Random Amino Acid Mutations and Protein Misfolding Lead to Shannon Limit in Sequence-Structure Communication

The transmission of genomic information from coding sequence to protein structure during protein synthesis is subject to stochastic errors. To analyze transmission limits in the presence of spurious errors, Shannon's noisy channel theorem is applied to a communication channel between amino acid sequences and their structures established from a large-scale statistical analysis of protein atomic coordinates. While Shannon's theorem confirms that in close to native conformations information is transmitted with limited error probability, additional random errors in sequence (amino acid substitutions) and in structure (structural defects) trigger a decrease in communication capacity toward a Shannon limit at 0.010 bits per amino acid symbol at which communication breaks down. In several controls, simulated error rates above a critical threshold and models of unfolded structures always produce capacities below this limiting value. Thus an essential biological system can be realistically modeled as a digital communication channel that is (a) sensitive to random errors and (b) restricted by a Shannon error limit. This forms a novel basis for predictions consistent with observed rates of defective ribosomal products during protein synthesis, and with the estimated excess of mutual information in protein contact potentials

Shannon Information Theory and Molecular Biology

The role and the contribution of Shannon Information Theory to the development of Molecular Biology has been the object of stimulating debates during the last thirty years. This seems to be connected with some semantic charms associated with the use of the word \u201cinformation\u201d in the biological context. Furthermore information itself, if viewed in a broader perspective, is far from being completely defined in a fashion that overcomes the technical level at which the classical Information Theory has been conceived. This review aims at building on the acknowledged contribution of Shannon Information Theory to Molecular Biology, so as to discover if it is only a technical tool to analyze DNA and proteinic sequences, or if it can rise, at least in perspective, to a higher role that exerts an influence on the construction of a suitable model for handling the genetic information in Molecular Biology

Impacts of 4D BIM on Construction Project Performance

A significant proportion of construction projects are failing to achieve their deadline finish dates. This advocate for solutions that could address the root causes of time impacting risks, leading to the use of 4D BIM for project planning. This study investigates the impacts of 4D BIM on construction projects. An exploratory sequential mixed method research was conducted to initially explore the topic via interviews and literature review, and, subsequently, the themes derived were put into questionnaires to elicit expert knowledge on a wider industry scale. The data were analysed using thematic analysis, reliability analysis, Kruskal-Wallis test and factor analysis. Across the objectives around the impacts of 4D BIM on project reliability, monitoring and diagnosis, the findings presented eight key ways the 4D BIM support project performance. Examples of component factors that were raised was planning efficiency to enhance planner output, assessment and directive with a better comparison of planned and actual progress, and thorough/comprehensive risk reflection to cover wide ranges of issues. Upon further reflection, the finding highlighted the issues of the lack of shared responsibility outside of the planner and BIM coordinator, severe lack of understanding and training regarding 4D BIM and complexity of carrying out the process effectively

Evaluating the discriminatory power of EQ-5D, HUI2 and HUI3 in a US general population survey using Shannon’s indices

OBJECTIVES: To compare quantitatively the discriminatory power of the EQ-5D, HUI2 and HUI3 in terms of absolute and relative informativity, using Shannon's indices. METHODS: EQ-5D and HUI2/3 data completed by a sample of the general adult US population (N = 3,691) were used. Five dimensions allowed head-to-head comparison of informativity: Mobility/Ambulation; Anxiety/Depression/Emotion; Pain/Discomfort (EQ-5D; HUI2; HUI3); Self-Care (EQ-5D; HUI2); and Cognition (HUI2; HUI3). Shannon's index and Shannon's Evenness index were used to assess absolute and relative informativity, both by dimension and by instrument as a whole. RESULTS: Absolute informativity was highest for HUI3, with the largest differences in Pain/Discomfort and Cognition. Relative informativity was highest for EQ-5D, with the largest differences in Mobility/Ambulation and Anxiety/Depression/Emotion. Absolute informativity by instrument was consistently highest for HUI3 and lowest for EQ-5D, and relative informativity was highest for EQ-5D and lowest for HUI3. DISCUSSION: Performance in terms of absolute and relative informativity of the common dimensions of the three instruments varies over dimensions. Several dimensions are suboptimal: Pain/Discomfort (EQ-5D) seems too crude with only 3 levels, and the level descriptions of Ambulation (HUI3) and Self-Care (HUI2) could be improved. In absence of a formal measure, Shannon's indices provide useful measures for assessing discriminatory power of utility instrument

