Information-processing capabilities as a transactive memory system : a comparative study of two distributed R&D teams

fi=vertaisarvioitu|en=peerReviewed

The long and winding road: Routine creation and replication in multi-site organizations

Prior research on organizational routines in the ‘capabilities’ literature has either studied how new routines are created during an exploratory process of variation and selection or how existing routines are replicated during a phase of exploitation. Few studies have analyzed the life cycle of new routine creation and replication as an integrated process. In an in-depth case study of England’s Highways Agency, this paper shows that the creation and replication of a new routine across multiple sites involves four sequential steps: envisioning, experimenting, entrenching and enacting. We contribute to the capabilities research in two ways: first, by showing how different organizational levels, capabilities and logics (cognitive and behavioural) shape the development of new routines; and second, by identifying how distinct evolutionary cycles of variation and selective retention occur during each step in the process. In contrast with prior research on replication as an exact copy of a template or existing routine, our study focuses on the replication of an entirely new routine (based on novel principles) that is adapted to fit local operational conditions during its large-scale replication across multiple sites. We draw upon insights from adjacent ‘practice research’ and suggest how capabilities and practice studies may complement each other in future research on the evolution of routines

Efficient construction of free energy profiles of breathing metal–organic frameworks using advanced molecular dynamics simulations

In order to reliably predict and understand the breathing behavior of highly flexible metal–organic frameworks from thermodynamic considerations, an accurate estimation of the free energy difference between their different metastable states is a prerequisite. Herein, a variety of free energy estimation methods are thoroughly tested for their ability to construct the free energy profile as a function of the unit cell volume of MIL-53(Al). The methods comprise free energy perturbation, thermodynamic integration, umbrella sampling, metadynamics, and variationally enhanced sampling. A series of molecular dynamics simulations have been performed in the frame of each of the five methods to describe structural transformations in flexible materials with the volume as the collective variable, which offers a unique opportunity to assess their computational efficiency. Subsequently, the most efficient method, umbrella sampling, is used to construct an accurate free energy profile at different temperatures for MIL-53(Al) from first principles at the PBE+D3(BJ) level of theory. This study yields insight into the importance of the different aspects such as entropy contributions and anharmonic contributions on the resulting free energy profile. As such, this thorough study provides unparalleled insight in the thermodynamics of the large structural deformations of flexible materials

Planning precision aquaculture activities in a changing and crowded sea

Extreme climate events are increasingly challenging the growth of the marine aquaculture sector, causing local influences on species performance and affecting production and yield - impacting where to locate cage aquaculture facilities. Here we produced scenario-based quantitative maps using modelled species-specific performance combined with predicted high-resolution future IPCC temperature scenarios. We ran a species-specific Dynamic Energy Budget mechanistic model for four model species, up to 2050, and mapped functional trait-based outcomes as: i) time to reach the commercial size, ii) feces produced and iii) uneaten food. A high spatial resolution suitability index allowed the sustainability of farming strategies for single- and multi-species to be identified across a 159.696 km2 surface extension (Italian Exclusive Economic Zone; 6% of the Mediterranean basin surface). Providing a good case study to shed light on difficult questions facing aquaculture planning around the world. Good future performance under both representative concentration pathway (RCP) scenarios were modelled for Sea bream and European seabass in inshore waters. Performance of Mediterranean mussels and Japanese oysters was found to decrease slightly when compared to the 2007–2010 time interval. Scenario-based quantitative maps represent a heterogeneous species-specific knowledge layer that is critical to better inform aquaculture management and development strategies. Yet this knowledge layer is missing from the process to develop climate-resilient risk maps and associated adaptation measures, as well as when informing stakeholders on potential site expansion and/or the establishment of nascent aquaculture industry sites

Multiscale QM/MM modelling of catalytic systems with ChemShell

Hybrid quantum mechanical/molecular mechanical (QM/MM) methods are a powerful computational tool for the investigation of all forms of catalysis, as they allow for an accurate description of reactions occurring at catalytic sites in the context of a complicated electrostatic environment. The scriptable computational chemistry environment ChemShell is a leading software package for QM/MM calculations, providing a flexible, high performance framework for modelling both biomolecular and materials catalysis. We present an overview of recent applications of ChemShell to problems in catalysis and review new functionality introduced into the redeveloped Python-based version of ChemShell to support catalytic modelling. These include a fully guided workflow for biomolecular QM/MM modelling, starting from an experimental structure, a periodic QM/MM embedding scheme to support modelling of metallic materials, and a comprehensive set of tutorials for biomolecular and materials modelling

Characterization of the Ubc13-Mms2 Lysine-63-linked ubiquitin conjugating complex

