1,423 research outputs found
From Nonspecific DNAâProtein Encounter Complexes to the Prediction of DNAâProtein Interactions
©2009 Gao, Skolnick. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.doi:10.1371/journal.pcbi.1000341DNAâprotein interactions are involved in many essential biological activities. Because there is no simple mapping code between DNA base pairs and protein amino acids, the prediction of DNAâprotein interactions is a challenging problem. Here, we present a novel computational approach for predicting DNA-binding protein residues and DNAâprotein interaction modes without knowing its specific DNA target sequence. Given the structure of a DNA-binding protein, the method first generates an ensemble of complex structures obtained by rigid-body docking with a nonspecific canonical B-DNA. Representative models are subsequently selected through clustering and ranking by their DNAâprotein interfacial energy. Analysis of these encounter complex models suggests that the recognition sites for specific DNA binding are usually favorable interaction sites for the nonspecific DNA probe and that nonspecific DNAâprotein interaction modes exhibit some similarity to specific DNAâprotein binding modes. Although the method requires as input the knowledge that the protein binds DNA, in benchmark tests, it achieves better performance in identifying DNA-binding sites than three previously established methods, which are based on sophisticated machine-learning techniques. We further apply our method to protein structures predicted through modeling and demonstrate that our method performs satisfactorily on protein models whose root-mean-square Ca deviation from native is up to 5 Ă
from their native structures. This study provides valuable structural insights into how a specific DNA-binding protein interacts with a nonspecific DNA sequence. The similarity between the specific DNAâprotein interaction mode and nonspecific interaction modes may reflect an important sampling step in search of its specific DNA targets by a DNA-binding protein
Cycle-based Cluster Variational Method for Direct and Inverse Inference
We elaborate on the idea that loop corrections to belief propagation could be
dealt with in a systematic way on pairwise Markov random fields, by using the
elements of a cycle basis to define region in a generalized belief propagation
setting. The region graph is specified in such a way as to avoid dual loops as
much as possible, by discarding redundant Lagrange multipliers, in order to
facilitate the convergence, while avoiding instabilities associated to minimal
factor graph construction. We end up with a two-level algorithm, where a belief
propagation algorithm is run alternatively at the level of each cycle and at
the inter-region level. The inverse problem of finding the couplings of a
Markov random field from empirical covariances can be addressed region wise. It
turns out that this can be done efficiently in particular in the Ising context,
where fixed point equations can be derived along with a one-parameter log
likelihood function to minimize. Numerical experiments confirm the
effectiveness of these considerations both for the direct and inverse MRF
inference.Comment: 47 pages, 16 figure
A cautionary note regarding count models of alcohol consumption in randomized controlled trials
BACKGROUND: Alcohol consumption is commonly used as a primary outcome in randomized alcohol treatment studies. The distribution of alcohol consumption is highly skewed, particularly in subjects with alcohol dependence. METHODS: In this paper, we will consider the use of count models for outcomes in a randomized clinical trial setting. These include the Poisson, over-dispersed Poisson, negative binomial, zero-inflated Poisson and zero-inflated negative binomial. We compare the Type-I error rate of these methods in a series of simulation studies of a randomized clinical trial, and apply the methods to the ASAP (Addressing the Spectrum of Alcohol Problems) trial. RESULTS: Standard Poisson models provide a poor fit for alcohol consumption data from our motivating example, and did not preserve Type-I error rates for the randomized group comparison when the true distribution was over-dispersed Poisson. For the ASAP trial, where the distribution of alcohol consumption featured extensive over-dispersion, there was little indication of significant randomization group differences, except when the standard Poisson model was fit. CONCLUSION: As with any analysis, it is important to choose appropriate statistical models. In simulation studies and in the motivating example, the standard Poisson was not robust when fit to over-dispersed count data, and did not maintain the appropriate Type-I error rate. To appropriately model alcohol consumption, more flexible count models should be routinely employed
Cooperation and Contagion in Web-Based, Networked Public Goods Experiments
A longstanding idea in the literature on human cooperation is that
cooperation should be reinforced when conditional cooperators are more likely
to interact. In the context of social networks, this idea implies that
cooperation should fare better in highly clustered networks such as cliques
than in networks with low clustering such as random networks. To test this
hypothesis, we conducted a series of web-based experiments, in which 24
individuals played a local public goods game arranged on one of five network
topologies that varied between disconnected cliques and a random regular graph.
