Non Linear Programming (NLP) Formulation for Quantitative Modeling of Protein Signal Transduction Pathways

Modeling of signal transduction pathways plays a major role in understanding cells' function and predicting cellular response. Mathematical formalisms based on a logic formalism are relatively simple but can describe how signals propagate from one protein to the next and have led to the construction of models that simulate the cells response to environmental or other perturbations. Constrained fuzzy logic was recently introduced to train models to cell specific data to result in quantitative pathway models of the specific cellular behavior. There are two major issues in this pathway optimization: i) excessive CPU time requirements and ii) loosely constrained optimization problem due to lack of data with respect to large signaling pathways. Herein, we address both issues: the former by reformulating the pathway optimization as a regular nonlinear optimization problem; and the latter by enhanced algorithms to pre/post-process the signaling network to remove parts that cannot be identified given the experimental conditions. As a case study, we tackle the construction of cell type specific pathways in normal and transformed hepatocytes using medium and large-scale functional phosphoproteomic datasets. The proposed Non Linear Programming (NLP) formulation allows for fast optimization of signaling topologies by combining the versatile nature of logic modeling with state of the art optimization algorithms.National Institutes of Health (U.S.) (Grant P50-GM068762)National Institutes of Health (U.S.) (Grant R24-DK090963)United States. Army Research Office (Grant W911NF-09-0001)German Research Foundation (Grant GSC 111

A plasmid DNA-launched SARS-CoV-2 reverse genetics system and coronavirus toolkit for COVID-19 research

The recent emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the underlying cause of Coronavirus Disease 2019 (COVID-19), has led to a worldwide pandemic causing substantial morbidity, mortality, and economic devastation. In response, many laboratories have redirected attention to SARS-CoV-2, meaning there is an urgent need for tools that can be used in laboratories unaccustomed to working with coronaviruses. Here we report a range of tools for SARS-CoV-2 research. First, we describe a facile single plasmid SARS-CoV-2 reverse genetics system that is simple to genetically manipulate and can be used to rescue infectious virus through transient transfection (without in vitro transcription or additional expression plasmids). The rescue system is accompanied by our panel of SARS-CoV-2 antibodies (against nearly every viral protein), SARS-CoV-2 clinical isolates, and SARS-CoV-2 permissive cell lines, which are all openly available to the scientific community. Using these tools, we demonstrate here that the controversial ORF10 protein is expressed in infected cells. Furthermore, we show that the promising repurposed antiviral activity of apilimod is dependent on TMPRSS2 expression. Altogether, our SARS-CoV-2 toolkit, which can be directly accessed via our website at https://mrcppu-covid.bio/, constitutes a resource with considerable potential to advance COVID-19 vaccine design, drug testing, and discovery science

Progressive Focusing and Trustworthiness in Qualitative Research: The Enabling Role of Computer-Assisted Qualitative Data Analysis Software (CAQDAS)

* The business and management community increasingly recognises that qualitative research is a ‘messy’, non-linear and often unpredictable undertaking. Yet, a considerable proportion of the qualitative research published in top journals is still presented as the result of a linear, predictable research process, thus wrongly suggesting deductive reasoning. * In this paper, we focus on a particular type of ‘messiness’ where during fieldwork, the research context is revealed to be more complex than anticipated, forcing the researcher to gradually refine/shift their focus to reflect ‘what really matters’. We adopt Stake’s notion of progressive focusing for this gradual approach. * Progressive focusing is well-suited to qualitative research in international business requiring complex iteration between theory and data, and the truthful yet coherent presentation of the research process. We propose that this dual challenge of complexity and trustworthiness may be addressed by using computer-assisted qualitative data analysis software (CAQDAS). * We present conceptual considerations and guidelines and offer a view on a ‘messy’, non-linear doctoral research project conducted using a progressive focusing approach, to demonstrate how CAQDAS can help to develop and re-negotiate insights from theory and interview data, as well as enhance trustworthiness, transparency and publication potential

Improving the efficiency and effectiveness of an industrial SARS-CoV-2 diagnostic facility.

On 11th March 2020, the UK government announced plans for the scaling of COVID-19 testing, and on 27th March 2020 it was announced that a new alliance of private sector and academic collaborative laboratories were being created to generate the testing capacity required. The Cambridge COVID-19 Testing Centre (CCTC) was established during April 2020 through collaboration between AstraZeneca, GlaxoSmithKline, and the University of Cambridge, with Charles River Laboratories joining the collaboration at the end of July 2020. The CCTC lab operation focussed on the optimised use of automation, introduction of novel technologies and process modelling to enable a testing capacity of 22,000 tests per day. Here we describe the optimisation of the laboratory process through the continued exploitation of internal performance metrics, while introducing new technologies including the Heat Inactivation of clinical samples upon receipt into the laboratory and a Direct to PCR protocol that removed the requirement for the RNA extraction step. We anticipate that these methods will have value in driving continued efficiency and effectiveness within all large scale viral diagnostic testing laboratories

Loosely coupled system.

http://deepblue.lib.umich.edu/bitstream/2027.42/35964/2/b1411810.0001.001.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/35964/1/b1411810.0001.001.tx

Reorganizing: An analysis of the 1976 reorganization of the U.S. intelligence community.

