aligned parallel corpora from bible translations for
fifty languages spanning a variety of language families. Although we use
parallel corpora, which guarantees having the same content in all languages,
interestingly in many cases languages within the same family cluster together.
In addition to natural languages, we perform language comparison for the coding
regions in the genomes of 12 different organisms (4 plants, 6 animals, and two
human subjects). Our result confirms a significant high-level difference in the
genetic language model of humans/animals versus plants. The proposed method is
a step toward defining a quantitative measure of similarity between languages,
with applications in languages classification, genre identification, dialect
identification, and evaluation of translations
An agent-based model for mRNA export through the nuclear pore complex.
mRNA export from the nucleus is an essential step in the expression of every protein- coding gene in eukaryotes, but many aspects of this process remain poorly understood. The density of export receptors that must bind an mRNA to ensure export, as well as how receptor distribution affects transport dynamics, is not known. It is also unclear whether the rate-limiting step for transport occurs at the nuclear basket, in the central channel, or on the cytoplasmic face of the nuclear pore complex. Using previously published biophysical and biochemical parameters of mRNA export, we implemented a three-dimensional, coarse-grained, agent-based model of mRNA export in the nanosecond regime to gain insight into these issues. On running the model, we observed that mRNA export is sensitive to the number and distribution of transport receptors coating the mRNA and that there is a rate-limiting step in the nuclear basket that is potentially associated with the mRNA reconfiguring itself to thread into the central channel. Of note, our results also suggest that using a single location-monitoring mRNA label may be insufficient to correctly capture the time regime of mRNA threading through the pore and subsequent transport. This has implications for future experimental design to study mRNA transport dynamics
Fast and accurate classification of echocardiograms using deep learning
Echocardiography is essential to modern cardiology. However, human
interpretation limits high throughput analysis, limiting echocardiography from
reaching its full clinical and research potential for precision medicine. Deep
learning is a cutting-edge machine-learning technique that has been useful in
analyzing medical images but has not yet been widely applied to
echocardiography, partly due to the complexity of echocardiograms' multi view,
multi modality format. The essential first step toward comprehensive computer
assisted echocardiographic interpretation is determining whether computers can
learn to recognize standard views. To this end, we anonymized 834,267
transthoracic echocardiogram (TTE) images from 267 patients (20 to 96 years, 51
percent female, 26 percent obese) seen between 2000 and 2017 and labeled them
according to standard views. Images covered a range of real world clinical
variation. We built a multilayer convolutional neural network and used
supervised learning to simultaneously classify 15 standard views. Eighty
percent of data used was randomly chosen for training and 20 percent reserved
for validation and testing on never seen echocardiograms. Using multiple images
from each clip, the model classified among 12 video views with 97.8 percent
overall test accuracy without overfitting. Even on single low resolution
images, test accuracy among 15 views was 91.7 percent versus 70.2 to 83.5
percent for board-certified echocardiographers. Confusional matrices, occlusion
experiments, and saliency mapping showed that the model finds recognizable
similarities among related views and classifies using clinically relevant image
features. In conclusion, deep neural networks can classify essential
echocardiographic views simultaneously and with high accuracy. Our results
provide a foundation for more complex deep learning assisted echocardiographic
interpretation.Comment: 31 pages, 8 figure
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