In contrast with previous theoretical work, we found that network topology had
no significant effect on average contributions. This result implies either that
individuals are not conditional cooperators, or else that cooperation does not
benefit from positive reinforcement between connected neighbors. We then tested
both of these possibilities in two subsequent series of experiments in which
artificial seed players were introduced, making either full or zero
contributions. First, we found that although players did generally behave like
conditional cooperators, they were as likely to decrease their contributions in
response to low contributing neighbors as they were to increase their
contributions in response to high contributing neighbors. Second, we found that
positive effects of cooperation were contagious only to direct neighbors in the
network. In total we report on 113 human subjects experiments, highlighting the
speed, flexibility, and cost-effectiveness of web-based experiments over those
conducted in physical labs
Health status of adults with Short Stature: A comparison with the normal population and one well-known chronic disease (Rheumatoid Arthritis)
BACKGROUND: To examine the subjective health status of adults with short stature (ShSt) and compare with the general population (GP) and one well-known chronic disease, rheumatoid artritis (RA). In addition, to explore the association between age, gender, height, educational level and different aspects of health status of adults with short stature. METHODS: A questionnaire was mailed to 72 subjects with short stature registered in the database of a Norwegian resource centre for rare disorders, response rate 61% (n = 44, age 16â61). Health status was assessed with SF-36 version 2. Comparison was done with age and gender matched samples from the general population in Norway (n = 264) and from subjects with RA (n = 88). RESULTS: The ShSt sample reported statistically significant impaired health status in all SF-36 subscales compared with the GP sample, most in the physical functioning, Mean Difference (MD) 34 (95% Confidence Interval (CI) 25â44). The ShSt reported poorer health status in mental health, MD 11 (95% CI 4â18) and social functioning, MD 11 (95% CI 2â20) but better in role physical MD 13 (95% CI 1â25) than the RA sample. On the other subscales there were minor difference between the ShSt and the RA sample. Within the short stature group there was a significant association between age and all SF-36 physical subcales, height was significantly associated with physical functioning while level of education was significantly associated with mental health. CONCLUSION: People with short stature reported impaired health status in all SF-36 subscales indicating that they have health problems that influence their daily living. Health status seems to decline with increasing age, and earlier than in the general population
Stated and revealed inequality aversion in three subject pools
This paper reports data from three subject pools (n=717 subjects) using techniques based on those of Loewenstein, et al. (1989) and Blanco, et al. (2011) to obtain parameters, respectively, of stated and revealed inequality aversion. We provide a replication opportunity for those papers, with two innovations: (i) a design which allows stated and revealed preferences to be compared at the individual level; (ii) assessment of robustness of findings across subjects from a UK university, a Turkish university and Amazon Mechanical Turk. Our findings on stated aversion to inequality are qualitatively similar to those of Loewenstein, et al. in each of our subject pools, whereas there are notable differences between some of our findings on revealed preference and those of Blanco, et al. We find that revealed advantageous inequality aversion is often stronger than revealed dis-advantageous inequality aversion. In most subject pools, we find some (weak) correlation between corresponding parameters of stated and revealed inequality aversion
Coverage, Continuity and Visual Cortical Architecture
The primary visual cortex of many mammals contains a continuous
representation of visual space, with a roughly repetitive aperiodic map of
orientation preferences superimposed. It was recently found that orientation
preference maps (OPMs) obey statistical laws which are apparently invariant
among species widely separated in eutherian evolution. Here, we examine whether
one of the most prominent models for the optimization of cortical maps, the
elastic net (EN) model, can reproduce this common design. The EN model
generates representations which optimally trade of stimulus space coverage and
map continuity. While this model has been used in numerous studies, no
analytical results about the precise layout of the predicted OPMs have been
obtained so far. We present a mathematical approach to analytically calculate
the cortical representations predicted by the EN model for the joint mapping of
stimulus position and orientation. We find that in all previously studied
regimes, predicted OPM layouts are perfectly periodic. An unbiased search
through the EN parameter space identifies a novel regime of aperiodic OPMs with
pinwheel densities lower than found in experiments. In an extreme limit,
aperiodic OPMs quantitatively resembling experimental observations emerge.