Ubiquitylation is an indispensable post-translational modification system in eukaryotic cells that leads to the covalent attachment of a small ubiquitin (Ub) protein onto a target. The traditional and best-characterized role for ubiquitylation is a fundamental regulatory mechanism whereby target proteins are tagged with a characteristic Lys48-linked Ub chain that signals for their elimination through proteasomal degradation. Challenging this conventional wisdom is the finding that some ubiquitylated proteins are modified by Ub chains linked through Lys63, providing a molecular signal that is thought to be structurally and functionally distinct from Lys48-linked Ub chains. Of further interest and significance is that the Lys63-linked Ub chains are apparently synthesized through a novel biochemical mechanism employing a unique complex formed between a true Ub conjugating enzyme (E2), Ubc13, and an E2-variant (Uev), Mms2 (or Uev1A). The goal of this thesis was to employ structural and functional approaches in order to better characterize the Ubc13-Mms2 Lys63-linked Ub conjugation complex. Error-free DNA damage tolerance (DDT) in the budding yeast is dependent on Lys63-linked Ub chains synthesized by Ubc13-Mms2 and thus provided the opportunity to experimentally test the function of the human UBC13 and MMS2 genes in a simple model organism. Human UBC13 and MMS2 were each shown to function in place of their yeast counterparts and in accordance, human Ubc13 was shown to physically interact with yeast Mms2, and vice versa. Two human MMS2 homologs were also tested and it was determined that UEV1A but not UEV1B can function in place of mms2 in yeast DDT. Physical interactions were observed between Ubc13 and Uev1A, but not between Ubc13 and Uev1B, suggesting that Ubc13-Uev complex formation is required for function. In collaboration with a research group at the University of Alberta, crystal structure and NMR data were used to develop a mechanistic model for the conjugation of Lys63-linked Ub chains by the Ubc13-Mms2 heterodimer, whereby the special orientation of two Ub molecules facilitates a specific Ub-Ub linkage via Lys63. In order to help support the in vitro model and to determine how the Ubc13-Mms2 structure relates to biological function, I used a structure-based approach to direct the creation of point mutations within four key regions of the Ubc13-Mms2 heterodimer; the Ubc13 active-site, the Ubc13-E3 (Ub ligating enzyme) interface, the Mms2-Ub interface, and the Ubc13-Mms2 interface. Underscoring the importance of the Ub conjugation by Ubc13-Mms2, a Ubc13-C87S active-site mutation was created that could bind to Mms2 but was unable to function in DDT. Regarding the Ubc13-E3 interface, a single Ubc13-M64A point mutation had a potent effect on disrupting Ubc13 function in DDT, as well as its physical interaction with Rad5, TRAF6, and CHFR. The results suggest that different RING finger E3s use the same Ubc13 surface to sequester the Ub conjugation activity of Ubc13-Mms2. Two human Mms2 mutations at Ser32 and Ile62, which are contained within the Mms2-Ub interface, were found to reduce the ability of Mms2 to bind Ub. When the corresponding yeast mutations are combined, a synergistic loss in DDT function is observed. The relative orientation of Ser32 and Ile62 suggests that the Mms2 and Tsg101 Uev families use different Uev surfaces to physically interact with Ub. A 200 ìM dissociation constant for the wild-type Mms2-Ub interaction was also determined. The systematic mutagenesis and testing of 14 Ubc13-Mms2 interface residues led to mutants with partial or complete disruption of binding and function. Using this data, a model involving the insertion of a specific Mms2-Phe residue into a unique Ubc13 hydrophobic pocket was created to explain the specificity of Mms2 for Ubc13, and not other E2s. In addition, the dissociation constant for the wild-type Ubc13-Mms2 heterodimer was determined to be approximately 50 nM. The structural and functional studies strongly support the notion that Ubc13-Mms2 complex has the unique ability to conjugate Lys63-linked Ub chains. However, several reported instances of Lys63-linked Ub chains in vivo have not yet been attributed to Ubc13 or Mms2. To address the disparity I was able to demonstrate and map a physical interaction between Mms2 and Rsp5, an E3 implicated in Lys63-linked Ub conjugation. Surprisingly, it was found that MMS2 is not responsible for the RSP5-dependent Lys63-linked Ub conjugation of a plasma membrane protein. A possible explanation for the apparent paradox is presented

Adaptation from interactions between metabolism and behaviour: self-sensitive behaviour in protocells

This thesis considers the relationship between adaptive behaviour and metabolism, using theoretical arguments supported by computational models to demonstrate mechanisms of adaptation that are uniquely available to systems based upon the metabolic organisation of self-production. It is argued how, by being sensitive to their metabolic viability, an organism can respond to the quality of its environment with respect to its metabolic well-being. This makes possible simple but powerful ‘self-sensitive’ adaptive behaviours such as “If I am healthy now, keep doing the same as I have been doing – otherwise do something else.” This strategy provides several adaptive benefits, including the ability to respond appropriately to phenomena never previously experienced by the organism nor by any of its ancestors; the ability to integrate different environmental influences to produce an appropriate response; and sensitivity to the organism’s present context and history of experience. Computational models are used to demonstrate these capabilities, as well as the possibility that self-sensitive adaptive behaviour can facilitate the adaptive evolution of populations of self-sensitive organisms through (i) processes similar to the Baldwin effect, (ii) increasing the likelihood of speciation events, and (iii) automatic behavioural adaptation to changes in the organism itself (such as genetic changes). In addition to these theoretical contributions, a computational model of self-sensitive behaviour is presented that recreates chemotaxis patterns observed in bacteria such as Azospirillum brasilense and Campylobacter jejuni. The models also suggest new explanations for previously unexplained asymmetric distributions of bacteria performing aerotaxis. More broadly, the work advocates further research into the relationship between behaviour and the metabolic organisation of self-production, an organisational property shared by all life. It also acts as an example of how abstract models that target theoretical concepts rather than natural phenomena can play a valuable role in the scientific endeavour