The structural determinants of intra-protein compensatory substitutions

Compensatory substitutions happen when one mutation is advantageously selected because it restores the loss of fitness induced by a previous deleterious mutation. How frequent such mutations occur in evolution and what is the structural and functional context permitting their emergence remain open questions. We built an atlas of intra-protein compensatory substitutions using a phylogenetic approach and a dataset of 1,630 bacterial protein families for which high-quality sequence alignments and experimentally derived protein structures were available. We identified more than 51,000 positions coevolving by the mean of predicted compensatory mutations. Using the evolutionary and structural properties of the analyzed positions, we demonstrate that compensatory mutations are scarce (typically only a few in the protein history) but widespread (the majority of proteins experienced at least one). Typical coevolving residues are evolving slowly, are located in the protein core outside secondary structure motifs, and are more often in contact than expected by chance, even after accounting for their evolutionary rate and solvent exposure. An exception to this general scheme is residues coevolving for charge compensation, which are evolving faster than noncoevolving sites, in contradiction with predictions from simple coevolutionary models, but similar to stem pairs in RNA. While sites with a significant pattern of coevolution by compensatory mutations are rare, the comparative analysis of hundreds of structures ultimately permits a better understanding of the link between the three-dimensional structure of a protein and its fitness landscape

Black-Hole Neutron Star Simulations with the BAM code: First Tests and Simulations

The first detections of black hole - neutron star mergers (GW200105 and GW200115) by the LIGO-Virgo-Kagra Collaboration mark a significant scientific breakthrough. The physical interpretation of pre- and post-merger signals requires careful cross-examination between observational and theoretical modelling results. Here we present the first set of black hole - neutron star simulations that were obtained with the numerical-relativity code BAM. Our initial data are constructed using the public LORENE spectral library which employs an excision of the black hole interior. BAM, in contrast, uses the moving-puncture gauge for the evolution. Therefore, we need to ``stuff'' the black hole interior with smooth initial data to evolve the binary system in time. This procedure introduces constraint violations such that the constraint damping properties of the evolution system are essential to increase the accuracy of the simulation and in particular to reduce spurious center-of-mass drifts. Within BAM we evolve the Z4c equations and we compare our gravitational-wave results with those of the SXS collaboration and results obtained with the SACRA code. While we find generally good agreement with the reference solutions and phase differences $\lesssim 0.5$ rad at the moment of merger, the absence of a clean convergence order in our simulations does not allow for a proper error quantification. We finally present a set of different initial conditions to explore how the merger of black hole neutron star systems depends on the involved masses, spins, and equations of state

Strategic determinants of big data analytics in the AEC sector: a multi-perspective framework

With constant flow of large data sets generated by different organisations, big data analytics promises to be a revolutionary game changer for Architecture, Engineering and Construction (AEC) industry. Despite the potential of Big Data, there has been little research conducted thus far to understand the Big Data phenomenon, specifically in the AEC industry. The objective of this research therefore is to understand the contributing factors for adopting big data in AEC firms. The investigation combined the perceived strategic value of BDA with the TOE framework (technology, organization, and environment), to develop and test a holistic model on big data adoption. A set of hypotheses derived from the extant literature was tested on data from structured surveys of about 365 firms, categorised as construction service firms (engineering and architecture) and construction firms (firms engaged in managing construction projects). The results indicated that the inhibitors and facilitators of BDA adoption are different in the construction services (architecture and engineering) and construction firms. For effective adoption of BDA solutions, the findings will guide the business managers to have realistic expectations of BDA integration challenges in AEC sector

From Single to Core-Shell Drops in Non-Confined Microfluidics

This paper was presented at the 4th Micro and Nano Flows Conference (MNF2014), which was held at University College, London, UK. The conference was organised by Brunel University and supported by the Italian Union of Thermofluiddynamics, IPEM, the Process Intensification Network, the Institution of Mechanical Engineers, the Heat Transfer Society, HEXAG - the Heat Exchange Action Group, and the Energy Institute, ASME Press, LCN London Centre for Nanotechnology, UCL University College London, UCL Engineering, the International NanoScience Community, www.nanopaprika.eu.For many encapsulation applications such as nutrients, cells and drugs, large core-shell drops are required. Conventional confined microfluidic devices are limited to a rather small sized (< 1mm) droplets because of difficulties associated with phase separation at low flow rates. We report a microfluidic device which can produce such large range of drop sizes (~200 Am- 6 mm) with varying shell thickness (~1 Am- 1 mm) under the maximum influence of buoyancy, which has so far remained unexplored. The existing physical model for single drop formation is extended for the core-shell drop. The facile nature of working with such systems means scale up would be easy

“On-The-Fly” Fabrication of Highly-Ordered Interconnected Cylindrical and Spherical Porous Microparticles via Dual Polymerization Zone Microfluidics