Stabilization of these layouts results from strong nonlocal interactions rather
than from a coverage-continuity-compromise. Our results demonstrate that
optimization models for stimulus representations dominated by nonlocal
suppressive interactions are in principle capable of correctly predicting the
common OPM design. They question that visual cortical feature representations
can be explained by a coverage-continuity-compromise.Comment: 100 pages, including an Appendix, 21 + 7 figure
Genomic-Bioinformatic Analysis of Transcripts Enriched in the Third-Stage Larva of the Parasitic Nematode Ascaris suum
Differential transcription in Ascaris suum was investigated using a genomic-bioinformatic approach. A cDNA archive enriched for molecules in the infective third-stage larva (L3) of A. suum was constructed by suppressive-subtractive hybridization (SSH), and a subset of cDNAs from 3075 clones subjected to microarray analysis using cDNA probes derived from RNA from different developmental stages of A. suum. The cDNAs (n = 498) shown by microarray analysis to be enriched in the L3 were sequenced and subjected to bioinformatic analyses using a semi-automated pipeline (ESTExplorer). Using gene ontology (GO), 235 of these molecules were assigned to âbiological processâ (n = 68), âcellular componentâ (n = 50), or âmolecular functionâ (n = 117). Of the 91 clusters assembled, 56 molecules (61.5%) had homologues/orthologues in the free-living nematodes Caenorhabditis elegans and C. briggsae and/or other organisms, whereas 35 (38.5%) had no significant similarity to any sequences available in current gene databases. Transcripts encoding protein kinases, protein phosphatases (and their precursors), and enolases were abundantly represented in the L3 of A. suum, as were molecules involved in cellular processes, such as ubiquitination and proteasome function, gene transcription, proteinâprotein interactions, and function. In silico analyses inferred the C. elegans orthologues/homologues (n = 50) to be involved in apoptosis and insulin signaling (2%), ATP synthesis (2%), carbon metabolism (6%), fatty acid biosynthesis (2%), gap junction (2%), glucose metabolism (6%), or porphyrin metabolism (2%), although 34 (68%) of them could not be mapped to a specific metabolic pathway. Small numbers of these 50 molecules were predicted to be secreted (10%), anchored (2%), and/or transmembrane (12%) proteins. Functionally, 17 (34%) of them were predicted to be associated with (non-wild-type) RNAi phenotypes in C. elegans, the majority being embryonic lethality (Emb) (13 types; 58.8%), larval arrest (Lva) (23.5%) and larval lethality (Lvl) (47%). A genetic interaction network was predicted for these 17 C. elegans orthologues, revealing highly significant interactions for nine molecules associated with embryonic and larval development (66.9%), information storage and processing (5.1%), cellular processing and signaling (15.2%), metabolism (6.1%), and unknown function (6.7%). The potential roles of these molecules in development are discussed in relation to the known roles of their homologues/orthologues in C. elegans and some other nematodes. The results of the present study provide a basis for future functional genomic studies to elucidate molecular aspects governing larval developmental processes in A. suum and/or the transition to parasitism
Proceedings of the 4th BEAT-PCD Conference and 5th PCD Training School
Primary ciliary dyskinesia (PCD) is an inherited ciliopathy leading to chronic suppurative lung disease, chronic rhinosinusitis, middle ear disease, sub-fertility and situs abnormalities. As PCD is rare, it is important that scientists and clinicians foster international collaborations to share expertise in order to provide the best possible diagnostic and management strategies. âBetter Experimental Approaches to Treat Primary Ciliary Dyskinesiaâ (BEAT-PCD) is a multidisciplinary network funded by EU COST Action (BM1407) to coordinate innovative basic science and clinical research from across the world to drive advances in the field. The fourth and final BEAT-PCD Conference and fifth PCD Training School were held jointly in March 2019 in Poznan, Poland. The varied program of plenaries, workshops, break-out sessions, oral and poster presentations were aimed to enhance the knowledge and skills of delegates, whilst also providing a collaborative platform to exchange ideas. In this final BEAT-PCD conference we were able to build upon programmes developed throughout the lifetime of the COST Action. These proceedings report on the conference, highlighting some of the successes of the BEAT-PCD programme
Hepatic S1P deficiency lowers plasma cholesterol levels in apoB-containing lipoproteins when LDLR function is compromised
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