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Osipovitch D.C.,Program in Experimental and Molecular Medicine | Parker A.S.,Dartmouth | Makokha C.D.,Trinity Partners LLC | Desrosiers J.,University of Rhode Island | And 2 more authors.
Protein Engineering, Design and Selection | Year: 2012

The unparalleled specificity and activity of therapeutic proteins has reshaped many aspects of modern clinical practice, and aggressive development of new protein drugs promises a continued revolution in disease therapy. As a result of their biological origins, however, therapeutic proteins present unique design challenges for the biomolecular engineer. For example, protein drugs are subject to immune surveillance within the patient's body; this anti-drug immune response can compromise therapeutic efficacy and even threaten patient safety. Thus, there is a growing demand for broadly applicable protein deimmunization strategies. We have recently developed optimization algorithms that integrate computational prediction of T-cell epitopes and bioinformatics-based assessment of the structural and functional consequences of epitope-deleting mutations. Here, we describe the first experimental validation of our deimmunization algorithms using Enterobacter cloacae P99 β-lactamase, a component of antibody-directed enzyme prodrug cancer therapies. Compared with wild-type or a previously deimmunized variant, our computationally optimized sequences exhibited significantly less in vitro binding to human type II major histocompatibility complex immune molecules. At the same time, our globally optimal design exhibited wild-type catalytic proficiency. We conclude that our deimmunization algorithms guide the protein engineer towards promising immunoevasive candidates and thereby have the potential to streamline biotherapeutic development. © 2012 The Author.


Prasad A.,Dartmouth | Butkiewicz M.,University of California at Riverside
IEEE Pervasive Computing | Year: 2013

HotMobile 13 highlighted how mobile computing has helped improve lives - for example, by providing better facilities to people in areas with resource constraints and helping traffic-clogged cities with carpooling. Yet mobile computing still has a long way to go in reaching its full potential and improving users' lives. © 2002-2012 IEEE.


Parker A.S.,Dartmouth | Choi Y.,Dartmouth | Bailey-Kellogg C.,Dartmouth
PLoS Computational Biology | Year: 2015

The immunogenicity of biotherapeutics can bottleneck development pipelines and poses a barrier to widespread clinical application. As a result, there is a growing need for improved deimmunization technologies. We have recently described algorithms that simultaneously optimize proteins for both reduced T cell epitope content and high-level function. In silico analysis of this dual objective design space reveals that there is no single global optimum with respect to protein deimmunization. Instead, mutagenic epitope deletion yields a spectrum of designs that exhibit tradeoffs between immunogenic potential and molecular function. The leading edge of this design space is the Pareto frontier, i.e. the undominated variants for which no other single design exhibits better performance in both criteria. Here, the Pareto frontier of a therapeutic enzyme has been designed, constructed, and evaluated experimentally. Various measures of protein performance were found to map a functional sequence space that correlated well with computational predictions. These results represent the first systematic and rigorous assessment of the functional penalty that must be paid for pursuing progressively more deimmunized biotherapeutic candidates. Given this capacity to rapidly assess and design for tradeoffs between protein immunogenicity and functionality, these algorithms may prove useful in augmenting, accelerating, and de-risking experimental deimmunization efforts. © 2015 Salvat et al.


Most organisms on earth sense light through the use of chromophore-bearing photoreceptive proteins with distinct and characteristic photocycle lengths, yet the biological significance of this adduct decay length is neither understood nor has been tested. In the filamentous fungus Neurospora crassa VIVID (VVD) is a critical player in the process of photoadaptation, the attenuation of light-induced responses and the ability to maintain photosensitivity in response to changing light intensities. Detailed in vitro analysis of the photochemistry of the blue light sensing, FAD binding, LOV domain of VVD has revealed residues around the site of photo-adduct formation that influence the stability of the adduct state (light state), that is, altering the photocycle length. We have examined the biological significance of VVD photocycle length to photoadaptation and report that a double substitution mutant (vvdI74VI85V), previously shown to have a very fast light to dark state reversion in vitro, shows significantly reduced interaction with the White Collar Complex (WCC) resulting in a substantial photoadaptation defect. This reduced interaction impacts photoreceptor transcription factor WHITE COLLAR-1 (WC-1) protein stability when N. crassa is exposed to light: The fast-reverting mutant VVD is unable to form a dynamic VVD-WCC pool of the size required for photoadaptation as assayed both by attenuation of gene expression and the ability to respond to increasing light intensity. Additionally, transcription of the clock gene frequency (frq) is sensitive to changing light intensity in a wild-type strain but not in the fast photo-reversion mutant indicating that the establishment of this dynamic VVD-WCC pool is essential in general photobiology and circadian biology. Thus, VVD photocycle length appears sculpted to establish a VVD-WCC reservoir of sufficient size to sustain photoadaptation while maintaining sensitivity to changing light intensity. The great diversity in photocycle kinetics among photoreceptors may be viewed as reflecting adaptive responses to specific and salient tasks required by organisms to respond to different photic environments. © 2015 Dasgupta et al.