Measuring the functional sequence complexity of proteins

<p>Abstract</p> <p>Background</p> <p>Abel and Trevors have delineated three aspects of sequence complexity, Random Sequence Complexity (RSC), Ordered Sequence Complexity (OSC) and Functional Sequence Complexity (FSC) observed in biosequences such as proteins. In this paper, we provide a method to measure functional sequence complexity.</p> <p>Methods and Results</p> <p>We have extended Shannon uncertainty by incorporating the data variable with a functionality variable. The resulting measured unit, which we call Functional bit (Fit), is calculated from the sequence data jointly with the defined functionality variable. To demonstrate the relevance to functional bioinformatics, a method to measure functional sequence complexity was developed and applied to 35 protein families. Considerations were made in determining how the measure can be used to correlate functionality when relating to the whole molecule and sub-molecule. In the experiment, we show that when the proposed measure is applied to the aligned protein sequences of ubiquitin, 6 of the 7 highest value sites correlate with the binding domain.</p> <p>Conclusion</p> <p>For future extensions, measures of functional bioinformatics may provide a means to evaluate potential evolving pathways from effects such as mutations, as well as analyzing the internal structural and functional relationships within the 3-D structure of proteins.</p

Network, degeneracy and bow tie. Integrating paradigms and architectures to grasp the complexity of the immune system

Recently, the network paradigm, an application of graph theory to biology, has proven to be a powerful approach to gaining insights into biological complexity, and has catalyzed the advancement of systems biology. In this perspective and focusing on the immune system, we propose here a more comprehensive view to go beyond the concept of network. We start from the concept of degeneracy, one of the most prominent characteristic of biological complexity, defined as the ability of structurally different elements to perform the same function, and we show that degeneracy is highly intertwined with another recently-proposed organizational principle, i.e. 'bow tie architecture'. The simultaneous consideration of concepts such as degeneracy, bow tie architecture and network results in a powerful new interpretative tool that takes into account the constructive role of noise (stochastic fluctuations) and is able to grasp the major characteristics of biological complexity, i.e. the capacity to turn an apparently chaotic and highly dynamic set of signals into functional information

The Universal Plausibility Metric (UPM) & Principle (UPP)

<p>Abstract</p> <p>Background</p> <p>Mere possibility is not an adequate basis for asserting scientific plausibility. A precisely defined universal bound is needed beyond which the assertion of <it>plausibility</it>, particularly in life-origin models, can be considered operationally falsified. But can something so seemingly relative and subjective as plausibility ever be quantified? Amazingly, the answer is, "Yes." A method of objectively measuring the plausibility of any chance hypothesis (The Universal Plausibility Metric [UPM]) is presented. A numerical inequality is also provided whereby any chance hypothesis can be definitively falsified when its UPM metric of ξ is < 1 (The Universal Plausibility Principle [UPP]). Both UPM and UPP pre-exist and are independent of any experimental design and data set.</p> <p>Conclusion</p> <p>No low-probability hypothetical plausibility assertion should survive peer-review without subjection to the UPP inequality standard of formal falsification (ξ < 1).</p

The Related Transcriptional Enhancer Factor-1 Isoform, TEAD4216, Can Repress Vascular Endothelial Growth Factor Expression in Mammalian Cells

Increased cellular production of vascular endothelial growth factor (VEGF) is responsible for the development and progression of multiple cancers and other neovascular conditions, and therapies targeting post-translational VEGF products are used in the treatment of these diseases. Development of methods to control and modify the transcription of the VEGF gene is an alternative approach that may have therapeutic potential. We have previously shown that isoforms of the transcriptional enhancer factor 1-related (TEAD4) protein can enhance the production of VEGF. In this study we describe a new TEAD4 isoform, TEAD4216, which represses VEGF promoter activity. The TEAD4216 isoform inhibits human VEGF promoter activity and does not require the presence of the hypoxia responsive element (HRE), which is the sequence critical to hypoxia inducible factor (HIF)-mediated effects. The TEAD4216 protein is localized to the cytoplasm, whereas the enhancer isoforms are found within the nucleus. The TEAD4216 isoform can competitively repress the stimulatory activity of the TEAD4434 and TEAD4148 enhancers. Synthesis of the native VEGF165 protein and cellular proliferation is suppressed by the TEAD4216 isoform. Mutational analysis indicates that nuclear or cytoplasmic localization of any isoform determines whether it acts as an enhancer or repressor, respectively. The TEAD4216 isoform appears to inhibit VEGF production independently of the HRE required activity by HIF, suggesting that this alternatively spliced isoform of TEAD4 may provide a novel approach to treat VEGF-dependent diseases

Search for a vector-like quark T′ → tH via the diphoton decay mode of the Higgs boson in proton-proton collisions at s \sqrt{s} = 13 TeV

A search for the electroweak production of a vector-like quark T′, decaying to a top quark and a Higgs boson is presented. The search is based on a sample of proton-proton collision events recorded at the LHC at = 13 TeV, corresponding to an integrated luminosity of 138 fb−1. This is the first T′ search that exploits the Higgs boson decay to a pair of photons. For narrow isospin singlet T′ states with masses up to 1.1 TeV, the excellent diphoton invariant mass resolution of 1–2% results in an increased sensitivity compared to previous searches based on the same production mechanism. The electroweak production of a T′ quark with mass up to 960 GeV is excluded at 95% confidence level, assuming a coupling strength κT = 0.25 and a relative decay width Γ/MT′ < 5%