The explanation of reorganizing processes is a central problem in organization theory. Each of the diverse theories which fall within the realm of organization theory contains its own set of assumptions about how organizations reorganize. This study used one of these theories, Weick's theory of organizing, to analyze a single reorganization--the 1976 reorganization of the U.S. intelligence community. The research methodology was neither an inductive, theory-generating methodology, nor a deductive, theory-testing methodology. Instead, this study was an iterative, theory-elaborating study. A variety of analyses were used to match 72 historical tales with 72 theoretical claims. The historical tales are anchored in original documents from the reorganization, which were studied during fifteen months of library research in the Gerald R. Ford Library. The theoretical claims are anchored in Weick's and others' writings on diverse components of the theory of organizing: e.g. enacted environments, enactment, bracketing, small wins, deviation-amplifying loops, loosely coupled systems, retrospective rationality, complication, sensemaking, requisite variety, and retention. The iterations between the documents and the theory made it possible to create a theory-based history of the 1976 reorganization, and a history-based elaboration of the theory of organizing. The historical tales and theoretical claims were then used to create a six-stage model of reorganizing processes: enacted environments, bracketed enactments, cause maps, workable realities, reorganizing packages, and residual structures. The model makes several contributions to organization theory. First, the model provides a detailed explanation of why environments are loosely coupled to structures. Second, the model integrates systemic, emergent models of reorganizing, with calculated, deliberate models of reorganizing. Third, the model proposes a meta-level, natural-language approach to organization theory. The study coincides with the emergence of a popular management literature on redesigning, reengineering, reinventing, reshuffling, restructuring, and rethinking. Reorganizing is on the organizational agenda. This dissertation identifies the topic of reorganizing, presents an empirical and theoretical analysis of reorganizing, and proposes a six-stage model of reorganizing processes. This dissertation can help organization theorists improve organizational practice.Ph.D.ManagementPublic administrationSocial SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/129297/2/9423282.pd

Particle Trapping in Stratified Estuaries - Definition of a Parameter Space

Estuarine turbidity maxima (ETM) retain suspended particulate matter (SPM) through advection, settling, aggregation and non-linearities in bed processes. This contribution defines for the first time a parameter space descriptive of ETM water-column particle trapping processes through a scaling analysis of the local and integral SPM balances. In the absence of long-term deposition, there are five primary parameters for the large particles or aggregates that are typically trapped. Rouse number P, the ratio of settling velocity WS of the SPM relative to the shear velocity U*, describes the material trapped in the ETM in terms of the local vertical balance between vertical mixing and aggregate settling. Advection number A= P ΔU/UT scales the landward transport of SPM by tidal and mean flow processes in terms of flood-ebb velocity difference (ΔU) and maximum tidal current (UT). Supply number SR = P UR/UT defines SPM supply and removal (UR is river flow). Changes in the estuarine inventory of SPM are described in terms of a Trapping Efficiency E, a ratio of peak ETM concentration to fluvial or marine supply concentration. The effects of aggregation in the integral dynamic balance are quantified by a Floc number F that describes the tendency of aggregates to form through shear-driven collisions. This study uses observations from two strongly advective systems (the Columbia and Fraser Rivers) plus literature values from 13 other estuaries to illustrate the applicability of the above scaling. The primary question investigated is the relationship of trapping efficiency E and Floc number F to other parameters, especially river flow (expressed in terms of supply number SR). The strongest SPM trapping (high E) occurs in mid-ETM, where A ~0. The extreme high flows observed in the Fraser River estuary show how ETM trapping becomes ineffective as the estuary length contracts to one tidal excursion or less (limit of high SR). Use of data from all 15 estuaries shows that there is a strong trend toward more efficient trapping for low SR. E and F are positively correlated, so that aggregation becomes more prominent in systems with weak to moderate river flow. Examination of tidal monthly and seasonal particle properties at four closely-spaced moorings in the Columbia emphasize the importance of strong ETM gradients – particle properties are diverse even when the hydrodynamic regime is apparently similar. Finally, scaling variables and data are combined to express ETM properties in terms of U*, UR and UT.

Resilience leadership judgment:Findings from a cosmology episode study of the shootdown of Flight MH17

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Another look at strategy-Structure relationships:: The resource-Based view

The authors argue that the creation and sustaining of a firm's competitive advantage must be heavily based on the dynamics of how the firm's resources are acquired and managed. Such a resource-based view leads into a study of the relationships between organizational learning and competitive advantage. Similarly, it requires greater integration of strategies and organizational structure. A case study of Salomon, a French manufacturer of outdoor sports equipment, is presented which illustrates very well how an analytical framework which integrates the concepts of competencies, organizational capabilities, organizational structure, and organizational learning, can explain this and similar firms' success.