A microfluidic platform with dual photopolymerization zones has been developed for production of novel uniform interconnected porous particles with shapes imposed either by the geometry of the external capillary or by the thermodynamic minimisation of interfacial area. Double w/o/w drops with well-defined internal droplet size and number were produced and then exposed to online photopolymerization to create the porous particles. Cylindrical interconnected porous particles were produced in a segmented flow where the drops took the shape of the capillary. The microfluidic set up included an extension capillary where the drops relaxed and conformed to their thermodynamically favoured morphology. Window opening of the particles occurred “on-the-fly” during UV polymerization without using any offline auxiliary methods. A distinction was made between critically and highly packed arrangements in double drops. The window opening occurred consistently for highly packed spherical drops, but only for critically packed drops containing more than 6 internal cores at internal phase ratio as low as 0.35. The size and number of cores, shape and structure of double drops could be precisely tuned by the flowrate and by packing structure of the inner droplets

Understanding the corpus of mobile payment services research: an analysis of the literature using co-citation analysis and social network analysis

Mobile Payment Services have advanced in the last two decades, gaining the attention of experts and researchers from around the world. A number of reviews and literature analysis studies have been carried out, aimed at analysing the numerous dimensions of mobile payment services; however, no researcher has attempted a co-citation analysis to scrutinise and comprehend the core knowledge structures that are integral parts of mobile payment services studies. Therefore, in order to fill this research gap, this research article aims to interpret the corpus of mobile payment services research, which was published during the period of 1997 to June 2017. Bibliometric and Social Network Analysis (SNA) methods were employed to formulate the core intellectual structure of research targeting mobile payment services. The Web of Knowledge (WoK) database was the key source from where 406 articles and 3,424 citations were obtained. These documents were analysed using co-citation analysis. UCINET was used to enlist the keynote research papers in the realm of mobile payment services as per factor analysis, citation and co-citation analysis, multidimensional scaling and centrality measurement. Seven core clusters of mobile payment services research emerged as a critical finding of this study; these clusters include (1) Adoption and usage; (2) Trust, risk and security; (3) Application; (4) Scheme; (5) Protocol; (6) Architecture; (7) Mobile payment corporation. The findings of this research study provide crucial guidelines for practitioners and researchers involved in this field.Mobile Payment Services have advanced in the last two decades, gaining the attention of experts and researchers from around the world. A number of reviews and literature analysis studies have been carried out, aimed at analysing the numerous dimensions of mobile payment services; however, no researcher has attempted a co-citation analysis to scrutinise and comprehend the core knowledge structures that are integral parts of mobile payment services studies. Therefore, in order to fill this research gap, this research article aims to interpret the corpus of mobile payment services research, which was published during the period of 1997 to June 2017. Bibliometric and Social Network Analysis (SNA) methods were employed to formulate the core intellectual structure of research targeting mobile payment services. The Web of Knowledge (WoK) database was the key source from where 406 articles and 3,424 citations were obtained. These documents were analysed using co-citation analysis. UCINET was used to enlist the keynote research papers in the realm of mobile payment services as per factor analysis, citation and co-citation analysis, multidimensional scaling and centrality measurement. Seven core clusters of mobile payment services research emerged as a critical finding of this study; these clusters include (1) Adoption and usage; (2) Trust, risk and security; (3) Application; (4) Scheme; (5) Protocol; (6) Architecture; (7) Mobile payment corporation. The findings of this research study provide crucial guidelines for practitioners and researchers involved in this field

IN SILICO STUDY OF PROTEIN PROTEIN INTERACTION STABILIZATION AND MECHANICAL FORCE APPLICATION ON BIOMOLECULES

Targeting protein-protein interactions is a challenging task in drug discovery process. Despite the challenges, several studies have provided evidences for the development of small molecules modulating protein-protein interactions. In Part I, it is demonstrated that how a small molecule can induce the formation of an otherwise unstable protein-protein complex. A study of the stabilization of a FKBP12-FRB complex by a small molecule rapamycin is presented. The stability of the complex is analyzed and its interactions are characterized at the atomic level by performing free energy calculations and computational alanine scanning. It is shown that rapamycin stabilizes the complex by acting as a bridge between the two proteins; and the complex is stable only in the presence of rapamycin. The reported results and the good performance of standard molecular modeling techniques in describing the model system can be interesting not only in the design and development of improved molecules acting as FKBP12\u2013FRB protein interaction stabilizers, but also in the somehow neglected study of protein-protein interactions stabilizers in general. In Part II, studies regarding computational modeling of the application of mechanical force to biomolecules is presented. This part is further divided into two chapters since the investigations have been performed on two biological systems. In the first chapter of Part II (chapter 6), it is described that how the osmolyte molecules affect the mechanical unfolding of a peptide. The mechanical unfolding of peptide has been performed by using Steered Molecular Dynamics. In this study, the effect of four different osmolytes on the free energy difference between the folded and the denatured state have been calculated. The observed trend mirrors the expected behavior of the studied osmolytes and unfolding pathways analysis allows an insight into the mechanism of action of osmolytes. After the successful application of Steered molecular dynamics technique on the \u3b2-hairpin peptide, the same is applied on tubulin heterodimers for the in-depth study of the lateral and longitudinal interactions which are responsible for the stability and dynamics of the microtubules. In the other chapter of Part II (chapter 7), these interactions are studied with the help of mechanical dissociation of the tubulin heterodimers. These studies have allowed the identification of the critical interactions responsible for the binding of tubulin heterodimers laterally as well as longitudinally. The observations obtained could be important for the design of compounds that target these interactions and acts as microtubule inhibitors or stabilizers