Georgakopoulos A.,University of Warwick | Winkler P.,Dartmouth
Combinatorics Probability and Computing | Year: 2014

We show that the expected time for a random walk on a (multi-)graph G to traverse all m edges of G, and return to its starting point, is at most 2m 2; if each edge must be traversed in both directions, the bound is 3m 2. Both bounds are tight and may be applied to graphs with arbitrary edge lengths. This has interesting implications for Brownian motion on certain metric spaces, including some fractals. © Cambridge University Press 2014.


Barghi A.,Bard College | Winkler P.,Dartmouth
Random Structures and Algorithms | Year: 2015

LetGλ be the graph whose vertices are points of a planar Poisson process of density λ, with vertices adjacent if they are within distance 1. A "fire" begins at some vertex and spreads to all neighbors in discrete steps; in the meantime f vertices can be deleted at each time-step. Let fλ be the least f such that, with probability 1, any fire on Gλ can be stopped in finite time. We show that fλ is bounded between two linear functions of λ. The lower bound makes use of a new result concerning oriented percolation in the plane; the constant factor in the upper bound is is tight, provided a certain conjecture, for which we offer supporting evidence, is correct. © 2013 Wiley Periodicals, Inc.


Mokhatab S.,Dartmouth | Corso S.,Comelt S.p.A.
Chemical Engineering (United States) | Year: 2016

Ongoing advances in both adsorbent materials and system engineering allow today's pressure swing adsorption (PSA) systems to produce nitrogen of varying purities and volumes at relatively low cost compared to cryogenic air separation.


Hughes J.,Tenet3 LLC | Cybenko G.,Dartmouth
Proceedings of SPIE - The International Society for Optical Engineering | Year: 2014

This paper presents a threat-driven quantitative mathematical framework for secure cyber-physical system design and assessment. Called The Three Tenets, this originally empirical approach has been used by the US Air Force Research Laboratory (AFRL) for secure system research and development. The Tenets were first documented in 2005 as a teachable methodology. The Tenets are motivated by a system threat model that itself consists of three elements which must exist for successful attacks to occur: - system susceptibility; - threat accessibility and; - threat capability. The Three Tenets arise naturally by countering each threat element individually. Specifically, the tenets are: Tenet 1: Focus on What's Critical - systems should include only essential functions (to reduce susceptibility); Tenet 2: Move Key Assets Out-of-Band - make mission essential elements and security controls difficult for attackers to reach logically and physically (to reduce accessibility); Tenet 3: Detect, React, Adapt - confound the attacker by implementing sensing system elements with dynamic response technologies (to counteract the attackers' capabilities). As a design methodology, the Tenets mitigate reverse engineering and subsequent attacks on complex systems. Quantified by a Bayesian analysis and further justified by analytic properties of attack graph models, the Tenets suggest concrete cyber security metrics for system assessment. © 2014 SPIE.


Thibeault C.A.,Dalhousie University | Trudeau K.,The Nova Scotia Hospital | d'Entremont M.,Dartmouth | Brown T.,Halifax
Archives of Psychiatric Nursing | Year: 2010

The role of inpatient mental health units is changing. Increasingly, people with acute and severe mental illness are admitted for short periods of intense treatment and are discharged quickly to community-based care. Reduction in average lengths of stay for psychiatric inpatients has been accompanied by a marginalization of the concept of therapeutic milieu in the mental health discourse. This phenomenological inquiry focuses on understanding the life-world of six people with acute psychiatric illness who were hospitalized on an acute inpatient psychiatric unit. Working together, a team of four, including mental health clinicians and consumers, developed and implemented this interpretive study using the phenomenology of Heidegger and Taylor. The principle investigator conducted the interviews, and the research team engaged in a complex interpretive process, reviewing narrative accounts, exploring personal meanings and key themes, and reconstructing shared meaning as lived and shared by participants. In this report, the authors describe patient experiences of a rule-bound, controlling, and sometimes oppressive milieu while highlighting patient experiences of healing and health as lived within that same milieu. The authors describe patients' embodied, dialectical, and often paradoxical experiences of fear and affirmation, alienation and connection, and abandonment and healing. The authors share selected narrative accounts to generate new understanding of patient experiences and suggest that the inpatient psychiatric milieu remains an important but often neglected component of psychiatric treatment. © 2010 Elsevier Inc.


Svitkina Z.,Google | Fleischer L.,Dartmouth
SIAM Journal on Computing | Year: 2011

We introduce several generalizations of classical computer science problems obtained by replacing simpler objective functions with general submodular functions. The new problems include submodular load balancing, which generalizes load balancing or minimum-makespan scheduling, submodular sparsest cut and submodular balanced cut, which generalize their respective graph cut problems, as well as submodular function minimization with a cardinality lower bound. We establish upper and lower bounds for the approximability of these problems with a polynomial number of queries to a function-value oracle. The approximation guarantees that most of our algorithms achieve are of the order of √n/ln n. We show that this is the inherent difficulty of the problems by proving matching lower bounds. We also give an improved lower bound for the problem of approximating a monotone submodular function everywhere. In addition, we present an algorithm for approximating submodular functions with a special structure, whose guarantee is close to the lower bound. Although quite restrictive, the class of functions with this structure includes the ones that are used for lower bounds both by us and in previous work. © 2011 Society for Industrial and Applied Mathematics.

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