Inhomogeneous DNA: conducting exons and insulating introns

Parts of DNA sequences known as exons and introns play very different role in coding and storage of genetic information. Here we show that their conducting properties are also very different. Taking into account long-range correlations among four basic nucleotides that form double-stranded DNA sequence, we calculate electron localization length for exon and intron regions. Analyzing different DNA molecules, we obtain that the exons have narrow bands of extended states, unlike the introns where all the states are well localized. The band of extended states is due to a specific form of the binary correlation function of the sequence of basic DNA nucleotides.Comment: 14 pages, 6 figure

Amortising the Cost of Mutation Based Fault Localisation using Statistical Inference

Mutation analysis can effectively capture the dependency between source code and test results. This has been exploited by Mutation Based Fault Localisation (MBFL) techniques. However, MBFL techniques suffer from the need to expend the high cost of mutation analysis after the observation of failures, which may present a challenge for its practical adoption. We introduce SIMFL (Statistical Inference for Mutation-based Fault Localisation), an MBFL technique that allows users to perform the mutation analysis in advance against an earlier version of the system. SIMFL uses mutants as artificial faults and aims to learn the failure patterns among test cases against different locations of mutations. Once a failure is observed, SIMFL requires either almost no or very small additional cost for analysis, depending on the used inference model. An empirical evaluation of SIMFL using 355 faults in Defects4J shows that SIMFL can successfully localise up to 103 faults at the top, and 152 faults within the top five, on par with state-of-the-art alternatives. The cost of mutation analysis can be further reduced by mutation sampling: SIMFL retains over 80% of its localisation accuracy at the top rank when using only 10% of generated mutants, compared to results obtained without sampling

Scan matching by cross-correlation and differential evolution

Scan matching is an important task, solved in the context of many high-level problems including pose estimation, indoor localization, simultaneous localization and mapping and others. Methods that are accurate and adaptive and at the same time computationally efficient are required to enable location-based services in autonomous mobile devices. Such devices usually have a wide range of high-resolution sensors but only a limited processing power and constrained energy supply. This work introduces a novel high-level scan matching strategy that uses a combination of two advanced algorithms recently used in this field: cross-correlation and differential evolution. The cross-correlation between two laser range scans is used as an efficient measure of scan alignment and the differential evolution algorithm is used to search for the parameters of a transformation that aligns the scans. The proposed method was experimentally validated and showed good ability to match laser range scans taken shortly after each other and an excellent ability to match laser range scans taken with longer time intervals between them.Web of Science88art. no. 85

Nbr1 Is a Novel Inhibitor of Ligand-Mediated Receptor Tyrosine Kinase Degradation

endocytic trafficking and selective autophagy. However, the exact function of Nbr1 in these contexts has not been studied in detail. Here we investigated the role of Nbr1 in the trafficking of receptor tyrosine kinases (RTKs). We report that ectopic Nbr1 expression inhibits the ligand-mediated lysosomal degradation of RTKs, and this is probably done via the inhibition of receptor internalization. Conversely, the depletion of endogenous NBR1 enhances RTK degradation. Analyses of truncation mutations demonstrated that the C terminus of Nbr1 is essential but not sufficient for this activity. Moreover, the C terminus of Nbr1 is essential but not sufficient for the localization of the protein to late endosomes. We demonstrate that the C terminus of Nbr1 contains a novel membrane-interacting amphipathic -helix, which is essential for the late endocytic localization of the protein but not for its effect on RTK degradation. Finally, autophagic and late endocytic localizations of Nbr1 are independent of one another, suggesting that the roles of Nbr1 in each context might be distinct. Our results define Nbr1 as a negative regulator of ligand-mediated RTK degradation and reveal the interplay between its various regions for protein localization and function

Machine learning-guided directed evolution for protein engineering

Machine learning (ML)-guided directed evolution is a new paradigm for biological design that enables optimization of complex functions. ML methods use data to predict how sequence maps to function without requiring a detailed model of the underlying physics or biological pathways. To demonstrate ML-guided directed evolution, we introduce the steps required to build ML sequence-function models and use them to guide engineering, making recommendations at each stage. This review covers basic concepts relevant to using ML for protein engineering as well as the current literature and applications of this new engineering paradigm. ML methods accelerate directed evolution by learning from information contained in all measured variants and using that information to select sequences that are likely to be improved. We then provide two case studies that demonstrate the ML-guided directed evolution process. We also look to future opportunities where ML will enable discovery of new protein functions and uncover the relationship between protein sequence and function.Comment: Made significant revisions to focus on aspects most relevant to applying machine learning to speed up directed evolutio

Genetic heterogeneity of pseudoxanthoma elasticum: the Chinese signature profile of ABCC6 and ENPP1 mutations.

Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder characterized by ectopic mineralization, is caused by mutations in the ABCC6 gene. We examined clinically 29 Chinese PXE patients from unrelated families, so far the largest cohort of Asian PXE patients. In a subset of 22 patients, we sequenced ABCC6 and another candidate gene, ENPP1, and conducted pathogenicity analyses for each variant. We identified a total of 17 distinct mutations in ABCC6, 15 of them being, to our knowledge, previously unreported, including 5 frameshift and 10 missense variants. In addition, a missense mutation in combination with a recurrent nonsense mutation in ENPP1 was discovered in a pediatric PXE case. No cases with p.R1141X or del23-29 mutations, common in Caucasian patient populations, were identified. The 10 missense mutations in ABCC6 were expressed in the mouse liver via hydrodynamic tail-vein injections. One mutant protein showed cytoplasmic accumulation indicating abnormal subcellular trafficking, while the other nine mutants showed correct plasma membrane location. These nine mutations were further investigated for their pathogenicity using a recently developed zebrafish mRNA rescue assay. Minimal rescue of the morpholino-induced phenotype was achieved with eight of the nine mutant human ABCC6 mRNAs tested, implying pathogenicity. This study demonstrates that the Chinese PXE population harbors unique ABCC6 mutations. These genetic data have implications for allele-specific therapy currently being developed for PXE